GleghornLab/Signor_2class · Datasets at Hugging Face

IdA string	IdB string	labels int64	mechanism string	effect string	score float64	sentence string	signor_id string
Q8TB45	Q93009	0	deubiquitination	up-regulates quantity by stabilization	0.2	Screening the DEPTOR interactome identified that the association of USP-7 deubiquitinase with DEPTOR was dependent upon S235 phosphorylation. Inhibition of USP-7 activity resulted in DEPTOR polyubiquitination and degradation. A scansite search suggested that ERK1 may be responsible for S235 phosphorylation, which was confirmed through the use of inhibitors, ERK1 knockdown, and an in vitro kinase assay.	SIGNOR-277588
P06493	P04183	1	phosphorylation	down-regulates	0.507	Given that the dimeric form of tk1 is less active than the tetrameric, we propose that mitotic phosphorylation of serine-13 is of physiological importance, in that it may counteract atp-dependent activation of tk1 by affecting its quaternary structure, thus attenuating its enzymatic function at the g2/m phase.	SIGNOR-95574
Q8NHV4	O14965	0	phosphorylation	up-regulates activity	0.557	Microtubule nucleation during central spindle assembly requires NEDD1 phosphorylation on serine 405 by Aurora A\| In the absence of Aurora A, the HURP (also known as DLGAP5) and NEDD1 proteins that are involved in nucleation of microtubules fail to concentrate in the midzone.	SIGNOR-272965
Q13188	P51955	1	phosphorylation	up-regulates	0.244	Our data suggest that mst2 phosphorylates nek2a thereby recruiting nek2a to centrosomes and promoting phosphorylation and displacement of centrosomal linker proteins	SIGNOR-169539
P60953	O14827	0	guanine nucleotide exchange factor	up-regulates activity	0.554	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-260575
Q00535	Q16643	1	phosphorylation	up-regulates activity	0.539	Phosphorylation of drebrin at S142 by Cdk5 relieves the intramolecular inhibition of F-actin bundling.	SIGNOR-279452
Q9H2X6	Q13131	0	phosphorylation	up-regulates activity	0.2	These results indicate that HIPK2 is a substrate of AMPKα2 in vitro and in vivo. Site-directed mutagenesis of Thr112 and Ser114 in the N terminus, and Thr1107 in the C terminus markedly reduced HIPK2 phosphorylation by AMPKα2 in vitro (Figure S5J).	SIGNOR-276469
Q99683	Q13627	0	phosphorylation	up-regulates activity	0.395	Moreover, Dyrk1A appears to directly phosphorylate the C-terminal domain of ASK1.\|The current finding that Dyrk1A enhances the activities of ASK1 and JNK1, it could act as a pro-apoptotic player.	SIGNOR-279366
Q969Q1	P55036	1	polyubiquitination	down-regulates quantity by destabilization	0.403	S5a/Rpn10 is a ubiquitin (Ub)-binding protein that is a subunit of the 26S proteasome but also exists free in the cytosol. It binds poly-Ub chains through its two Ub-interacting motifs (UIMs). We discovered that, unlike typical substrates of Ub ligases (E3s), S5a can be ubiquitinated by all E3s tested including multimeric and monomeric Ring finger E3s (MuRF1, Siah2, Parkin, APC, and SCF(betaTRCP1)), the U-box E3, CHIP, and HECT domain E3s (E6AP and Nedd4) when assayed with UbcH5 or related Ub-conjugating enzymes.The short half-life of S5a presumably is because of the presence of the UIM domain and reflects the ubiquitination of free S5a by many E3s. Surprisingly, the same four Lys residues on S5a, Lys-74, Lys-122, Lys-262, and Lys-365 were ubiquitinated by MuRF1 and E6AP (Fig. 10).	SIGNOR-272741
P36888	P35222	1	phosphorylation	up-regulates activity	0.409	Endogenous beta-catenin co-immunoprecipitated with endogenous activated FLT3, and recombinant activated FLT3 directly phosphorylated recombinant beta-catenin. Finally, FLT3 inhibitor decreased tyrosine phosphorylation of beta-catenin in leukemia cells obtained from FLT3-ITD-positive AML patients. These data demonstrate that FLT3 activation induces beta-catenin tyrosine phosphorylation and nuclear localization, and thus suggest a mechanism for the association of FLT3 activation and beta-catenin oncogeneic signaling in AML.	SIGNOR-260124
Q99835	Q2M1P5	1	relocalization	up-regulates activity	0.632	Here, we demonstrate that Kif7, a mammalian homologue of Drosophila Costal2 (Cos2), is a cilia-associated protein that regulates signaling from the membrane protein Smoothened (Smo) to Gli transcription factorsIn response to activation of Smo Kif7 at the cilia tip may antagonize Sufu to promote activation of Gli proteins.	SIGNOR-209605
Q01105	P48736	0	phosphorylation	up-regulates activity	0.336	We show that PI3Kgamma phosphorylates I2PP2A on serine 9 and 93 residues resulting in enhanced interaction of I2PP2A with PP2A.	SIGNOR-278320
P61586	Q3KRB8	0	gtpase-activating protein	down-regulates activity	0.502	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-260467
Q15139	P48426	1	phosphorylation	down-regulates	0.2	We conclude that the type ii pip kinases are physiological targets for pkd phosphorylation, and that this modification is likely to regulate inositol lipid turnover by inhibition of these lipid kinases.	SIGNOR-145370
P38936	Q15208	0	phosphorylation	down-regulates quantity by destabilization	0.2	More importantly, with the direct regulation of p21 stability by phosphorylation on Ser 146, we define here the first downstream signaling mechanisms by which NDR kinases can control G1/S progression.\|NDR kinases regulate p21 stability by phosphorylation of S146 on p21. \|	SIGNOR-272961
O75592	Q8TEK3	0	transcriptional regulation	down-regulates quantity by repression	0.2	Overexpression of DOT1L decreased the expression of HECTD4 and MYCBP2 in LNCaP, C42B, and 22rv1 cells (Supplementary Fig. 5c), suggesting that DOT1L plays a role in repressing these targets either directly or indirectly.	SIGNOR-267151
P17252	P11387	1	phosphorylation	up-regulates activity	0.2	In vitro kinase assays demonstrated that Ser(10) can be phosphorylated by casein kinase II, Ser(21) can be phosphorylated by protein kinase Calpha, and Ser(112) and Ser(394) can be phosphorylated by Cdk1.Collectively these results indicate that topo I is phosphorylated during mitosis at multiple sites, one of which enhances DNA relaxation activity in vitro and interaction with DNA in cells.	SIGNOR-276154
Q9UPW6	Q15797	0	transcriptional regulation	up-regulates quantity	0.2	Chromatin immunoprecipitation (ChIP) revealed a subset of the BIG (BMP4 induced genes) signature, including Satb2, Smad6, Hand1, Gadd45γ and Gata3, that was bound by Smad1/5 in the developing mandible, revealing direct Smad-mediated regulation	SIGNOR-268934
Q13535	O75717	1	phosphorylation	up-regulates activity	0.539	And-1 is phosphorylated at T826 by ATR following replication stress, and this phosphorylation is required for And-1 to accumulate at the damage sites, where And-1 promotes the interaction between Claspin and Chk1, thereby stimulating efficient Chk1 activation by ATR.	SIGNOR-262664
P05771	P49840	1	phosphorylation	down-regulates	0.327	Convergence of multiple signaling cascades at glycogen synthase kinase 3: edg receptor-mediated phosphorylation and inactivation by lysophosphatidic acid through a protein kinase c-dependent intracellular pathway.	SIGNOR-115718
P53779	Q00535	0	phosphorylation	down-regulates activity	0.345	Here, we show that cdk5 directly phosphorylates c-Jun N-terminal kinase 3 (JNK3) on Thr131 and inhibits its kinase activity, leading to reduced c-Jun phosphorylation.	SIGNOR-250668
P30279	P49841	0	phosphorylation	down-regulates	0.454	Glycogen synthase kinase-3beta and p38 phosphorylate cyclin d2 on thr280 to trigger its ubiquitin/proteasome-dependent degradation in hematopoietic cells	SIGNOR-154668
P29474	P36873	0	dephosphorylation	up-regulates activity	0.2	The increase in eNOS activity coincided with specific dephosphorylation of eNOS-Thr495, known to enhance eNOS activity. Inhibition of protein phosphatase 1 (PP1) by calyculin A, tautomycetin, or siRNA against PP1 reversed NF-induced eNOS-Thr495 dephosphorylation	SIGNOR-248501
P49841	Q16665	1	phosphorylation	down-regulates activity	0.332	Glycogen synthase kinase 3 \u03b2 (GSK3\u03b2) phosphorylates HIF-1\u03b1 at three serine residues (Ser-551, Ser-555, and Ser-589) located within its oxygen-dependent degradation domain (ODDD) [12] (Figure 5). Phosphorylation at these residues by GSK3\u03b2 enhances HIF-1\u03b1 degradation in a pVHL-independent manner, resulting in suppression of the HIF-1 activity [12,13].\|Phosphorylation at these residues by GSK3beta enhances HIF-1alpha degradation in a pVHL independent manner, resulting in suppression of the HIF-1 activity , ].	SIGNOR-278294
P78536	Q99075	1	cleavage	up-regulates activity	0.591	ADAM17 is involved in the release and activation of several growth factors and cytokine receptor ligands. Among the growth factors activated by ADAM17 are TGF-alpha, amphiregulin, epiregulin and HB-EGF	SIGNOR-259844
P16220	P51608	0	post transcriptional regulation	up-regulates quantity by expression	0.531	Interestingly, Creb1 was one of the activated MeCP2 targets that we validated by quantitative real-time RT-PCR (Fig. 1C), and using ChIP analysis we found that in vivo MeCP2 binds to the promoter region of Creb1, with significantly enhanced binding in MECP2-Tg samples compared to WT (p < 0.05) \| In addition, Sst and CREB1 protein levels were increased in MECP2-Tg hypothalami compared to WT, indicating that MeCP2 indeed enhances expression of Sst and Creb1	SIGNOR-264682
Q13131	Q16526	1	phosphorylation	down-regulates	0.384	Ampk was shown to regulate the stability of the core clock component cry1 though phosphorylation of cry1 ser71, which stimulates the direct binding of the fbox protein fbxl3 to cry1, targeting it for ubiquitin-mediated degradation	SIGNOR-176472
P62837	P50542	1	ubiquitination	down-regulates quantity by destabilization	0.416	Here we report on the identification of the protein-ubiquitin ligases that are responsible for the ubiquitination of the peroxisomal protein import receptor Pex5. It is demonstrated that each of the three RING peroxins Pex2, Pex10, and Pex12 exhibits ubiquitin-protein isopeptide ligase activity. Our results show that Pex2 mediates the Ubc4-dependent polyubiquitination whereas Pex12 facilitates the Pex4-dependent monoubiquitination of Pex5.While polyubiquitinated Pex5 is degraded by the proteasome, monoubiquitinated Pex5 is destined for a new round of the receptor cycle.	SIGNOR-253023
O43318	P53805	1	phosphorylation	up-regulates activity	0.2	Here we showed that TAK1 directly phosphorylated RCAN1 at two novel sites (serine 94 and -136), resulting in activation of calcineurin-NFAT signaling.\|Indeed, low doses of RCAN1 facilitated calcineurin-nuclear factor of activated T cells signaling in the presence of TGF-\u03b2-activated kinase 1+TAB1 ( ), suggesting that TGF-\u03b2-activated kinase 1 augments calcineurin-nuclear factor of activated T cells signaling through RCAN1.	SIGNOR-279535
P07101	P27361	0	phosphorylation	up-regulates	0.482	In this paper we have studied the phosphorylation and activation of alternatively spliced forms of human th by mapkap kinase-1 , mapkap kinase-2, map kinase, and cam kinase-11	SIGNOR-34678
P99999	Q9BXM7	0	null	down-regulates quantity	0.382	There is a strong cyto-protective role of PINK1 in maintaining mitochondrial homeostasis via different mechanisms. Overexpression of wild-type PINK1 in SH-SY5Y neuroblastoma cells stabilizes respiring mitochondrial networks through various mechanisms that include maintaining mitochondrial membrane potential, reducing basal and neurotoxin-induced ROS, suppression of cytochrome c release, reversal of toxin-induced fission, and suppression of autophagy	SIGNOR-249704
Q9UNE7	Q7Z2Y5	1	polyubiquitination	down-regulates quantity by destabilization	0.2	Our results indicate that Nrk is ubiquitinated by CHIP in a chaperone-dependent manner, resulting in its proteasomal degradation.	SIGNOR-274110
Q14686	P28482	0	phosphorylation	up-regulates activity	0.2	In vitro phosphorylation studies with His-tagged TRBP (795–931) suggested that S884 can be phosphorylated by MAPK (ERK2) in vitro (Fig. 10A).Analysis of in vitro and in vivo receptor interactions with TRBP suggested that S884 allowed selective interactions for ERβ, TR, and RXR vs. ERα.	SIGNOR-265882
Q9UPS8	Q01196	0	transcriptional regulation	down-regulates quantity by repression	0.2	In healthy individual, RUNX1/FLI1 complex negatively regulates ANKRD26 gene expression in MKs.	SIGNOR-266069
P23528	Q96GD0	0	dephosphorylation	down-regulates activity	0.447	Chronophin, a novel HAD-type serine protein phosphatase, regulates cofilin-dependent actin dynamics\|Cofilin is a key regulator of actin cytoskeletal dynamics whose activity is controlled by phosphorylation of a single serine residue. We report the biochemical isolation of chronophin (CIN), a unique cofilin-activating phosphatase of the haloacid dehalogenase (HAD) superfamily.	SIGNOR-248764
P49841	O15516	1	phosphorylation	down-regulates quantity by destabilization	0.341	We have identified a conserved cluster of serines that include, Ser431, which is a prerequisite phosphorylation site for the generation of BMAL dependent phospho-primed CLOCK and for the potential GSK-3 phosphorylation at Ser427.	SIGNOR-276270
O96013	Q15139	0	phosphorylation	up-regulates activity	0.252	When PKD3 was knocked-down using isoform-specific shRNA (PKD3-shRNA), PAK4 activity (judged by its phosphorylation status at the activation loop using the pS474-PAK4 antibody) was decreased	SIGNOR-275930
Q6ZVD7	Q9UHC6	1	transcriptional regulation	down-regulates quantity by repression	0.2	In this study we performed chromatin immunoprecipitation coupled to shotgun cloning to discover novel STOX1A target genes. Our results show that CNTNAP2, a member of the neurexin family, is directly downregulated by STOX1A.	SIGNOR-269065
P00519	P05412	1	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
O15530	Q04759	1	phosphorylation	up-regulates	0.572	We demonstrate that 3-phosphoinositide-dependent kinase 1 (pdk1) has an essential role in this pathway by regulating the activation of pkc and through signal-dependent recruiting of both pkc and card11 to lipid rafts.	SIGNOR-134869
Q13546	Q12933	0	ubiquitination	up-regulates activity	0.895	Following binding to tradd, traf2 was thought to mediate non-degradative lys-63-linked polyubiquitination of rip1 via its ring e3 ligase domain. Rip1 is known to directly interact with traf2.	SIGNOR-59689
P00519	P42345	1	phosphorylation	down-regulates	0.453	Abl binds directly to raft1 and phosphorylates raft1 in vitro and in vivo. c-abl inhibits autophosphorylation of raft1 and raft1-mediated phosphorylation p70(s6k).	SIGNOR-76562
Q13950	P10451	1	transcriptional regulation	up-regulates quantity	0.488	Ets-1 and Runx2 are critical transcriptional regulators of OPN expression in CT26 colorectal cancer cells. Suppression of these transcription factors results in significant down-regulation of the OPN metastasis protein.	SIGNOR-245336
P68400	P30622	1	phosphorylation	up-regulates	0.293	Herein, we have identified polo-like kinase 1 (plk1) and casein kinase 2 (ck2) as two kinases of clip-170 and mapped s195 and s1318 as their respective phosphorylation sites.Plk1- and ck2-associated phosphorylations of clip-170 are involved in the timely formation of kinetochore-microtubule attachments in mitosis	SIGNOR-167168
P17612	Q9Y259	1	phosphorylation	up-regulates activity	0.253	Choline kinase beta (CKbeta) is one of the CK isozymes involved in the biosynthesis of phosphatidylcholine. \| This study provides evidence for CKβ phosphorylation by protein kinase A (PKA).\|Phosphorylation sites were located on CKβ residues serine-39 and serine-40 as determined by mass spectrometry and site-directed mutagenesis. Phosphorylation increased the catalytic efficiencies for the substrates choline and ATP about 2-fold, without affecting ethanolamine phosphorylation, and the S39D/S40D CKβ phosphorylation mimic behaved kinetically very similar.	SIGNOR-275629
Q6JBY9	P45983	0	phosphorylation	down-regulates activity	0.286	CapZIP was also phosphorylated rapidly by SAPK3/p38γ and SAPK4/p38δ, and even faster and more extensively by JNK1α1, these protein kinases phosphorylating CapZIP in vitro to >3, approx. 2 and >5 mol of phosphate/mol of protein respectively within a few minutes. Following tryptic digestion and C18 chromatography, further sites phosphorylated by JNK1α1 were identified as Ser-68, Ser-83 and Ser-216 (results not shown), and are highlighted in Figure 3.Using this antibody, we showed by immunoblotting that bacterially expressed CapZIP was phosphorylated at Ser-108 by SAPK4/p38δ, JNK1α1 and ERK2 in vitro, as well as by SAPK3/p38γ (results not shown).An important clue to the function of CapZIP and its phosphorylation came from the finding that it binds to the actin-capping protein CapZ (Figure 7A), and that cellular stresses trigger the dissociation of these two proteins (Figure 7B).Such an effect is presumably lost when CapZIP is phosphorylated and dissociates from CapZ.	SIGNOR-263085
Q5S007	P30048	1	phosphorylation	down-regulates activity	0.413	Here, we show that LRRK2 interacts with human peroxiredoxin 3 (PRDX3), a mitochondrial member of the antioxidant family of thioredoxin (Trx) peroxidases. Importantly, mutations in the LRRK2 kinase domain significantly increased phosphorylation of PRDX3 compared to wild-type. The increase in PRDX3 phosphorylation was associated with decreased peroxidase activity and increased death in LRRK2-expressing but not in LRRK2-depleted or vector-transfected neuronal cells.	SIGNOR-262891
P49841	Q14449	1	phosphorylation	down-regulates activity	0.323	Phosphorylation of clustered serine residues in the N-terminus of BPS domain negatively regulates formation of the complex between human Grb14 and insulin receptor\| In vitro kinase assay using the motif-derived peptides showed that the serine residues located in N-terminal (Ser358, Ser362 and Ser366) and C-terminal (Ser419 and Ser423) regions of the BPS domain were phosphorylated by GSK-3.	SIGNOR-264867
Q16543	O75385	0	phosphorylation	down-regulates activity	0.2	Serine/Threonine Kinase Unc-51-like Kinase-1 (Ulk1) Phosphorylates the Co-chaperone Cell Division Cycle Protein 37 (Cdc37) and Thereby Disrupts the Stability of Cdc37 Client Proteins.\|Ulk1-mediated phosphorylation of Ser-339 in Cdc37 compromised the recruitment of client kinases to a complex comprising Cdc37 and heat shock protein 90 (Hsp90) but only modestly affected Cdc37 binding to Hsp90.	SIGNOR-280158
Q9GZV1	P31751	0	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
Q13936	P43146	0	null	up-regulates activity	0.2	DCC activation by a netrin-1 gradient creates a high-level [Ca2+]i gradient by triggering LCC activity and by stimulating the cAMP–PKA pathway, which further activates LCC in the plasma membrane (PM) and Ca2+ channels in the ER.	SIGNOR-268291
P07101	Q13555	0	phosphorylation	up-regulates activity	0.332	In both isoforms, Ser-40 was found to be phosphorylated by PKA, and Ser-19 and Ser-40 were found to be phosphorylated by CaM-PK II. The putative phosphorylation site generated by alternative splicing (Ser-31) was phosphorylated specifically by CaM-PK II in TH-2 only. \| Unlike TH-1, phosphorylation of TH-2 by CaM-PK II resulted in an increase of the Ki value for dopamine.	SIGNOR-250709
Q9ULV1	Q9ULT6	0	ubiquitination	down-regulates quantity	0.565	Here we show that the cell-surface transmembrane E3 ubiquitin ligase zinc and ring finger 3 (ZNRF3) and its homologue ring finger 43 (RNF43) are negative feedback regulators of Wnt signalling. ZNRF3 is associated with the Wnt receptor complex, and inhibits Wnt signalling by promoting the turnover of frizzled and LRP6.	SIGNOR-260115
P16284	P16591	0	phosphorylation	up-regulates activity	0.322	PECAM-1 Is Phosphorylated by Fer and, To a Lesser Extent, by Fes. These results suggest that Fer not only functions as a tyrosine kinase for PECAM-1 but also that Fer modulates the downstream signaling of PECAM-1 by inducing phosphorylation of SHP-2 and Gab1.	SIGNOR-262866
P38646	P33981	0	phosphorylation	up-regulates	0.2	Mortalin binds to mps1, and is phosphorylated by mps1 on thr62 and ser65. The phosphorylated mortalin then super-activates mps1 in a feedback manner. Mps1-associated acceleration of centrosome duplication depends on the presence of mortalin and super-activation by the thr62/ser65 phosphorylated mortalin	SIGNOR-156185
P06493	Q9Y6Q9	1	phosphorylation	down-regulates	0.368	We demonstrate that aib1 is phosphorylated on ser728 and ser867 by cdk1/cyclin b at the onset of mitosis and remains phosphorylated until exit from m phase.	SIGNOR-195233
O60825	P51812	0	phosphorylation	up-regulates activity	0.2	Heart 6-phosphofructo-2-kinase activation by insulin results from ser-466 and ser-483 phosphorylation and requires 3-phosphoinositide-dependent kinase-1, but not protein kinase b.	SIGNOR-23753
O14757	P62714	0	dephosphorylation	down-regulates activity	0.266	Phosphorylation of Chk1 by ATR is antagonized by a Chk1-regulated protein phosphatase 2A circuit\|In response to genotoxic stress, Chk1 is phosphorylated on serines 317 (S317) and 345 (S345) by the ataxia-telangiectasia-related (ATR) protein kinase. Phosphorylation of Chk1 on these C-terminal serine residues is used as an indicator of Chk1 activation in vivo.	SIGNOR-248578
Q12860	P78357	0	relocalization	up-regulates activity	0.625	These results suggest that the targeting of contactin to different axonal domains may be determined, in part, via its association with Caspr.	SIGNOR-269073
Q7Z6Z7	P20226	1	ubiquitination	down-regulates quantity	0.337	Having established that Huwe1 mediates TBP ubiquitination in vitro, we then asked which E2 conjugating enzymes work best with Huwe1 in this reaction.\|Upregulation of Huwe1 expression during myogenesis induces TBP degradation and myotube differentiation.	SIGNOR-278696
P01112	Q8TEU7	0	guanine nucleotide exchange factor	up-regulates	0.336	Gefs catalyse the transition from gdp-bound, inactive ras to gtp-bound, active ras.	SIGNOR-183796
Q8N122	Q15418	0	phosphorylation	up-regulates	0.546	Ser719, ser721, and ser722 are the predominant rsk-dependent phosphorylation sites in raptor raptor phosphorylation regulates mtorc1 activity	SIGNOR-180466
O15534	P78368	0	phosphorylation	down-regulates	0.394	Ck1_ and ck1_2 can promote proteasome-dependent per1 degradation in mammalian tissue culture cells, and their removal by rnai leads to an increased abundance of per1.	SIGNOR-137751
Q15382	P49815	0	gtpase-activating protein	down-regulates activity	0.922	Tsc2 functions as a gap to inhibit rheb activity. Tsc2 displays gap (gtpase-activating protein) activity specifically towards the small g protein rheb and inhibits its ability to stimulate the mtor signaling pathway. It has recently been shown that tsc2 has gtpase-activating protein (gap) activity towards the ras family small gtpase rheb (ras homolog enriched in brain), and tsc1/2 antagonizes the mtor signaling pathway via stimulation of gtp hydrolysis of rheb.	SIGNOR-128432
Q07666	Q13882	0	phosphorylation	up-regulates	0.748	Sik/brk is the first identified tyrosine kinase that can phosphorylate sam68 and regulate its activity within the nucleus, where it resides during most of the cell cycle	SIGNOR-80020
Q13422	P68400	0	phosphorylation	down-regulates	0.29	We identified four novelikarosphosphorylation sites that are phosphorylated by ck2 kinase. / ck2-mediated phosphorylation inhibits ikaros' localization to pc-hc / hyperphosphorylation of ikaros promotes its degradation by the ubiquitin/proteasome pathway / these results suggest that ck2 kinase directly phosphorylates amino acids 13, 23, 63, 101 and 294 in vivo	SIGNOR-174832
P40763	Q00535	0	phosphorylation	up-regulates	0.402	We report here that the cdk5/p35 complex associates with stat3 and phosphorylates stat3 on the ser-727 residue in vitro and in vivo. Ser phosphorylation of stat3 and transcription of stat3 target genes, such as c-fos and junb, in a cdk5-dependent manner.	SIGNOR-124325
P27361	P49137	1	phosphorylation	up-regulates	0.475	Erk phosphorylates multiple cytoplasmatic and cytoskeletal proteins, including mapk-activated protein kinases and the ribosomal p70-s6 kinase	SIGNOR-201687
O15534	P48729	0	phosphorylation	down-regulates quantity by destabilization	0.318	CKI\u03b1-Dependent Phosphorylation and Degradation of PER1.	SIGNOR-279700
P53350	P11388	1	phosphorylation	up-regulates	0.481	Here we report that when phosphorylated, ser 1524 of topo iialpha acts as a binding site for the brct domain of mdc1 (mediator of dna damage checkpoint protein-1), thereby recruiting mdc1 to chromatin	SIGNOR-182844
P46934	Q14457	1	ubiquitination	up-regulates quantity by stabilization	0.46	BECN1 stability was increased by NEDD4 via K6 and K27 ubiquitination during autophagy induction, thereby promoting autophagy activation.\|Further, NEDD4 mediated K6- and K27- linkage ubiquitination of BECN1, leading to elevated stability of BECN1 and increased autophagy.	SIGNOR-278558
Q53ET0	Q99576	1	transcriptional regulation	up-regulates quantity	0.2	CRTC2 knockdown attenuates glucocorticoid-responsive GILZ mRNA expression in HeLa cells	SIGNOR-256109
P36888	P42229	1	phosphorylation	up-regulates activity	0.605	FLT3-ITDs induced a strong activation of STAT5. FLT3-ITD mutants induce an autophosphorylation of the receptor, interleukin 3-independent growth in Ba/F3 cells, and a strong STAT5 and mitogen-activated protein kinase (MAPK) activation.	SIGNOR-261516
P02818	P07711	0	cleavage	down-regulates quantity by destabilization	0.2	This study has been undertaken to compare the degradation of BGP by the cysteine proteinases cathepsins L, B, H, S, and the aspartic proteinase cathepsin D. Cathepsins B, L, H, and S readily cleave BGP at the G7-A8 bond; cathepsin L also cleaves at R43-R44; cathepsin B also cleaves at R44-F45; and cathepsin D cleaves only at A41-Y42.	SIGNOR-256322
Q00613	P53350	0	phosphorylation	down-regulates	0.444	Hsf1 was phosphorylated by plk1 at ser(216) of the dsgxxs motif during the timing of mitosis and a phospho-defective mutant form of hsf1 inhibited mitotic progression. Phosphorylated hsf1 during spindle pole localization underwent ubiquitin degradation through the scf(beta-trcp) pathway.	SIGNOR-180915
Q9UKA9	P12931	1	post transcriptional regulation	down-regulates quantity by repression	0.285	Splicing of the c-src N1 exon in neuronal cells depends in part on an intronic cluster of RNA regulatory elements called the downstream control sequence (DCS). \|nPTB binds more stably to the DCS RNA than PTB does but is a weaker repressor of splicing in vitro. nPTB also greatly enhances the binding of two other proteins, hnRNP H and KSRP, to the DCS RNA.	SIGNOR-261267
P14618	Q9H6Z9	0	hydroxylation	up-regulates activity	0.436	Interaction of PKM2 with prolyl hydroxylase 3 (PHD3) enhances PKM2 binding to HIF-1α and PKM2 coactivator function. Mass spectrometry and anti-hydroxyproline antibody assays demonstrate PKM2 hydroxylation on proline-403/408. PHD3 knockdown inhibits PKM2 coactivator function, reduces glucose uptake and lactate production, and increases O(2) consumption in cancer cells.	SIGNOR-267476
Q01534	P68400	0	phosphorylation	up-regulates activity	0.2	CK2-dependent C-terminal phosphorylation at T300 directs the nuclear transport of TSPY protein	SIGNOR-250969
Q15717	O96017	0	phosphorylation	down-regulates activity	0.55	Given the fact that Chk2 phosphorylates HuR at residues S88, S100 and T118 and that each individual phosphorylation site by Chk2 plays a distinct role in regulating HuR- binding to different target mRNAs (22,42), we further tested HuR mutants with alanine substitutions at each of the Chk2 phosphorylation sites.	SIGNOR-278163
Q70EL2	Q96EA4	1	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
Q92793	P48551	1	acetylation	up-regulates activity	0.347	By binding to IFNalphaR2 within the region where two adjacent proline boxes bear phospho-Ser364 and phospho-Ser384, CBP acetylates IFNalphaR2 on Lys399, which in turn serves as the docking site for interferon regulatory factor 9 (IRF9)RF9 interacts with the acetyl-Lys399 motif by means of its IRF homology2 (IH2) domain, leading to formation of the ISGF3 complex that includes IRF9, STAT1, and STAT2.	SIGNOR-217783
P01137	P05412	0	transcriptional regulation	up-regulates quantity by expression	0.542	MAPKs have cis-acting regulatory elements in the mouse-TGF promoter region, which respond to various transcription factors, including specificity protein-1 and activating protein 1. Thus, it is possible that apoptotic cell-induced TGF-beta mRNA expression is mediated through activation of these transcription factors via MAPK signaling. Xiao et al. reported that all of the MAPK members, including p38/ERK/JNK, are required for apoptotic Jurkat cells up-regulation of TGF-beta production	SIGNOR-251713
P60510	O15379	1	dephosphorylation	down-regulates activity	0.379	Here we demonstrate that, in addition to protein-protein interactions with NCoR/SMRT, the activity of HDAC3 is regulated by both phosphorylation and dephosphorylation. A protein kinase CK2 phosphoacceptor site in the HDAC3 protein was identified at position Ser424, which is a nonconserved residue among the class I HDACs. Mutation of this residue was found to reduce deacetylase activity.\|Significantly, both overexpression and siRNA knock-down approaches, and analysis of cells devoid of PP4c, unequivocally show that HDAC3 activity is inversely proportional to the cellular abundance of PP4(c).	SIGNOR-248548
P78527	P54619	1	phosphorylation	up-regulates activity	0.2	PRKDC interacted with the AMPK complex and phosphorylated its nucleotide-sensing γ1 subunit PRKAG1/AMPKγ1 at Ser192 and Thr284, both events being significantly reduced upon the activation of the AMPK complex. Alanine substitutions of PRKDC phosphorylation sites in PRKAG1 reduced AMPK complex activation without affecting its nucleotide sensing capacity.	SIGNOR-277503
O15327	P31749	1	dephosphorylation	down-regulates activity	0.374	Further, we show that INPP4B but not PTEN is able to reduce tyrosine phosphorylation of Akt1 and both the lipid and PTP activity of INPP4B likely contribute to the reduction of Akt1 phosphorylation.\|Further, we show that INPP4B but not PTEN is able to reduce tyrosine phosphorylation of Akt1 and both the lipid and protein tyrosine phosphatase activity of INPP4B likely contribute to the reduction of Akt1 phosphorylation.	SIGNOR-277106
P17302	P17252	0	phosphorylation	down-regulates	0.535	Using immunoblotting and phosphospecific antibodies we were able to show that serine-262 (s262) on cx43 becomes phosphorylated in response to growth factor or pkc stimulation of cardiomyocytes.In cell-cell contact forming cultures, the s262d mutation reversed while the s262a mutation increased the inhibitory effect of cx43.Phosphorylation at s262, a pkc site that becomes phosphorylated in the cell environment in response to growth factor stimulation, cancels cx43 inhibition only in contact-forming myocytes.	SIGNOR-120907
P35611	P17252	0	phosphorylation	up-regulates	0.2	These data demonstrate that adducin is a significant in vivo substrate for pkc or other pma-activated kinases in a variety of cells, and that phosphorylation of adducin occurs in dendritic spines that are believed to respond to external signals by changes in morphology and reorganization of cytoskeletal structures. Ser-726 and ser-713 in the c-terminal marcks-related domains of alpha- and beta-adducin, respectively, were identified as the major phosphorylation sites common for pka and pkc.	SIGNOR-43744
P51617	Q9H4G4	1	phosphorylation	up-regulates activity	0.325	We found that TIRAP-MyD88 dependent kinase IRAK1 phosphorylated GAPR-1 at Serine 58 site. The phosphorylation of GAPR-1 promoted its interaction with TRAM-TRIF dependent inhibitor TMED7, and impaired TMED7-mediated disruption of the TRAM-TRIF complex to trigger IFN-β and the IL10 secretion.	SIGNOR-262887
Q96J02	O15105	1	ubiquitination	down-regulates	0.506	We identified atrophin 1-interacting protein 4 (aip4) as an e3 ubiquitin ligase that specifically targets smad7 for ubiquitin-dependent degradation without affecting the turnover of the activated tbetari. Surprisingly, we found that despite the ability to degrade smad7, aip4 can inhibit tgf-beta signaling, presumably by enhancing the association of smad7 with the activated tbetari.	SIGNOR-137951
Q99683	O75460	1	phosphorylation	up-regulates activity	0.618	ASK1 may directly phosphorylate IRE1\u03b1 at sites other than the IRE1\u03b1 autophosphorylation site.	SIGNOR-279213
P23409	P15173	0	transcriptional regulation	up-regulates quantity by expression	0.433	[...] confirming that myogenin binds to the E1 and E2 E boxes located in close proximity to the MRF4 transcription start site.	SIGNOR-255642
P24941	P28482	0	phosphorylation	up-regulates	0.497	In addition to its role in stimulating cyclin d1 expression and nuclear translocation of cdk2, erk regulates thr-160 phosphorylation of cdk2-cyclin e.	SIGNOR-94003
O75390	A8MUP2	0	methylation	down-regulates activity	0.2	A mitochondrial matrix-located methyltransferase, methyltransferase-like protein 12 (METTL12), has been reported to methylate CS on the lysine 368 (K368) [15] and K395 residues [16] which are near the active site of CS. The methylation on K395 inhibits CS activity, which can be antagonized by its substrate oxaloacetate.	SIGNOR-267638
P12931	P52789	1	phosphorylation	up-regulates activity	0.362	Here we find that c-Src can interact with and phosphorylate hexokinases HK1 and HK2, the rate limiting enzymes in glycolysis.\|Moreover, c-Src could efficiently stimulate the catalytic activities of HK1 and HK2, but failed to stimulate their corresponding mutants (XREF_FIG and XREF_SUPPLEMENTARY).	SIGNOR-278499
P01106	Q969H0	0	ubiquitination	down-regulates quantity	0.762	We now show that the F-box protein Fbw7 interacts with and thereby destabilizes c-Myc in a manner dependent on phosphorylation of MB1. Whereas wild-type Fbw7 promoted c-Myc turnover in cells, an Fbw7 mutant lacking the F-box domain delayed it.	SIGNOR-243545
Q13618	Q66K74	1	ubiquitination	down-regulates quantity	0.242	Gigaxonin is the substrate-specific adaptor for a new Cul3-E3-ubiquitin ligase family that promotes the proteasome dependent degradation of its partners MAP1B, MAP8 and tubulin cofactor B.	SIGNOR-268947
P52564	Q9ULV5	1	phosphorylation	up-regulates activity	0.2	Regulation of Hsf4b nuclear translocation and transcription activity by phosphorylation at threonine 472\| At the upstream, MEK6 was found to interact with Hsf4b and enhance Hsf4b's nuclear translocation and transcription activity, probably by phosphorylation at sites such as T472. Taken together, our results suggest that phosphotylation of Hsf4b at T472 by protein kinases such as MEI	SIGNOR-275493
P38936	Q9NRM7	0	phosphorylation	down-regulates quantity	0.417	Phosphorylation by Lats2 induces degradation of p21 and promotes apoptosis.\|Subsequently, Lats2 phosphorylates p21 at S146.	SIGNOR-279530
P31749	P29401	1	phosphorylation	up-regulates activity	0.282	Akt phosphorylates TKT on Thr382, markedly enhancing enzyme activity and increasing carbon flow through the nonoxidative PPP, thereby increasing purine synthesis.	SIGNOR-265101
Q92915	Q8NEV1	0	phosphorylation	up-regulates activity	0.269	Bioluminescence-based screening of small molecule modulators of the FGF14:Nav1.6 complex identified 4,5,6,7 -: tetrabromobenzotriazole (TBB), a potent casein kinase 2 (CK2) inhibitor, as a strong suppressor of FGF14:Nav1.6 interaction. Inhibition of CK2 through TBB reduces the interaction of FGF14 with Nav1.6 and Nav1.2 channels. Mass spectrometry confirmed direct phosphorylation of FGF14 by CK2 at S228 and S230, and mutation to alanine at these sites modified FGF14 modulation of Nav1.6-mediated currents.	SIGNOR-275743

Q8TB45

Q93009

0

deubiquitination

up-regulates quantity by stabilization

0.2

Screening the DEPTOR interactome identified that the association of USP-7 deubiquitinase with DEPTOR was dependent upon S235 phosphorylation. Inhibition of USP-7 activity resulted in DEPTOR polyubiquitination and degradation. A scansite search suggested that ERK1 may be responsible for S235 phosphorylation, which was confirmed through the use of inhibitors, ERK1 knockdown, and an in vitro kinase assay.

SIGNOR-277588

P06493

P04183

1

phosphorylation

down-regulates

0.507

Given that the dimeric form of tk1 is less active than the tetrameric, we propose that mitotic phosphorylation of serine-13 is of physiological importance, in that it may counteract atp-dependent activation of tk1 by affecting its quaternary structure, thus attenuating its enzymatic function at the g2/m phase.

SIGNOR-95574

Q8NHV4

O14965

0

phosphorylation

up-regulates activity

0.557

Microtubule nucleation during central spindle assembly requires NEDD1 phosphorylation on serine 405 by Aurora A| In the absence of Aurora A, the HURP (also known as DLGAP5) and NEDD1 proteins that are involved in nucleation of microtubules fail to concentrate in the midzone.

SIGNOR-272965

Q13188

P51955

1

phosphorylation

up-regulates

0.244

Our data suggest that mst2 phosphorylates nek2a thereby recruiting nek2a to centrosomes and promoting phosphorylation and displacement of centrosomal linker proteins

SIGNOR-169539

P60953

O14827

0

guanine nucleotide exchange factor

up-regulates activity

0.554

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-260575

Q00535

Q16643

1

phosphorylation

up-regulates activity

0.539

Phosphorylation of drebrin at S142 by Cdk5 relieves the intramolecular inhibition of F-actin bundling.

SIGNOR-279452

Q9H2X6

Q13131

0

phosphorylation

up-regulates activity

0.2

These results indicate that HIPK2 is a substrate of AMPKα2 in vitro and in vivo. Site-directed mutagenesis of Thr112 and Ser114 in the N terminus, and Thr1107 in the C terminus markedly reduced HIPK2 phosphorylation by AMPKα2 in vitro (Figure S5J).

SIGNOR-276469

Q99683

Q13627

0

phosphorylation

up-regulates activity

0.395

Moreover, Dyrk1A appears to directly phosphorylate the C-terminal domain of ASK1.|The current finding that Dyrk1A enhances the activities of ASK1 and JNK1, it could act as a pro-apoptotic player.

SIGNOR-279366

Q969Q1

P55036

1

polyubiquitination

down-regulates quantity by destabilization

0.403

S5a/Rpn10 is a ubiquitin (Ub)-binding protein that is a subunit of the 26S proteasome but also exists free in the cytosol. It binds poly-Ub chains through its two Ub-interacting motifs (UIMs). We discovered that, unlike typical substrates of Ub ligases (E3s), S5a can be ubiquitinated by all E3s tested including multimeric and monomeric Ring finger E3s (MuRF1, Siah2, Parkin, APC, and SCF(betaTRCP1)), the U-box E3, CHIP, and HECT domain E3s (E6AP and Nedd4) when assayed with UbcH5 or related Ub-conjugating enzymes.The short half-life of S5a presumably is because of the presence of the UIM domain and reflects the ubiquitination of free S5a by many E3s. Surprisingly, the same four Lys residues on S5a, Lys-74, Lys-122, Lys-262, and Lys-365 were ubiquitinated by MuRF1 and E6AP (Fig. 10).

SIGNOR-272741

P36888

P35222

1

phosphorylation

up-regulates activity

0.409

Endogenous beta-catenin co-immunoprecipitated with endogenous activated FLT3, and recombinant activated FLT3 directly phosphorylated recombinant beta-catenin. Finally, FLT3 inhibitor decreased tyrosine phosphorylation of beta-catenin in leukemia cells obtained from FLT3-ITD-positive AML patients. These data demonstrate that FLT3 activation induces beta-catenin tyrosine phosphorylation and nuclear localization, and thus suggest a mechanism for the association of FLT3 activation and beta-catenin oncogeneic signaling in AML.

SIGNOR-260124

Q99835

Q2M1P5

1

relocalization

up-regulates activity

0.632

Here, we demonstrate that Kif7, a mammalian homologue of Drosophila Costal2 (Cos2), is a cilia-associated protein that regulates signaling from the membrane protein Smoothened (Smo) to Gli transcription factorsIn response to activation of Smo Kif7 at the cilia tip may antagonize Sufu to promote activation of Gli proteins.

SIGNOR-209605

Q01105

P48736

0

phosphorylation

up-regulates activity

0.336

We show that PI3Kgamma phosphorylates I2PP2A on serine 9 and 93 residues resulting in enhanced interaction of I2PP2A with PP2A.

SIGNOR-278320

P61586

Q3KRB8

0

gtpase-activating protein

down-regulates activity

0.502

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-260467

Q15139

P48426

1

phosphorylation

down-regulates

0.2

We conclude that the type ii pip kinases are physiological targets for pkd phosphorylation, and that this modification is likely to regulate inositol lipid turnover by inhibition of these lipid kinases.

SIGNOR-145370

P38936

Q15208

0

phosphorylation

down-regulates quantity by destabilization

0.2

More importantly, with the direct regulation of p21 stability by phosphorylation on Ser 146, we define here the first downstream signaling mechanisms by which NDR kinases can control G1/S progression.|NDR kinases regulate p21 stability by phosphorylation of S146 on p21. |

SIGNOR-272961

O75592

Q8TEK3

0

transcriptional regulation

down-regulates quantity by repression

0.2

Overexpression of DOT1L decreased the expression of HECTD4 and MYCBP2 in LNCaP, C42B, and 22rv1 cells (Supplementary Fig. 5c), suggesting that DOT1L plays a role in repressing these targets either directly or indirectly.

SIGNOR-267151

P17252

P11387

1

phosphorylation

up-regulates activity

0.2

In vitro kinase assays demonstrated that Ser(10) can be phosphorylated by casein kinase II, Ser(21) can be phosphorylated by protein kinase Calpha, and Ser(112) and Ser(394) can be phosphorylated by Cdk1.Collectively these results indicate that topo I is phosphorylated during mitosis at multiple sites, one of which enhances DNA relaxation activity in vitro and interaction with DNA in cells.

SIGNOR-276154

Q9UPW6

Q15797

0

transcriptional regulation

up-regulates quantity

0.2

Chromatin immunoprecipitation (ChIP) revealed a subset of the BIG (BMP4 induced genes) signature, including Satb2, Smad6, Hand1, Gadd45γ and Gata3, that was bound by Smad1/5 in the developing mandible, revealing direct Smad-mediated regulation

SIGNOR-268934

Q13535

O75717

1

phosphorylation

up-regulates activity

0.539

And-1 is phosphorylated at T826 by ATR following replication stress, and this phosphorylation is required for And-1 to accumulate at the damage sites, where And-1 promotes the interaction between Claspin and Chk1, thereby stimulating efficient Chk1 activation by ATR.

SIGNOR-262664

P05771

P49840

1

phosphorylation

down-regulates

0.327

Convergence of multiple signaling cascades at glycogen synthase kinase 3: edg receptor-mediated phosphorylation and inactivation by lysophosphatidic acid through a protein kinase c-dependent intracellular pathway.

SIGNOR-115718

P53779

Q00535

0

phosphorylation

down-regulates activity

0.345

Here, we show that cdk5 directly phosphorylates c-Jun N-terminal kinase 3 (JNK3) on Thr131 and inhibits its kinase activity, leading to reduced c-Jun phosphorylation.

SIGNOR-250668

P30279

P49841

0

phosphorylation

down-regulates

0.454

Glycogen synthase kinase-3beta and p38 phosphorylate cyclin d2 on thr280 to trigger its ubiquitin/proteasome-dependent degradation in hematopoietic cells

SIGNOR-154668

P29474

P36873

0

dephosphorylation

up-regulates activity

0.2

The increase in eNOS activity coincided with specific dephosphorylation of eNOS-Thr495, known to enhance eNOS activity. Inhibition of protein phosphatase 1 (PP1) by calyculin A, tautomycetin, or siRNA against PP1 reversed NF-induced eNOS-Thr495 dephosphorylation

SIGNOR-248501

P49841

Q16665

1

phosphorylation

down-regulates activity

0.332

Glycogen synthase kinase 3 \u03b2 (GSK3\u03b2) phosphorylates HIF-1\u03b1 at three serine residues (Ser-551, Ser-555, and Ser-589) located within its oxygen-dependent degradation domain (ODDD) [12] (Figure 5). Phosphorylation at these residues by GSK3\u03b2 enhances HIF-1\u03b1 degradation in a pVHL-independent manner, resulting in suppression of the HIF-1 activity [12,13].|Phosphorylation at these residues by GSK3beta enhances HIF-1alpha degradation in a pVHL independent manner, resulting in suppression of the HIF-1 activity , ].

SIGNOR-278294

P78536

Q99075

1

cleavage

up-regulates activity

0.591

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

SIGNOR-259844

P16220

P51608

0

post transcriptional regulation

up-regulates quantity by expression

0.531

Interestingly, Creb1 was one of the activated MeCP2 targets that we validated by quantitative real-time RT-PCR (Fig. 1C), and using ChIP analysis we found that in vivo MeCP2 binds to the promoter region of Creb1, with significantly enhanced binding in MECP2-Tg samples compared to WT (p < 0.05) | In addition, Sst and CREB1 protein levels were increased in MECP2-Tg hypothalami compared to WT, indicating that MeCP2 indeed enhances expression of Sst and Creb1

SIGNOR-264682

Q13131

Q16526

1

phosphorylation

down-regulates

0.384

Ampk was shown to regulate the stability of the core clock component cry1 though phosphorylation of cry1 ser71, which stimulates the direct binding of the fbox protein fbxl3 to cry1, targeting it for ubiquitin-mediated degradation

SIGNOR-176472

P62837

P50542

1

ubiquitination

down-regulates quantity by destabilization

0.416

Here we report on the identification of the protein-ubiquitin ligases that are responsible for the ubiquitination of the peroxisomal protein import receptor Pex5. It is demonstrated that each of the three RING peroxins Pex2, Pex10, and Pex12 exhibits ubiquitin-protein isopeptide ligase activity. Our results show that Pex2 mediates the Ubc4-dependent polyubiquitination whereas Pex12 facilitates the Pex4-dependent monoubiquitination of Pex5.While polyubiquitinated Pex5 is degraded by the proteasome, monoubiquitinated Pex5 is destined for a new round of the receptor cycle.

SIGNOR-253023

O43318

P53805

1

phosphorylation

up-regulates activity

0.2

Here we showed that TAK1 directly phosphorylated RCAN1 at two novel sites (serine 94 and -136), resulting in activation of calcineurin-NFAT signaling.|Indeed, low doses of RCAN1 facilitated calcineurin-nuclear factor of activated T cells signaling in the presence of TGF-\u03b2-activated kinase 1+TAB1 ( ), suggesting that TGF-\u03b2-activated kinase 1 augments calcineurin-nuclear factor of activated T cells signaling through RCAN1.

SIGNOR-279535

P07101

P27361

0

phosphorylation

up-regulates

0.482

In this paper we have studied the phosphorylation and activation of alternatively spliced forms of human th by mapkap kinase-1 , mapkap kinase-2, map kinase, and cam kinase-11

SIGNOR-34678

P99999

Q9BXM7

0

null

down-regulates quantity

0.382

There is a strong cyto-protective role of PINK1 in maintaining mitochondrial homeostasis via different mechanisms. Overexpression of wild-type PINK1 in SH-SY5Y neuroblastoma cells stabilizes respiring mitochondrial networks through various mechanisms that include maintaining mitochondrial membrane potential, reducing basal and neurotoxin-induced ROS, suppression of cytochrome c release, reversal of toxin-induced fission, and suppression of autophagy

SIGNOR-249704

Q9UNE7

Q7Z2Y5

1

polyubiquitination

down-regulates quantity by destabilization

0.2

Our results indicate that Nrk is ubiquitinated by CHIP in a chaperone-dependent manner, resulting in its proteasomal degradation.

SIGNOR-274110

Q14686

P28482

0

phosphorylation

up-regulates activity

0.2

In vitro phosphorylation studies with His-tagged TRBP (795–931) suggested that S884 can be phosphorylated by MAPK (ERK2) in vitro (Fig. 10A).Analysis of in vitro and in vivo receptor interactions with TRBP suggested that S884 allowed selective interactions for ERβ, TR, and RXR vs. ERα.

SIGNOR-265882

Q9UPS8

Q01196

0

transcriptional regulation

down-regulates quantity by repression

0.2

In healthy individual, RUNX1/FLI1 complex negatively regulates ANKRD26 gene expression in MKs.

SIGNOR-266069

P23528

Q96GD0

0

dephosphorylation

down-regulates activity

0.447

Chronophin, a novel HAD-type serine protein phosphatase, regulates cofilin-dependent actin dynamics|Cofilin is a key regulator of actin cytoskeletal dynamics whose activity is controlled by phosphorylation of a single serine residue. We report the biochemical isolation of chronophin (CIN), a unique cofilin-activating phosphatase of the haloacid dehalogenase (HAD) superfamily.

SIGNOR-248764

P49841

O15516

1

phosphorylation

down-regulates quantity by destabilization

0.341

We have identified a conserved cluster of serines that include, Ser431, which is a prerequisite phosphorylation site for the generation of BMAL dependent phospho-primed CLOCK and for the potential GSK-3 phosphorylation at Ser427.

SIGNOR-276270

O96013

Q15139

0

phosphorylation

up-regulates activity

0.252

When PKD3 was knocked-down using isoform-specific shRNA (PKD3-shRNA), PAK4 activity (judged by its phosphorylation status at the activation loop using the pS474-PAK4 antibody) was decreased

SIGNOR-275930

Q6ZVD7

Q9UHC6

1

transcriptional regulation

down-regulates quantity by repression

0.2

In this study we performed chromatin immunoprecipitation coupled to shotgun cloning to discover novel STOX1A target genes. Our results show that CNTNAP2, a member of the neurexin family, is directly downregulated by STOX1A.

SIGNOR-269065

P00519

P05412

1

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

O15530

Q04759

1

phosphorylation

up-regulates

0.572

We demonstrate that 3-phosphoinositide-dependent kinase 1 (pdk1) has an essential role in this pathway by regulating the activation of pkc and through signal-dependent recruiting of both pkc and card11 to lipid rafts.

SIGNOR-134869

Q13546

Q12933

0

ubiquitination

up-regulates activity

0.895

Following binding to tradd, traf2 was thought to mediate non-degradative lys-63-linked polyubiquitination of rip1 via its ring e3 ligase domain. Rip1 is known to directly interact with traf2.

SIGNOR-59689

P00519

P42345

1

phosphorylation

down-regulates

0.453

Abl binds directly to raft1 and phosphorylates raft1 in vitro and in vivo. c-abl inhibits autophosphorylation of raft1 and raft1-mediated phosphorylation p70(s6k).

SIGNOR-76562

Q13950

P10451

1

transcriptional regulation

up-regulates quantity

0.488

Ets-1 and Runx2 are critical transcriptional regulators of OPN expression in CT26 colorectal cancer cells. Suppression of these transcription factors results in significant down-regulation of the OPN metastasis protein.

SIGNOR-245336

P68400

P30622

1

phosphorylation

up-regulates

0.293

Herein, we have identified polo-like kinase 1 (plk1) and casein kinase 2 (ck2) as two kinases of clip-170 and mapped s195 and s1318 as their respective phosphorylation sites.Plk1- and ck2-associated phosphorylations of clip-170 are involved in the timely formation of kinetochore-microtubule attachments in mitosis

SIGNOR-167168

P17612

Q9Y259

1

phosphorylation

up-regulates activity

0.253

Choline kinase beta (CKbeta) is one of the CK isozymes involved in the biosynthesis of phosphatidylcholine. | This study provides evidence for CKβ phosphorylation by protein kinase A (PKA).|Phosphorylation sites were located on CKβ residues serine-39 and serine-40 as determined by mass spectrometry and site-directed mutagenesis. Phosphorylation increased the catalytic efficiencies for the substrates choline and ATP about 2-fold, without affecting ethanolamine phosphorylation, and the S39D/S40D CKβ phosphorylation mimic behaved kinetically very similar.

SIGNOR-275629

Q6JBY9

P45983

0

phosphorylation

down-regulates activity

0.286

CapZIP was also phosphorylated rapidly by SAPK3/p38γ and SAPK4/p38δ, and even faster and more extensively by JNK1α1, these protein kinases phosphorylating CapZIP in vitro to >3, approx. 2 and >5 mol of phosphate/mol of protein respectively within a few minutes. Following tryptic digestion and C18 chromatography, further sites phosphorylated by JNK1α1 were identified as Ser-68, Ser-83 and Ser-216 (results not shown), and are highlighted in Figure 3.Using this antibody, we showed by immunoblotting that bacterially expressed CapZIP was phosphorylated at Ser-108 by SAPK4/p38δ, JNK1α1 and ERK2 in vitro, as well as by SAPK3/p38γ (results not shown).An important clue to the function of CapZIP and its phosphorylation came from the finding that it binds to the actin-capping protein CapZ (Figure 7A), and that cellular stresses trigger the dissociation of these two proteins (Figure 7B).Such an effect is presumably lost when CapZIP is phosphorylated and dissociates from CapZ.

SIGNOR-263085

Q5S007

P30048

1

phosphorylation

down-regulates activity

0.413

Here, we show that LRRK2 interacts with human peroxiredoxin 3 (PRDX3), a mitochondrial member of the antioxidant family of thioredoxin (Trx) peroxidases. Importantly, mutations in the LRRK2 kinase domain significantly increased phosphorylation of PRDX3 compared to wild-type. The increase in PRDX3 phosphorylation was associated with decreased peroxidase activity and increased death in LRRK2-expressing but not in LRRK2-depleted or vector-transfected neuronal cells.

SIGNOR-262891

P49841

Q14449

1

phosphorylation

down-regulates activity

0.323

Phosphorylation of clustered serine residues in the N-terminus of BPS domain negatively regulates formation of the complex between human Grb14 and insulin receptor| In vitro kinase assay using the motif-derived peptides showed that the serine residues located in N-terminal (Ser358, Ser362 and Ser366) and C-terminal (Ser419 and Ser423) regions of the BPS domain were phosphorylated by GSK-3.

SIGNOR-264867

Q16543

O75385

0

phosphorylation

down-regulates activity

0.2

Serine/Threonine Kinase Unc-51-like Kinase-1 (Ulk1) Phosphorylates the Co-chaperone Cell Division Cycle Protein 37 (Cdc37) and Thereby Disrupts the Stability of Cdc37 Client Proteins.|Ulk1-mediated phosphorylation of Ser-339 in Cdc37 compromised the recruitment of client kinases to a complex comprising Cdc37 and heat shock protein 90 (Hsp90) but only modestly affected Cdc37 binding to Hsp90.

SIGNOR-280158

Q9GZV1

P31751

0

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

Q13936

P43146

0

null

up-regulates activity

0.2

DCC activation by a netrin-1 gradient creates a high-level [Ca2+]i gradient by triggering LCC activity and by stimulating the cAMP–PKA pathway, which further activates LCC in the plasma membrane (PM) and Ca2+ channels in the ER.

SIGNOR-268291

P07101

Q13555

0

phosphorylation

up-regulates activity

0.332

In both isoforms, Ser-40 was found to be phosphorylated by PKA, and Ser-19 and Ser-40 were found to be phosphorylated by CaM-PK II. The putative phosphorylation site generated by alternative splicing (Ser-31) was phosphorylated specifically by CaM-PK II in TH-2 only. | Unlike TH-1, phosphorylation of TH-2 by CaM-PK II resulted in an increase of the Ki value for dopamine.

SIGNOR-250709

Q9ULV1

Q9ULT6

0

ubiquitination

down-regulates quantity

0.565

Here we show that the cell-surface transmembrane E3 ubiquitin ligase zinc and ring finger 3 (ZNRF3) and its homologue ring finger 43 (RNF43) are negative feedback regulators of Wnt signalling. ZNRF3 is associated with the Wnt receptor complex, and inhibits Wnt signalling by promoting the turnover of frizzled and LRP6.

SIGNOR-260115

P16284

P16591

0

phosphorylation

up-regulates activity

0.322

PECAM-1 Is Phosphorylated by Fer and, To a Lesser Extent, by Fes. These results suggest that Fer not only functions as a tyrosine kinase for PECAM-1 but also that Fer modulates the downstream signaling of PECAM-1 by inducing phosphorylation of SHP-2 and Gab1.

SIGNOR-262866

P38646

P33981

0

phosphorylation

up-regulates

0.2

Mortalin binds to mps1, and is phosphorylated by mps1 on thr62 and ser65. The phosphorylated mortalin then super-activates mps1 in a feedback manner. Mps1-associated acceleration of centrosome duplication depends on the presence of mortalin and super-activation by the thr62/ser65 phosphorylated mortalin

SIGNOR-156185

P06493

Q9Y6Q9

1

phosphorylation

down-regulates

0.368

We demonstrate that aib1 is phosphorylated on ser728 and ser867 by cdk1/cyclin b at the onset of mitosis and remains phosphorylated until exit from m phase.

SIGNOR-195233

O60825

P51812

0

phosphorylation

up-regulates activity

0.2

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

SIGNOR-23753

O14757

P62714

0

dephosphorylation

down-regulates activity

0.266

Phosphorylation of Chk1 by ATR is antagonized by a Chk1-regulated protein phosphatase 2A circuit|In response to genotoxic stress, Chk1 is phosphorylated on serines 317 (S317) and 345 (S345) by the ataxia-telangiectasia-related (ATR) protein kinase. Phosphorylation of Chk1 on these C-terminal serine residues is used as an indicator of Chk1 activation in vivo.

SIGNOR-248578

Q12860

P78357

0

relocalization

up-regulates activity

0.625

These results suggest that the targeting of contactin to different axonal domains may be determined, in part, via its association with Caspr.

SIGNOR-269073

Q7Z6Z7

P20226

1

ubiquitination

down-regulates quantity

0.337

Having established that Huwe1 mediates TBP ubiquitination in vitro, we then asked which E2 conjugating enzymes work best with Huwe1 in this reaction.|Upregulation of Huwe1 expression during myogenesis induces TBP degradation and myotube differentiation.

SIGNOR-278696

P01112

Q8TEU7

0

guanine nucleotide exchange factor

up-regulates

0.336

Gefs catalyse the transition from gdp-bound, inactive ras to gtp-bound, active ras.

SIGNOR-183796

Q8N122

Q15418

0

phosphorylation

up-regulates

0.546

Ser719, ser721, and ser722 are the predominant rsk-dependent phosphorylation sites in raptor raptor phosphorylation regulates mtorc1 activity

SIGNOR-180466

O15534

P78368

0

phosphorylation

down-regulates

0.394

Ck1_ and ck1_2 can promote proteasome-dependent per1 degradation in mammalian tissue culture cells, and their removal by rnai leads to an increased abundance of per1.

SIGNOR-137751

Q15382

P49815

0

gtpase-activating protein

down-regulates activity

0.922

Tsc2 functions as a gap to inhibit rheb activity. Tsc2 displays gap (gtpase-activating protein) activity specifically towards the small g protein rheb and inhibits its ability to stimulate the mtor signaling pathway. It has recently been shown that tsc2 has gtpase-activating protein (gap) activity towards the ras family small gtpase rheb (ras homolog enriched in brain), and tsc1/2 antagonizes the mtor signaling pathway via stimulation of gtp hydrolysis of rheb.

SIGNOR-128432

Q07666

Q13882

0

phosphorylation

up-regulates

0.748

Sik/brk is the first identified tyrosine kinase that can phosphorylate sam68 and regulate its activity within the nucleus, where it resides during most of the cell cycle

SIGNOR-80020

Q13422

P68400

0

phosphorylation

down-regulates

0.29

We identified four novelikarosphosphorylation sites that are phosphorylated by ck2 kinase. / ck2-mediated phosphorylation inhibits ikaros' localization to pc-hc / hyperphosphorylation of ikaros promotes its degradation by the ubiquitin/proteasome pathway / these results suggest that ck2 kinase directly phosphorylates amino acids 13, 23, 63, 101 and 294 in vivo

SIGNOR-174832

P40763

Q00535

0

phosphorylation

up-regulates

0.402

We report here that the cdk5/p35 complex associates with stat3 and phosphorylates stat3 on the ser-727 residue in vitro and in vivo. Ser phosphorylation of stat3 and transcription of stat3 target genes, such as c-fos and junb, in a cdk5-dependent manner.

SIGNOR-124325

P27361

P49137

1

phosphorylation

up-regulates

0.475

Erk phosphorylates multiple cytoplasmatic and cytoskeletal proteins, including mapk-activated protein kinases and the ribosomal p70-s6 kinase

SIGNOR-201687

O15534

P48729

0

phosphorylation

down-regulates quantity by destabilization

0.318

CKI\u03b1-Dependent Phosphorylation and Degradation of PER1.

SIGNOR-279700

P53350

P11388

1

phosphorylation

up-regulates

0.481

Here we report that when phosphorylated, ser 1524 of topo iialpha acts as a binding site for the brct domain of mdc1 (mediator of dna damage checkpoint protein-1), thereby recruiting mdc1 to chromatin

SIGNOR-182844

P46934

Q14457

1

ubiquitination

up-regulates quantity by stabilization

0.46

BECN1 stability was increased by NEDD4 via K6 and K27 ubiquitination during autophagy induction, thereby promoting autophagy activation.|Further, NEDD4 mediated K6- and K27- linkage ubiquitination of BECN1, leading to elevated stability of BECN1 and increased autophagy.

SIGNOR-278558

Q53ET0

Q99576

1

transcriptional regulation

up-regulates quantity

0.2

CRTC2 knockdown attenuates glucocorticoid-responsive GILZ mRNA expression in HeLa cells

SIGNOR-256109

P36888

P42229

1

phosphorylation

up-regulates activity

0.605

FLT3-ITDs induced a strong activation of STAT5. FLT3-ITD mutants induce an autophosphorylation of the receptor, interleukin 3-independent growth in Ba/F3 cells, and a strong STAT5 and mitogen-activated protein kinase (MAPK) activation.

SIGNOR-261516

P02818

P07711

0

cleavage

down-regulates quantity by destabilization

0.2

This study has been undertaken to compare the degradation of BGP by the cysteine proteinases cathepsins L, B, H, S, and the aspartic proteinase cathepsin D. Cathepsins B, L, H, and S readily cleave BGP at the G7-A8 bond; cathepsin L also cleaves at R43-R44; cathepsin B also cleaves at R44-F45; and cathepsin D cleaves only at A41-Y42.

SIGNOR-256322

Q00613

P53350

0

phosphorylation

down-regulates

0.444

Hsf1 was phosphorylated by plk1 at ser(216) of the dsgxxs motif during the timing of mitosis and a phospho-defective mutant form of hsf1 inhibited mitotic progression. Phosphorylated hsf1 during spindle pole localization underwent ubiquitin degradation through the scf(beta-trcp) pathway.

SIGNOR-180915

Q9UKA9

P12931

1

post transcriptional regulation

down-regulates quantity by repression

0.285

Splicing of the c-src N1 exon in neuronal cells depends in part on an intronic cluster of RNA regulatory elements called the downstream control sequence (DCS). |nPTB binds more stably to the DCS RNA than PTB does but is a weaker repressor of splicing in vitro. nPTB also greatly enhances the binding of two other proteins, hnRNP H and KSRP, to the DCS RNA.

SIGNOR-261267

P14618

Q9H6Z9

0

hydroxylation

up-regulates activity

0.436

Interaction of PKM2 with prolyl hydroxylase 3 (PHD3) enhances PKM2 binding to HIF-1α and PKM2 coactivator function. Mass spectrometry and anti-hydroxyproline antibody assays demonstrate PKM2 hydroxylation on proline-403/408. PHD3 knockdown inhibits PKM2 coactivator function, reduces glucose uptake and lactate production, and increases O(2) consumption in cancer cells.

SIGNOR-267476

Q01534

P68400

0

phosphorylation

up-regulates activity

0.2

CK2-dependent C-terminal phosphorylation at T300 directs the nuclear transport of TSPY protein

SIGNOR-250969

Q15717

O96017

0

phosphorylation

down-regulates activity

0.55

Given the fact that Chk2 phosphorylates HuR at residues S88, S100 and T118 and that each individual phosphorylation site by Chk2 plays a distinct role in regulating HuR- binding to different target mRNAs (22,42), we further tested HuR mutants with alanine substitutions at each of the Chk2 phosphorylation sites.

SIGNOR-278163

Q70EL2

Q96EA4

1

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

Q92793

P48551

1

acetylation

up-regulates activity

0.347

By binding to IFNalphaR2 within the region where two adjacent proline boxes bear phospho-Ser364 and phospho-Ser384, CBP acetylates IFNalphaR2 on Lys399, which in turn serves as the docking site for interferon regulatory factor 9 (IRF9)RF9 interacts with the acetyl-Lys399 motif by means of its IRF homology2 (IH2) domain, leading to formation of the ISGF3 complex that includes IRF9, STAT1, and STAT2.

SIGNOR-217783

P01137

P05412

0

transcriptional regulation

up-regulates quantity by expression

0.542

MAPKs have cis-acting regulatory elements in the mouse-TGF promoter region, which respond to various transcription factors, including specificity protein-1 and activating protein 1. Thus, it is possible that apoptotic cell-induced TGF-beta mRNA expression is mediated through activation of these transcription factors via MAPK signaling. Xiao et al. reported that all of the MAPK members, including p38/ERK/JNK, are required for apoptotic Jurkat cells up-regulation of TGF-beta production

SIGNOR-251713

P60510

O15379

1

dephosphorylation

down-regulates activity

0.379

Here we demonstrate that, in addition to protein-protein interactions with NCoR/SMRT, the activity of HDAC3 is regulated by both phosphorylation and dephosphorylation. A protein kinase CK2 phosphoacceptor site in the HDAC3 protein was identified at position Ser424, which is a nonconserved residue among the class I HDACs. Mutation of this residue was found to reduce deacetylase activity.|Significantly, both overexpression and siRNA knock-down approaches, and analysis of cells devoid of PP4c, unequivocally show that HDAC3 activity is inversely proportional to the cellular abundance of PP4(c).

SIGNOR-248548

P78527

P54619

1

phosphorylation

up-regulates activity

0.2

PRKDC interacted with the AMPK complex and phosphorylated its nucleotide-sensing γ1 subunit PRKAG1/AMPKγ1 at Ser192 and Thr284, both events being significantly reduced upon the activation of the AMPK complex. Alanine substitutions of PRKDC phosphorylation sites in PRKAG1 reduced AMPK complex activation without affecting its nucleotide sensing capacity.

SIGNOR-277503

O15327

P31749

1

dephosphorylation

down-regulates activity

0.374

Further, we show that INPP4B but not PTEN is able to reduce tyrosine phosphorylation of Akt1 and both the lipid and PTP activity of INPP4B likely contribute to the reduction of Akt1 phosphorylation.|Further, we show that INPP4B but not PTEN is able to reduce tyrosine phosphorylation of Akt1 and both the lipid and protein tyrosine phosphatase activity of INPP4B likely contribute to the reduction of Akt1 phosphorylation.

SIGNOR-277106

P17302

P17252

0

phosphorylation

down-regulates

0.535

Using immunoblotting and phosphospecific antibodies we were able to show that serine-262 (s262) on cx43 becomes phosphorylated in response to growth factor or pkc stimulation of cardiomyocytes.In cell-cell contact forming cultures, the s262d mutation reversed while the s262a mutation increased the inhibitory effect of cx43.Phosphorylation at s262, a pkc site that becomes phosphorylated in the cell environment in response to growth factor stimulation, cancels cx43 inhibition only in contact-forming myocytes.

SIGNOR-120907

P35611

P17252

0

phosphorylation

up-regulates

0.2

These data demonstrate that adducin is a significant in vivo substrate for pkc or other pma-activated kinases in a variety of cells, and that phosphorylation of adducin occurs in dendritic spines that are believed to respond to external signals by changes in morphology and reorganization of cytoskeletal structures. Ser-726 and ser-713 in the c-terminal marcks-related domains of alpha- and beta-adducin, respectively, were identified as the major phosphorylation sites common for pka and pkc.

SIGNOR-43744

P51617

Q9H4G4

1

phosphorylation

up-regulates activity

0.325

We found that TIRAP-MyD88 dependent kinase IRAK1 phosphorylated GAPR-1 at Serine 58 site. The phosphorylation of GAPR-1 promoted its interaction with TRAM-TRIF dependent inhibitor TMED7, and impaired TMED7-mediated disruption of the TRAM-TRIF complex to trigger IFN-β and the IL10 secretion.

SIGNOR-262887

Q96J02

O15105

1

ubiquitination

down-regulates

0.506

We identified atrophin 1-interacting protein 4 (aip4) as an e3 ubiquitin ligase that specifically targets smad7 for ubiquitin-dependent degradation without affecting the turnover of the activated tbetari. Surprisingly, we found that despite the ability to degrade smad7, aip4 can inhibit tgf-beta signaling, presumably by enhancing the association of smad7 with the activated tbetari.

SIGNOR-137951

Q99683

O75460

1

phosphorylation

up-regulates activity

0.618

ASK1 may directly phosphorylate IRE1\u03b1 at sites other than the IRE1\u03b1 autophosphorylation site.

SIGNOR-279213

P23409

P15173

0

transcriptional regulation

up-regulates quantity by expression

0.433

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

SIGNOR-255642

P24941

P28482

0

phosphorylation

up-regulates

0.497

In addition to its role in stimulating cyclin d1 expression and nuclear translocation of cdk2, erk regulates thr-160 phosphorylation of cdk2-cyclin e.

SIGNOR-94003

O75390

A8MUP2

0

methylation

down-regulates activity

0.2

A mitochondrial matrix-located methyltransferase, methyltransferase-like protein 12 (METTL12), has been reported to methylate CS on the lysine 368 (K368) [15] and K395 residues [16] which are near the active site of CS. The methylation on K395 inhibits CS activity, which can be antagonized by its substrate oxaloacetate.

SIGNOR-267638

P12931

P52789

1

phosphorylation

up-regulates activity

0.362

Here we find that c-Src can interact with and phosphorylate hexokinases HK1 and HK2, the rate limiting enzymes in glycolysis.|Moreover, c-Src could efficiently stimulate the catalytic activities of HK1 and HK2, but failed to stimulate their corresponding mutants (XREF_FIG and XREF_SUPPLEMENTARY).

SIGNOR-278499

P01106

Q969H0

0

ubiquitination

down-regulates quantity

0.762

We now show that the F-box protein Fbw7 interacts with and thereby destabilizes c-Myc in a manner dependent on phosphorylation of MB1. Whereas wild-type Fbw7 promoted c-Myc turnover in cells, an Fbw7 mutant lacking the F-box domain delayed it.

SIGNOR-243545

Q13618

Q66K74

1

ubiquitination

down-regulates quantity

0.242

Gigaxonin is the substrate-specific adaptor for a new Cul3-E3-ubiquitin ligase family that promotes the proteasome dependent degradation of its partners MAP1B, MAP8 and tubulin cofactor B.

SIGNOR-268947

P52564

Q9ULV5

1

phosphorylation

up-regulates activity

0.2

Regulation of Hsf4b nuclear translocation and transcription activity by phosphorylation at threonine 472| At the upstream, MEK6 was found to interact with Hsf4b and enhance Hsf4b's nuclear translocation and transcription activity, probably by phosphorylation at sites such as T472. Taken together, our results suggest that phosphotylation of Hsf4b at T472 by protein kinases such as MEI

SIGNOR-275493

P38936

Q9NRM7

0

phosphorylation

down-regulates quantity

0.417

Phosphorylation by Lats2 induces degradation of p21 and promotes apoptosis.|Subsequently, Lats2 phosphorylates p21 at S146.

SIGNOR-279530

P31749

P29401

1

phosphorylation

up-regulates activity

0.282

Akt phosphorylates TKT on Thr382, markedly enhancing enzyme activity and increasing carbon flow through the nonoxidative PPP, thereby increasing purine synthesis.

SIGNOR-265101

Q92915

Q8NEV1

0

phosphorylation

up-regulates activity

0.269

Bioluminescence-based screening of small molecule modulators of the FGF14:Nav1.6 complex identified 4,5,6,7 -: tetrabromobenzotriazole (TBB), a potent casein kinase 2 (CK2) inhibitor, as a strong suppressor of FGF14:Nav1.6 interaction. Inhibition of CK2 through TBB reduces the interaction of FGF14 with Nav1.6 and Nav1.2 channels. Mass spectrometry confirmed direct phosphorylation of FGF14 by CK2 at S228 and S230, and mutation to alanine at these sites modified FGF14 modulation of Nav1.6-mediated currents.

SIGNOR-275743