GleghornLab/Signor_2class · Datasets at Hugging Face

IdA string	IdB string	labels int64	mechanism string	effect string	score float64	sentence string	signor_id string
P27361	Q15797	1	phosphorylation	down-regulates	0.528	Ras signaling was shown previously to induce the phosphorylation of the bmp mediator smad1 at four erk consensus sites in the linker domain (kretzschmar et al. 1997a). Phosphorylation of these four sites inhibits smad1 accumulation in the nucleus	SIGNOR-66755
Q15797	Q8N4C8	0	phosphorylation	down-regulates activity	0.2	Msn kinases directly phosphorylate α-helix 1 of Smad. we have identified Misshapen (Msn) and the mammalian orthologs TNIK, MINK1, and MAP4K4 as the kinases responsible for α-helix 1 phosphorylation.	SIGNOR-276336
Q13131	O14929	1	phosphorylation	up-regulates activity	0.2	Together, these results indicate that AMPK phosphorylated DNMT1-Ser730, RBBP7-Ser314, and HAT1-Ser190\|AMPK increased HAT1 activity through phosphorylation of HAT1-Ser190 and RBBP7-Ser314	SIGNOR-264782
P53671	O43791	1	phosphorylation	down-regulates activity	0.2	LIMK2 phosphorylates SPOP at S59, S171 and S226.\|Together, these results depict that LIMK2-mediated SPOP degradation is a key mechanism that regulates AR stability.	SIGNOR-278338
Q01094	O96017	0	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
P07900	P05129	0	phosphorylation	down-regulates	0.258	Threonine residue set, thr(115)/thr(425)/thr(603), of hsp90_ is specifically phosphorylated by pkc_phosphorylation of hsp90_ by pkc_ decreases the binding affinity of hsp90_ towards atp and co-chaperones such as cdc37 (cell-division cycle 37), thereby decreasing its chaperone activity.	SIGNOR-202812
P31749	Q6A1A2	0	phosphorylation	up-regulates	0.2	Akt to the plasma membrane where it is phosphorylated and activated by phosphoinositide-dependent kinase (pdk) 1 and pdk2.	SIGNOR-252628
P19784	P41236	1	phosphorylation	up-regulates activity	0.307	Recombinant wild-type I-2 and the Ala-120/121 mutant were phosphorylated synergistically by GSK-3 and casein kinase II. The Thr-72 and Ser-86 mutants, however, did not undergo this synergistic phosphorylation. Our studies indicate that Thr-72 is the only GSK-3 site and that Ser-86 is the casein kinase II site required for the potentiation of GSK-3 action.	SIGNOR-251021
Q96J02	O15519	1	ubiquitination	down-regulates quantity	0.614	Depends on JNK-mediated phosphorylation and activation of the E3 ubiquitin ligase Itch, which specifically ubiquitinates c-FLIP and induces its proteasomal degradation.	SIGNOR-245307
P28482	Q9NQ66	1	phosphorylation	up-regulates activity	0.398	coimmunoprecipitation detected a specific association between the activated erk and plc beta1 within the nucleus. In vitro studies revealed that recombinant plc beta1 could be efficiently phosphorylated by activated mitogen-activated protein kinase but not by pka. The erk phosphorylation site was mapped to serine 982 this result suggests that erk-evoked phosphorylation of plc beta1 at serine 982 plays a critical role in the activation of the nuclear pi cycle and is also crucial to the mitogenic action of igf-i.	SIGNOR-106561
P10275	Q13043	0	phosphorylation	down-regulates activity	0.2	Here we showed that MST1 is an androgen receptor kinase and phosphorylates androgen receptor at Ser-650 ( ).\|Mst1 plays a critical role in the regulation of programmed cell death and it has been implicated in PCa development. Interestingly, MST1 has been detected in AR-chromatin complexes, and forced expression of MST1 reduces AR binding to androgen-responsive elements along the PSA promoter.	SIGNOR-280143
P14416	P43250	0	phosphorylation	down-regulates activity	0.447	GRK6 is located predominantly in dopaminergic neurons [ xref ] and functionally phosphorylates DRD2.	SIGNOR-279046
Q9GZV5	P49674	0	phosphorylation	down-regulates	0.366	LATS1/2-mediated phosphorylation of a conserved serine in this region (Ser311 in human TAZ; Ser397 in human YAP) primes for further phosphorylation by CK1_/_ kinases (Ser314 on human TAZ; Ser400/403 in human YAP)	SIGNOR-230747
P18858	P06493	0	phosphorylation	up-regulates activity	0.364	We show that three residues (ser51, ser76, and ser91), which are part of cyclin-dependent kinase sites, are phosphorylated in a cell cycle-dependent manner.	SIGNOR-103242
P51955	Q9UMX1	1	phosphorylation	up-regulates activity	0.2	Intriguingly, Nek2A is found to stabilize SuFu at least partly depending on its kinase activity, thereby triggering phosphorylation of the SuFu protein.\|Nek2A phosphorylates and stabilizes SuFu: A new strategy of Gli2/Hedgehog signaling regulatory mechanism.	SIGNOR-279235
P17600	Q13131	0	phosphorylation	down-regulates activity	0.2	It has been reported that site 1 of syn i can be phosphorylated by pka. Pka-mediated synapsin i ser9 phosphorylation occurs in response to cgs 21680 treatment. Results show that the adenosine a2a receptor agonist, cgs 21680, increases neurotransmitter release, in particular, glutamate and noradrenaline and such response is mediated by protein kinase a activation, which in turn increased synapsin i phosphorylation	SIGNOR-78891
Q13315	P15374	1	phosphorylation	up-regulates activity	0.331	Mechanistically, in response to DNA damage, the deubiquitinase UCHL3 is phosphorylated and activated by ATM.	SIGNOR-279794
Q96RR4	Q16566	1	phosphorylation	up-regulates activity	0.62	Phosphorylation and activation of Ca(2+)-calmodulin-dependent protein kinase IV by Ca(2+)-calmodulin-dependent protein kinase Ia kinase. Phosphorylation of threonine 196 is essential for activation.	SIGNOR-250718
P55085	P24158	0	cleavage	down-regulates activity	0.373	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-263601
Q13191	P43405	1	ubiquitination	down-regulates quantity	0.696	In summary, the studies presented here provide evidence that Cbl-b negatively regulates Syk through ubiquitination.\|The results presented suggest that Cbl-b ubiquitinates active phosphorylated Syk and thus functions to dampen B cell antigen receptor signaling after signaling is initiated and thus plays a role in the normal down modulation of B cell antigen receptor signaling.	SIGNOR-278754
Q9UNE7	P06730	1	ubiquitination	down-regulates quantity by destabilization	0.332	This collaborative activity of cIAP1 and CHIP directs eIF4E toward degradation, controlling its levels and suppressing tumorigenesis.\|We next sought to investigate whether eIF4E ubiquitination is enhanced by the collaborative activity of cIAP1 and CHIP, which we define as both the E3 ligase activity of cIAP1 alone and the E3 ligase activity of cIAP1 and CHIP together.	SIGNOR-278669
P60709	Q9NZI8	0	post transcriptional regulation	up-regulates quantity	0.34	We found that ZBP1 is necessary for netrin-1 stimulated local translation of β-actin mRNA in axonal growth cones. ZBP1 binds to β-actin mRNA in the soma and transports it to the growth cone on microtubules.	SIGNOR-268160
P53667	Q5VT25	0	phosphorylation	up-regulates activity	0.404	Activation of LIM kinases by myotonic dystrophy kinase-related Cdc42-binding kinase alpha. \ In vitro, MRCKalpha phosphorylated the protein kinase domain of LIM kinases, and the site in LIMK2 phosphorylated by MRCKalpha proved to be threonine 505 within the activation segment.	SIGNOR-250721
P42224	P23458	0	phosphorylation	up-regulates activity	0.79	The central event in cytokine_dependent transcriptional regulation is phosphorylation of STATs on a single tyrosine residue at their C_terminus (Darnell, 1997b). The reaction is catalyzed by cytokine receptor_associated tyrosine kinases of the Janus type (Jak) at the cell membrane and triggers the homo_ and heterodimerization of STAT molecules via reciprocal phosphotyrosineSH2 domain interactions	SIGNOR-236373
Q86UE8	O14757	0	phosphorylation	down-regulates activity	0.269	Chk1 phosphorylates GST-fusion fragments of TLK1 in vitro.When Chk1 protein was depleted in cells transfected with pSuper-Chk1, TLK activity was not suppressed after short aphidicolin treatment of S-phase cells (Figure 8a, b).	SIGNOR-262740
O60341	P68400	0	phosphorylation	up-regulates activity	0.318	We demonstrated here that phosphorylation and dephosphorylation of LSD1 at S131 and S137 was mediated by casein kinase 2 (CK2) and wild-type p53-induced phosphatase 1 (WIP1), respectively. LSD1, RNF168 and 53BP1 interacted with each other directly. CK2-mediated phosphorylation of LSD1 exhibited no impact on its interaction with 53BP1, but promoted its interaction with RNF168 and RNF168-dependent 53BP1 ubiquitination and subsequent recruitment to the DNA damage sites.	SIGNOR-276903
Q96T88	Q5UIP0	1	polyubiquitination	down-regulates activity	0.2	UHRF1 mediates K63-linked polyubiquitination of RIF1, and results in its dissociation from 53BP1 and DSBs thereby facilitating HR initiation.	SIGNOR-277193
Q5T9L3	P56704	1	relocalization	up-regulates activity	0.641	WNT secretion requires its binding to the carrier protein wntless (WLS);	SIGNOR-256599
O43318	P22607	0	phosphorylation	up-regulates activity	0.293	Indeed, we found that TAK1 was tyrosine phosphorylated in HEK293 cells transiently expressing constitutively active FGFR3 (K650E), but not the kinase-dead receptor (K508M), indicating that activated FGFR3 can either directly or indirectly tyrosine phosphorylate TAK1 (XREF_FIG).	SIGNOR-279176
P17612	P10276	1	phosphorylation	down-regulates activity	0.405	Mutagenesis of serine 219 (S219) and S369 at the PKA sites on RARA to either double alanines or double glutamic acids showed that both PKA sites are important for RARA activity.	SIGNOR-276281
P38936	P16885	0	phosphorylation	up-regulates quantity by stabilization	0.2	Phosphorylation at Ser-146 by PKCδ increases p21 stability	SIGNOR-262963
P17612	P35236	1	phosphorylation	down-regulates	0.361	B2 adrenergic receptor stimulation induces the pka dependent phosphorylation of heptp and releases bound p38 mapk	SIGNOR-182522
P04637	Q9H4B4	0	phosphorylation	up-regulates activity	0.706	Upon exposure of cells to hydrogen peroxide (h(2)o(2)) phosphorylation of p53 was rapidly induced in human fibroblast gm00637, and this phosphorylation occurred on serine 9, serine 15, serine 20, but not on serine 392. In addition, h(2)o(2)-induced phosphorylation of p53 was followed by induction of p21, suggesting functional activation of p53. Ectopic expression of a plk3 dominant negative mutant, plk3(k52r), in gm00637 cells suppressed h(2)o(2)-induced serine 20 phosphorylation. Taken together, our studies strongly suggest that the oxidative stress-induced activation of p53 is at least in part mediated by plk3.	SIGNOR-109239
P12931	Q9NZC7	1	phosphorylation	up-regulates	0.48	The tyrosine kinase, src, phosphorylates wwox at tyrosine 33 in the first ww domain and enhances its binding to p73.	SIGNOR-123819
O95997	Q9UQM7	0	phosphorylation	down-regulates quantity by destabilization	0.309	CaMKII phosphorylates securin at PP2A substrate site(s).Securin is destabilized by phosphorylation and stabilized by PP2A-dependent dephosphorylation on separase	SIGNOR-276381
Q14995	O00327	1	transcriptional regulation	down-regulates quantity by repression	0.467	A retinoic acid receptor-related orphan receptor (ROR) response element within the BMAL1 promoter is responsive to both ROR and REV-ERB (encoded by the genes NR1D1 and NR1D2); ROR activates the transcription of BMAL1, whereas REV-ERB suppresses its transcription.	SIGNOR-268006
P19484	P16298	0	dephosphorylation	up-regulates activity	0.377	Lysosomal Ca2+ release via mucolipin 1 (MCOLN1) activates calcineurin, which binds and de-phosphorylates TFEB, thus promoting its nuclear translocation.	SIGNOR-255306
P21802	Q02156	0	phosphorylation	up-regulates	0.2	Phosphorylation of serine 779 in fibroblast growth factor receptor 1 and 2 by protein kinase c(epsilon) regulates ras/mitogen-activated protein kinase signaling and neuronal differentiation	SIGNOR-201675
Q13501	Q05655	0	phosphorylation	up-regulates activity	0.367	Data presented here suggested that Vps34 stimulates tumor development mainly through PKC-\u03b4- activation of p62.\|In conclusion, elevation of Vps34 results in tumor progression via the PKC-\u03b4-phosphorylation of p62 at S349 and PKC-\u03b4 involved phosphorylation of Raf 1 at Y340/341.\|Vps34 induces PKC-\u03b4-dependent phosphorylation of p62.	SIGNOR-280086
P11309	P61073	1	phosphorylation	up-regulates quantity	0.365	Pim-1 and Pim-3 enhance phosphorylation and cell surface expression of CXCR4.\|When the in vitro phosphorylated fragments were detected with the anti-phospho (Ser339)-CXCR4 antibody, it became evident that both Pim-1 and Pim-3, but not Pim-2 can phosphorylate CXCR4 on Ser339 (XREF_FIG).	SIGNOR-278450
Q13085	P60510	0	dephosphorylation	up-regulates activity	0.242	PP4 was also found to directly interact with pACC1‑Ser79 in human HepG2 cells. In conclusion, the present study showed that PP4 may be a novel regulator in hepatic lipogenesis through dephosphorylating ACC1 on serine 79, suggesting that PP4 may be a promising therapeutic target in lipid metabolism disorders.	SIGNOR-267724
Q9UQM7	P14136	1	phosphorylation	down-regulates activity	0.427	On the other hand, GFAP was phosphorylated to approximately 1.9 mol of phosphate/mol of GFAP by Ca(2+)-CaM-dependent protein kinase II, and this phosphorylation did induce disassembly of the filament. Sequential analysis of the purified phosphopeptides revealed that only Ser8 on GFAP was phosphorylated by cdc2 kinase, whereas Ser13, Ser17, Ser34, and Ser389 on GFAP were phosphorylated by Ca(2+)-CaM-dependent protein kinase II.	SIGNOR-250626
Q9BYP7	Q9UP95	1	phosphorylation	down-regulates activity	0.464	We have shown that with-no-lysine kinase 3 (WNK3) possesses several properties that suggest it could be the Cl−/volume-sensitive regulatory kinase that, in association with protein phosphatases, reciprocally modifies the phosphorylation/dephosphorylation states of the SLC12 proteins and thus their activities\|WNK3 activates NKCC1/2 and NCC and inhibits the KCCs	SIGNOR-264627
Q92993	Q01130	1	acetylation	down-regulates	0.466	In this study, we provide the first evidence that the acetyltransferase tip60 acetylates srsf2 on its lysine 52 residue inside the rna recognition motif, and promotes its proteasomal degradation.	SIGNOR-170594
Q07817	O60260	0	ubiquitination	down-regulates quantity by destabilization	0.2	In cells, we found BCL-XL levels were reduced by overexpression of PARK2, but this catalytic activity was blocked by the proteasome inhibitor MG132, suggesting degradation of BCL-XL protein by PARK2 is dependent on the proteasome system (XREF_FIG A).\|PARK2 directly binds to and ubiquitinates BCL-XL.	SIGNOR-278661
P23470	P53667	1	dephosphorylation	down-regulates activity	0.26	PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity.	SIGNOR-254711
P05067	P53355	0	phosphorylation	up-regulates quantity	0.287	DAPK1, but not its kinase deficient mutant (K42A), significantly increased human AŒ≤ secretion in neuronal cell culture models. Moreover, knockdown of DAPK1 expression or inhibition of DAPK1 catalytic activity significantly decreased AŒ≤ secretion. Furthermore, DAPK1, but not K42A, triggered Thr668 phosphorylation of APP, which may initiate and facilitate amyloidogenic APP processing leading to the generation of AŒ≤.\|Furthermore, DAPK1, but not K42A, triggered Thr668 phosphorylation of APP, which may initiate and facilitate amyloidogenic APP processing leading to the generation of Abeta.	SIGNOR-279518
P18433	Q14721	1	dephosphorylation	down-regulates	0.2	Ptpalpha inhibits kv channels more strongly than ptpepsilon;this correlates with constitutive association of ptpalpha with kv2.1, driven by membranal localization of ptpalpha.	SIGNOR-148301
Q9UGK3	O60674	0	phosphorylation	up-regulates activity	0.343	To examine this possibility, STAP-2 was co-transfected with constitutively active tyrosine kinases in HEK-293 cells. STAP-2 was strongly phosphorylated by various tyrosine kinases, including v-Src (Fig.2 A-a), a JAK2 tyrosine kinase \|On the other hand, the phosphorylation levels of Y22F, Y310F, and Y322F by GST-JH1 were reduced to 8060% of the levels of wild-type STAP-2, which suggests that these three are potential phosphorylation sites by activated JAK2.	SIGNOR-249372
Q96EB6	Q09472	1	deacetylation	down-regulates	0.835	Sirt1 induces deacetylation and repression of p300 itself (81). Mutational analysis demonstrated that sirt1 repression of p300 involves both lysine 1020 and lysine 1024	SIGNOR-182511
O00750	P14373	0	ubiquitination	down-regulates	0.402	We now show that trim27 functions as an e3 ligase and mediates lysine 48 polyubiquitination of pi3kc2_, leading to a decrease in pi3k enzyme activity.	SIGNOR-177935
P61586	Q70Z35	0	guanine nucleotide exchange factor	up-regulates activity	0.406	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-260570
Q13535	P30307	1	phosphorylation	up-regulates activity	0.643	We also found that activated ATR phosphorylates CDC25C (Cell Division Cycle 25C) at serine 216, which in turn inactivates the cyclin B1/Cyclin-Dependent Kinase 1(CDK1) complex and induces G2-phase arrest.	SIGNOR-279008
P37231	P18146	0	transcriptional regulation	down-regulates quantity by repression	0.62	Previous studies have reported that the PPARγ proximal promoter contains an overlapping binding site for Egr-1, which is involved in the down-regulation of PPARγ. In the present study, we have provided direct evidence that leptin causes PPARγ reduction in primary cultured PASMC; this effect is coupled to leptin-induced ERK1/2 activation and subsequent induction of Egr-1, which further down-regulates PPARγ expression and results in PASMC proliferation. The present study confirmed that ERK1/2 signaling cascade mediated leptin-induced PPARγ reduction by up-regulation of Egr-1 in PASMC.	SIGNOR-263508
P06493	Q9Y2I6	1	phosphorylation	down-regulates quantity by destabilization	0.422	In this study, we show that Nlp can be phosphorylated by cell cycle protein kinase Cdc2/cyclin B1. The phosphorylation sites of Nlp are mapped at Ser185 and Ser589. the phosphorylation at the site Ser589 by Cdc2/cyclin B1 plays an important role in Nlp protein stability probably due to its effect on protein degradation.	SIGNOR-259831
P27361	Q15046	1	phosphorylation	up-regulates	0.2	Lysrs serves as a key signaling molecule in the immune response by regulating gene expression. Lysrs was phosphorylated on serine 207 in a mapk-dependent manner, released from the multisynthetase complex, and translocated into the nucleus.	SIGNOR-186125
Q9NRS4	P0DTC2	1	cleavage	up-regulates activity	0.2	TMPRSS2 and TMPRSS4 serine proteases mediate this process by inducing cleavage of the S protein and enhancing membrane fusion.	SIGNOR-262306
O95644	P27361	0	phosphorylation	down-regulates	0.532	We show that jnk, erk, and p38 physically associate with the nfatc n-terminal regulatory domain and can directly phosphorylate functionally important residues involved in regulating nfatc subcellular localization, namely ser(172) and the conserved nfatc ser-pro repeats.	SIGNOR-74564
Q9UGL1	P06493	0	phosphorylation	down-regulates activity	0.258	Phosphorylation of the histone demethylase KDM5B and regulation of the phenotype of triple negative breast cancer\|Here, we demonstrate that KDM5B is phosphorylated at Ser1456 by the cyclin-dependent kinase 1 (CDK1). Phosphorylation of KDM5B at Ser1456 attenuated the occupancy of KDM5B on the promoters of pluripotency genes.	SIGNOR-273435
O43791	Q9UBN7	1	ubiquitination	down-regulates quantity	0.2	Cullin3 SPOP ubiquitin E3 ligase promotes the poly-ubiquitination and degradation of HDAC6	SIGNOR-268862
Q9BQ95	Q9Y4K3	0	ubiquitination	down-regulates activity	0.79	Here we demonstrate that engagement of a subset of Toll-like receptors (TLR1, TLR2 and TLR4) results in the recruitment of mitochondria to macrophage phagosomes and augments mROS production. This response involves translocation of a TLR signalling adaptor, tumour necrosis factor receptor-associated factor 6 (TRAF6), to mitochondria, where it engages the protein ECSIT (evolutionarily conserved signalling intermediate in Toll pathways), which is implicated in mitochondrial respiratory chain assembly. Interaction with TRAF6 leads to ECSIT ubiquitination and enrichment at the mitochondrial periphery, resulting in increased mitochondrial and cellular ROS generation	SIGNOR-260370
Q6PHR2	P10071	1	phosphorylation	up-regulates activity	0.561	We show that ULK3 is able to phosphorylate three mammalian GLI proteins in vitro	SIGNOR-260799
P24666	P12931	1	dephosphorylation	up-regulates activity	0.438	LMWPTP dephosphorylated pY(527)-Src and pY(416)-Src in vitro, with greater specificity for pY(527)Src. Activation of LMWPTP produced strong activation of Src mediated by fast dephosphorylation of pY(527)-Src, followed by slower deactivation of this kinase via dephosphorylation of pY(416)Src.	SIGNOR-248454
Q9NVW2	P01106	1	ubiquitination	down-regulates quantity by destabilization	0.37	This suggests that RLIM negatively regulates the transcriptional activity of c-Myc.\|We further showed that RLIM can promote polyubiquitination of c-Myc in cells.	SIGNOR-278551
Q07869	Q7LBC6	0	transcriptional regulation	up-regulates quantity by expression	0.2	We show that Jhdm2a expression is induced by beta-adrenergic stimulation, and that Jhdm2a directly regulates peroxisome proliferator-activated receptor alpha (Ppara) and Ucp1 expression.	SIGNOR-266637
P17252	P21731-2	1	phosphorylation	down-regulates activity	0.521	These data suggest a model whereby agonist-induced PKC phosphorylation of Ser(145) partially impairs TPbeta signalling while GRK2/3 phosphorylation at both Ser(239) and Ser(357) within its IC(3) and C-tail domains, respectively, sterically inhibits G-protein coupling, profoundly desensitizing signalling, and promotes beta-arrestin association and, in turn, facilitates TPbeta internalization.	SIGNOR-274092
Q99878	Q86Y13	0	monoubiquitination	up-regulates activity	0.2	2A-HUB catalyzes monoubiquitination of H2A at lysine 119, functioning as a combinatoric component of the repression machinery required for specific gene regulation programs. Thus, 2A-HUB mediates a selective repression of a specific set of chemokine genes in macrophages, critically modulating migratory responses to TLR activation. H2A monoubiquitination acts to prevent FACT recruitment at the transcriptional promoter region, blocking RNA polymerase II release at the early stage of elongation.	SIGNOR-271762
Q9UBN7	P49841	0	phosphorylation	up-regulates activity	0.381	GSK3beta was found to co-localize with HDAC6 in hippocampal neurons, and inhibition of GSK3beta resulted in decreased binding of antibody to phosphoserine-22, a potential GSK3beta phosphorylation site in HDAC6.\|This suggests that GSK3\u03b2 may directly phosphorylate HDAC6 at this site, although further work with purified proteins is needed to determine whether this is the case.\|The fact that HDAC6 is the predominant cytoplasmic deacetylase in neurons suggests that GSK3beta dependent phosphorylation may enhance HDAC6 activity, resulting in a decrease in acetylation of tubulin and an inhibition of both mitochondrial motility and the transport of other kinesin-1 dependent cargoes.	SIGNOR-278941
O00141	Q92542	1	phosphorylation	down-regulates quantity	0.337	Furthermore, SGK1 directly bound to and phosphorylated Nicastrin on Ser437, thereby promoting protein degradation.\|We showed that SGK1 downregulates Nicastrin protein levels.	SIGNOR-280122
P09917	P49137	0	phosphorylation	up-regulates activity	0.546	Arachidonic acid promotes phosphorylation of 5-lipoxygenase at Ser-271 by MAPK-activated protein kinase 2 (MK2). when stimulated with only exogenous arachidonic acid, activity for the S271A mutant was significantly lower as compared with wild type 5-LO.	SIGNOR-250143
P15311	P25098	0	phosphorylation	up-regulates	0.2	Grk2 phosphorylates glutathione s-transferase (gst)-ezrin, but not an ezrin fusion protein lacking threonine 567 (t567), in vitro. These results suggest that t567, the regulatory phosphorylation site responsible for maintaining ezrin in its active conformation, represents the principle site of grk2-mediated phosphorylation.	SIGNOR-135622
Q12913	P28482	1	dephosphorylation	down-regulates	0.406	In this study we show that one of these potential targets, the erk1/2, is indeed a direct dep-1 substrate in vivo.	SIGNOR-161536
O43474	P42226	0	transcriptional regulation	up-regulates quantity by expression	0.345	STAT6 coordinates and synergizes with both PPAR? and Krppel-like factor 4 (KLF4), a member of a family of proteins that contribute to macrophage function.	SIGNOR-249568
P15336	Q99986	0	phosphorylation	up-regulates	0.371	Vrk1 phosphorylates atf2 mainly on thr-73, stabilizing the atf2 protein and increasing its intracellular level.	SIGNOR-124330
P68400	Q13144	1	phosphorylation	up-regulates activity	0.386	Two conserved sites (Ser712/713) are phosphorylated by casein kinase 2. They lie at the extreme C-terminus and are required for the interaction of eIF2Bepsilon with its substrate, eIF2, in vivo and for eIF2B activity in vitro.	SIGNOR-250859
Q15831	O43524	0	transcriptional regulation	down-regulates quantity	0.634	SGK-1 Negatively Regulates LKB1 Expression via FOXO3 Transcription Factor	SIGNOR-255758
Q5T447	Q9H2D6	1	polyubiquitination	down-regulates quantity by destabilization	0.438	Here, we identify a novel Tara-binding protein HECTD3, a putative member of HECT E3 ubiquitin ligases. HECTD3 directly binds Tara in vitro and forms a complex with Tara in vivo. Overexpression of HECTD3 enhances the ubiquitination of Tara in vivo and promotes the turnover of Tara, whereas depletion of HECTD3 by small interfering RNA decreases Tara degradation.	SIGNOR-271770
O95405	Q15796	1	relocalization	up-regulates activity	0.908	Smad anchor for receptor activation (SARA) is known as Smad cofactor that interacts directly with Smad2/3 and functions to recruit Smad2/3 to the TGF-beta receptor.	SIGNOR-165786
Q9H6E5	P48729	0	phosphorylation	up-regulates activity	0.267	We identified a phosphorylated residue (serine 6, S6) on Star-PAP in the zinc finger region, the domain required for PIPKIα interaction. We show that S6 is phosphorylated by CKIα within the nucleus which is required for Star-PAP nuclear retention and interaction with PIPKIα.	SIGNOR-273619
P46531	P53350	0	phosphorylation	down-regulates quantity by destabilization	0.402	As shown in Fig. S4D, the C-terminal NOTCH1 fragment was readily phosphorylated by PLK1. Additionally, when the two putative phosphorylation sites, Ser-1791 and Ser-2349, were replaced by Ala, WT NOTCH1-IC but not the mutant was efficiently phosphorylated (Fig. S4E). We found that mutation of Ser-1791/2349 promotes NOTCH1-IC stabilization (Fig. S4F).	SIGNOR-277491
P98155	Q8WY64	0	ubiquitination	down-regulates quantity by destabilization	0.698	Here we demonstrate that Idol also targets two closely related LDLR family members, VLDLR and ApoE receptor 2 (ApoER2), proteins implicated in both neuronal development and lipid metabolism. Idol triggers ubiquitination of the VLDLR and ApoER2 on their cytoplasmic tails, leading to their degradation.	SIGNOR-271487
P48730	Q13315	0	phosphorylation	up-regulates activity	0.34	These results elucidated the specificity of this in vivo degradation assay, and further implicated that CKI\u03b4-dependent phosphorylation events is the major signaling route through which DNA damage-dependent activation of ATM might control timely turnover of Mdm2 during genotoxic stress. (A) ATM-mediated phosphorylation of CK1\u03b4 promotes CK1\u03b4 nuclear localization.\|We further demonstrated that DNA damage-induced activation of ATM directly phosphorylated CKI\u03b4 at two well-conserved S/TQ sites, which promotes CKI\u03b4 nuclear localization to increase CKI\u03b4-mediated phosphorylation of Mdm2, thereby facilitating subsequent Mdm2 ubiquitination by SCF\u03b2-TRCP.	SIGNOR-279504
Q16665	P15692	1	transcriptional regulation	up-regulates quantity	0.773	Transcription of the human erythropoietin (EPO) gene is activated in Hep3B cells exposed to hypoxia. Hypoxia-inducible factor 1 (HIF-1) is a nuclear factor whose DNA binding activity is induced by hypoxia in Hep3B cells, and HIF-1 binds at a site in the EPO gene enhancer that is required for hypoxic activation of transcription.	SIGNOR-256592
Q99814	O60341	1	transcriptional regulation	down-regulates quantity by repression	0.28	To this end, we confirm that KDM3A, KDM4B, KDM4C, KDM5B, KDM5C, and KDM62 are direct targets of HIF-1a while extent the list of known targets to KDM2A, KDM2B, KDM4D, KDM5A, and KDM6A. The results demonstrated that majority of the KDMs were similarly induced (KDM2A, KDM2B, KDM3A, KDM4B, KDM4C, KDM4D, KDM5A, KDM5B, KDM5C, KDM6B, and KDM7A) or repressed (KDM NO66 and KDM1A) by both HIF-1a and HIF-2a.	SIGNOR-271588
P17252	P09758	1	phosphorylation	down-regulates activity	0.2	Analyses using HCT116 cells expressing WT Trop-2 (HCT116/WT) or Trop-2 alanine-substituted at Ser-303 (HCT116/S303A) or Ser-322 (HCT116/S322A) revealed that Trop-2 is phosphorylated at Ser-322. sing protein kinase C (PKC) inhibitors and PKC-specific siRNAs, we found that PKCα and PKCδ are responsible for Trop-2 phosphorylation.	SIGNOR-273821
P52945	O43791	0	ubiquitination	down-regulates quantity	0.326	Pdx1 C terminus-interacting factor-1 (Pcif1, also known as SPOP) is a nuclear protein that inhibits Pdx1 transactivation. Here, we show that Pcif1 targets Pdx1 for ubiquitination and proteasomal degradation.	SIGNOR-268859
Q13501	P48729	0	phosphorylation	up-regulates activity	0.391	Mechanistically, CSNK1A1 interacted with STING1 upon the CGAS-STING1 pathway activation and promoted STING1 autophagic degradation by enhancing the phosphorylation of SQSTM1/p62 at serine 351 (serine 349 in human), which was critical for SQSTM1-mediated STING1 autophagic degradation.	SIGNOR-273769
P52630	P49840	0	phosphorylation	down-regulates quantity by destabilization	0.263	GSK3α/β are critical kinases to regulate STAT2 protein stability mediated by FBXW7.The 4-point mutant (STAT2-4A) of STAT2 at S381A/T385A/E389A/S393A inhibited GSK3α/β-mediated STAT2 phosphorylation.	SIGNOR-276761
P29972	P17252	0	phosphorylation	up-regulates	0.2	Activation of protein kinase c (pkc) by 1-oleoyl-2-acetyl-sn-glycerol (oag) induced a marked increase of aqp1-dependent water permeability. This regulation was abolished in mutated aqp1 channels lacking both consensus pkc phosphorylation sites thr(157) and thr(239) (termed aqp1 deltapkc).	SIGNOR-155106
Q7Z434	Q96J02	0	ubiquitination	down-regulates quantity by destabilization	0.646	These data collectively indicate that AIP4 is the E3 ligase for MAVS.\|We generated single substitutions (K362A, K371A or K420A) and combined point substitutions of MAVS and tested their degradation. K371A or K420A MAVS showed partial resistance to PCBP2-induced degradation (data not shown), whereas MAVS with the combined substitutions K371A and K420A (KK-AA) completely withstood the degradation	SIGNOR-260362
Q9NR80	P61586	1	guanine nucleotide exchange factor	up-regulates activity	0.667	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-260531
P42345	Q15349	1	phosphorylation	up-regulates activity	0.392	Subsequently, mTOR phosphorylates and activates the 70-kDa ribosomal protein S6 kinase (p70S6K), which results in increased translation either directly or indirectly by activating initiation and elongation factors, eIF-2, eIF-4E (through 4E-BP) and eEF-2 (Bodine et al. xref	SIGNOR-279232
P48454	Q13469	1	dephosphorylation	up-regulates activity	0.408	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-248512
P42229	P23470	0	dephosphorylation	up-regulates activity	0.265	PTPRG activation by the P1-WD peptide affected the tyrosine phosphorylation of several signaling molecules. Data analysis identified 31 molecules whose phosphorylation was modified in a statistically significant manner (Table I). inhibition of ABL1, BMX, BTK, DAB1, ITGB1, JAK2, KDR, KIT, LIMK1, MET, PDGFRB, SHC1, and VCL correlates with tyrosine dephosphorylation. In contrast, SRC inhibition correlates with hyperphosphorylation of the inhibitory Tyr530 residue and with dephosphorylation of the activatory Tyr419. Moreover, CDK2 and CTTN inhibition correlates with a hyperphosphorylation of the inhibitory Tyr15 and Tyr470, respectively. In contrast, a subgroup of 13 proteins, including BLNK, DOK2, ERBB2, GRIN2B, INSR, PDGFRA, PRKCD, PXN, STAT1, STAT2, STAT3, STAT5A, and ZAP70, appears to be activated by PTPRG activity.	SIGNOR-254730
P49768	P42574	0	cleavage	up-regulates activity	0.454	Remarkably, the caspases acting on PS1 could be subdivided in two groups. One group, containing caspase-8, -6 and -11, cleaved PS1 after residues ENDD329 and to a lesser extent after residues AQRD341. A second group consisting of caspase-3, -7 and -1 acted uniquely on AQRD341. Importantly, these two cleavage sites were also recognized by caspases in the C-terminal PS1 fragment produced by constitutive proteolysis.	SIGNOR-261756
P28482	P36507	0	phosphorylation	up-regulates	0.744	Mapk1 is phosphorylated by map2k1/mek1 and map2k2/mek2 on thr-185 and tyr-187 in response to external stimuli like insulin or ngf. Both phosphorylations are required for activity.	SIGNOR-86709
P84022	P24941	0	phosphorylation	down-regulates activity	0.743	In the nucleus cdk2/4-mediated phosphorylation of smad3 occurs mostly at thr8, thr179, and ser213. Cdk-dependent phosphorylation of smad3 inhibits its transcriptional activity	SIGNOR-182971
P51812	P19634	1	phosphorylation	up-regulates activity	0.414	In pressured arteries, RSK2 dependent activation of NHE-1 was associated with increased intracellular Ca 2+ transients, which would be expected to increase MLCK activity, thereby contributing to basal tone and myogenic responses.\|Together, these data indicate that Ser 703 in NHE-1 is phosphorylated by RSK2, that RSK2 is associated with NHE-1, and that the time course of NHE-1 phosphorylation in response to intraluminal pressure is fast enough for this phosphorylation event to contribute to myogenic vasoconstriction.	SIGNOR-280119
P17535	P15407	1	transcriptional regulation	up-regulates quantity by expression	0.817	Members of the AP1 family distinctly regulated the fra-1 promoter. In particular, coexpression of c-Jun, Jun-D, and Fra-2 up-regulated fra-1 transcription.	SIGNOR-261603
Q9Y5S9	Q96SB4	0	phosphorylation	down-regulates	0.261	We demonstrate that y14 is phosphorylated at its repeated arginine/serine (rs) dipeptides, likely by sr protein-specific kinases. Phosphorylation of y14 abolished its interaction with ejc components as well as factors that function downstream of the ejc.	SIGNOR-139555

P27361

Q15797

1

phosphorylation

down-regulates

0.528

Ras signaling was shown previously to induce the phosphorylation of the bmp mediator smad1 at four erk consensus sites in the linker domain (kretzschmar et al. 1997a). Phosphorylation of these four sites inhibits smad1 accumulation in the nucleus

SIGNOR-66755

Q15797

Q8N4C8

0

phosphorylation

down-regulates activity

0.2

Msn kinases directly phosphorylate α-helix 1 of Smad. we have identified Misshapen (Msn) and the mammalian orthologs TNIK, MINK1, and MAP4K4 as the kinases responsible for α-helix 1 phosphorylation.

SIGNOR-276336

Q13131

O14929

1

phosphorylation

up-regulates activity

0.2

Together, these results indicate that AMPK phosphorylated DNMT1-Ser730, RBBP7-Ser314, and HAT1-Ser190|AMPK increased HAT1 activity through phosphorylation of HAT1-Ser190 and RBBP7-Ser314

SIGNOR-264782

P53671

O43791

1

phosphorylation

down-regulates activity

0.2

LIMK2 phosphorylates SPOP at S59, S171 and S226.|Together, these results depict that LIMK2-mediated SPOP degradation is a key mechanism that regulates AR stability.

SIGNOR-278338

Q01094

O96017

0

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

P07900

P05129

0

phosphorylation

down-regulates

0.258

Threonine residue set, thr(115)/thr(425)/thr(603), of hsp90_ is specifically phosphorylated by pkc_phosphorylation of hsp90_ by pkc_ decreases the binding affinity of hsp90_ towards atp and co-chaperones such as cdc37 (cell-division cycle 37), thereby decreasing its chaperone activity.

SIGNOR-202812

P31749

Q6A1A2

0

phosphorylation

up-regulates

0.2

Akt to the plasma membrane where it is phosphorylated and activated by phosphoinositide-dependent kinase (pdk) 1 and pdk2.

SIGNOR-252628

P19784

P41236

1

phosphorylation

up-regulates activity

0.307

Recombinant wild-type I-2 and the Ala-120/121 mutant were phosphorylated synergistically by GSK-3 and casein kinase II. The Thr-72 and Ser-86 mutants, however, did not undergo this synergistic phosphorylation. Our studies indicate that Thr-72 is the only GSK-3 site and that Ser-86 is the casein kinase II site required for the potentiation of GSK-3 action.

SIGNOR-251021

Q96J02

O15519

1

ubiquitination

down-regulates quantity

0.614

Depends on JNK-mediated phosphorylation and activation of the E3 ubiquitin ligase Itch, which specifically ubiquitinates c-FLIP and induces its proteasomal degradation.

SIGNOR-245307

P28482

Q9NQ66

1

phosphorylation

up-regulates activity

0.398

coimmunoprecipitation detected a specific association between the activated erk and plc beta1 within the nucleus. In vitro studies revealed that recombinant plc beta1 could be efficiently phosphorylated by activated mitogen-activated protein kinase but not by pka. The erk phosphorylation site was mapped to serine 982 this result suggests that erk-evoked phosphorylation of plc beta1 at serine 982 plays a critical role in the activation of the nuclear pi cycle and is also crucial to the mitogenic action of igf-i.

SIGNOR-106561

P10275

Q13043

0

phosphorylation

down-regulates activity

0.2

Here we showed that MST1 is an androgen receptor kinase and phosphorylates androgen receptor at Ser-650 ( ).|Mst1 plays a critical role in the regulation of programmed cell death and it has been implicated in PCa development. Interestingly, MST1 has been detected in AR-chromatin complexes, and forced expression of MST1 reduces AR binding to androgen-responsive elements along the PSA promoter.

SIGNOR-280143

P14416

P43250

0

phosphorylation

down-regulates activity

0.447

GRK6 is located predominantly in dopaminergic neurons [ xref ] and functionally phosphorylates DRD2.

SIGNOR-279046

Q9GZV5

P49674

0

phosphorylation

down-regulates

0.366

LATS1/2-mediated phosphorylation of a conserved serine in this region (Ser311 in human TAZ; Ser397 in human YAP) primes for further phosphorylation by CK1_/_ kinases (Ser314 on human TAZ; Ser400/403 in human YAP)

SIGNOR-230747

P18858

P06493

0

phosphorylation

up-regulates activity

0.364

We show that three residues (ser51, ser76, and ser91), which are part of cyclin-dependent kinase sites, are phosphorylated in a cell cycle-dependent manner.

SIGNOR-103242

P51955

Q9UMX1

1

phosphorylation

up-regulates activity

0.2

Intriguingly, Nek2A is found to stabilize SuFu at least partly depending on its kinase activity, thereby triggering phosphorylation of the SuFu protein.|Nek2A phosphorylates and stabilizes SuFu: A new strategy of Gli2/Hedgehog signaling regulatory mechanism.

SIGNOR-279235

P17600

Q13131

0

phosphorylation

down-regulates activity

0.2

It has been reported that site 1 of syn i can be phosphorylated by pka. Pka-mediated synapsin i ser9 phosphorylation occurs in response to cgs 21680 treatment. Results show that the adenosine a2a receptor agonist, cgs 21680, increases neurotransmitter release, in particular, glutamate and noradrenaline and such response is mediated by protein kinase a activation, which in turn increased synapsin i phosphorylation

SIGNOR-78891

Q13315

P15374

1

phosphorylation

up-regulates activity

0.331

Mechanistically, in response to DNA damage, the deubiquitinase UCHL3 is phosphorylated and activated by ATM.

SIGNOR-279794

Q96RR4

Q16566

1

phosphorylation

up-regulates activity

0.62

Phosphorylation and activation of Ca(2+)-calmodulin-dependent protein kinase IV by Ca(2+)-calmodulin-dependent protein kinase Ia kinase. Phosphorylation of threonine 196 is essential for activation.

SIGNOR-250718

P55085

P24158

0

cleavage

down-regulates activity

0.373

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-263601

Q13191

P43405

1

ubiquitination

down-regulates quantity

0.696

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

SIGNOR-278754

Q9UNE7

P06730

1

ubiquitination

down-regulates quantity by destabilization

0.332

This collaborative activity of cIAP1 and CHIP directs eIF4E toward degradation, controlling its levels and suppressing tumorigenesis.|We next sought to investigate whether eIF4E ubiquitination is enhanced by the collaborative activity of cIAP1 and CHIP, which we define as both the E3 ligase activity of cIAP1 alone and the E3 ligase activity of cIAP1 and CHIP together.

SIGNOR-278669

P60709

Q9NZI8

0

post transcriptional regulation

up-regulates quantity

0.34

We found that ZBP1 is necessary for netrin-1 stimulated local translation of β-actin mRNA in axonal growth cones. ZBP1 binds to β-actin mRNA in the soma and transports it to the growth cone on microtubules.

SIGNOR-268160

P53667

Q5VT25

0

phosphorylation

up-regulates activity

0.404

Activation of LIM kinases by myotonic dystrophy kinase-related Cdc42-binding kinase alpha. \ In vitro, MRCKalpha phosphorylated the protein kinase domain of LIM kinases, and the site in LIMK2 phosphorylated by MRCKalpha proved to be threonine 505 within the activation segment.

SIGNOR-250721

P42224

P23458

0

phosphorylation

up-regulates activity

0.79

The central event in cytokine_dependent transcriptional regulation is phosphorylation of STATs on a single tyrosine residue at their C_terminus (Darnell, 1997b). The reaction is catalyzed by cytokine receptor_associated tyrosine kinases of the Janus type (Jak) at the cell membrane and triggers the homo_ and heterodimerization of STAT molecules via reciprocal phosphotyrosineSH2 domain interactions

SIGNOR-236373

Q86UE8

O14757

0

phosphorylation

down-regulates activity

0.269

Chk1 phosphorylates GST-fusion fragments of TLK1 in vitro.When Chk1 protein was depleted in cells transfected with pSuper-Chk1, TLK activity was not suppressed after short aphidicolin treatment of S-phase cells (Figure 8a, b).

SIGNOR-262740

O60341

P68400

0

phosphorylation

up-regulates activity

0.318

We demonstrated here that phosphorylation and dephosphorylation of LSD1 at S131 and S137 was mediated by casein kinase 2 (CK2) and wild-type p53-induced phosphatase 1 (WIP1), respectively. LSD1, RNF168 and 53BP1 interacted with each other directly. CK2-mediated phosphorylation of LSD1 exhibited no impact on its interaction with 53BP1, but promoted its interaction with RNF168 and RNF168-dependent 53BP1 ubiquitination and subsequent recruitment to the DNA damage sites.

SIGNOR-276903

Q96T88

Q5UIP0

1

polyubiquitination

down-regulates activity

0.2

UHRF1 mediates K63-linked polyubiquitination of RIF1, and results in its dissociation from 53BP1 and DSBs thereby facilitating HR initiation.

SIGNOR-277193

Q5T9L3

P56704

1

relocalization

up-regulates activity

0.641

WNT secretion requires its binding to the carrier protein wntless (WLS);

SIGNOR-256599

O43318

P22607

0

phosphorylation

up-regulates activity

0.293

Indeed, we found that TAK1 was tyrosine phosphorylated in HEK293 cells transiently expressing constitutively active FGFR3 (K650E), but not the kinase-dead receptor (K508M), indicating that activated FGFR3 can either directly or indirectly tyrosine phosphorylate TAK1 (XREF_FIG).

SIGNOR-279176

P17612

P10276

1

phosphorylation

down-regulates activity

0.405

Mutagenesis of serine 219 (S219) and S369 at the PKA sites on RARA to either double alanines or double glutamic acids showed that both PKA sites are important for RARA activity.

SIGNOR-276281

P38936

P16885

0

phosphorylation

up-regulates quantity by stabilization

0.2

Phosphorylation at Ser-146 by PKCδ increases p21 stability

SIGNOR-262963

P17612

P35236

1

phosphorylation

down-regulates

0.361

B2 adrenergic receptor stimulation induces the pka dependent phosphorylation of heptp and releases bound p38 mapk

SIGNOR-182522

P04637

Q9H4B4

0

phosphorylation

up-regulates activity

0.706

Upon exposure of cells to hydrogen peroxide (h(2)o(2)) phosphorylation of p53 was rapidly induced in human fibroblast gm00637, and this phosphorylation occurred on serine 9, serine 15, serine 20, but not on serine 392. In addition, h(2)o(2)-induced phosphorylation of p53 was followed by induction of p21, suggesting functional activation of p53. Ectopic expression of a plk3 dominant negative mutant, plk3(k52r), in gm00637 cells suppressed h(2)o(2)-induced serine 20 phosphorylation. Taken together, our studies strongly suggest that the oxidative stress-induced activation of p53 is at least in part mediated by plk3.

SIGNOR-109239

P12931

Q9NZC7

1

phosphorylation

up-regulates

0.48

The tyrosine kinase, src, phosphorylates wwox at tyrosine 33 in the first ww domain and enhances its binding to p73.

SIGNOR-123819

O95997

Q9UQM7

0

phosphorylation

down-regulates quantity by destabilization

0.309

CaMKII phosphorylates securin at PP2A substrate site(s).Securin is destabilized by phosphorylation and stabilized by PP2A-dependent dephosphorylation on separase

SIGNOR-276381

Q14995

O00327

1

transcriptional regulation

down-regulates quantity by repression

0.467

A retinoic acid receptor-related orphan receptor (ROR) response element within the BMAL1 promoter is responsive to both ROR and REV-ERB (encoded by the genes NR1D1 and NR1D2); ROR activates the transcription of BMAL1, whereas REV-ERB suppresses its transcription.

SIGNOR-268006

P19484

P16298

0

dephosphorylation

up-regulates activity

0.377

Lysosomal Ca2+ release via mucolipin 1 (MCOLN1) activates calcineurin, which binds and de-phosphorylates TFEB, thus promoting its nuclear translocation.

SIGNOR-255306

P21802

Q02156

0

phosphorylation

up-regulates

0.2

Phosphorylation of serine 779 in fibroblast growth factor receptor 1 and 2 by protein kinase c(epsilon) regulates ras/mitogen-activated protein kinase signaling and neuronal differentiation

SIGNOR-201675

Q13501

Q05655

0

phosphorylation

up-regulates activity

0.367

Data presented here suggested that Vps34 stimulates tumor development mainly through PKC-\u03b4- activation of p62.|In conclusion, elevation of Vps34 results in tumor progression via the PKC-\u03b4-phosphorylation of p62 at S349 and PKC-\u03b4 involved phosphorylation of Raf 1 at Y340/341.|Vps34 induces PKC-\u03b4-dependent phosphorylation of p62.

SIGNOR-280086

P11309

P61073

1

phosphorylation

up-regulates quantity

0.365

Pim-1 and Pim-3 enhance phosphorylation and cell surface expression of CXCR4.|When the in vitro phosphorylated fragments were detected with the anti-phospho (Ser339)-CXCR4 antibody, it became evident that both Pim-1 and Pim-3, but not Pim-2 can phosphorylate CXCR4 on Ser339 (XREF_FIG).

SIGNOR-278450

Q13085

P60510

0

dephosphorylation

up-regulates activity

0.242

PP4 was also found to directly interact with pACC1‑Ser79 in human HepG2 cells. In conclusion, the present study showed that PP4 may be a novel regulator in hepatic lipogenesis through dephosphorylating ACC1 on serine 79, suggesting that PP4 may be a promising therapeutic target in lipid metabolism disorders.

SIGNOR-267724

Q9UQM7

P14136

1

phosphorylation

down-regulates activity

0.427

On the other hand, GFAP was phosphorylated to approximately 1.9 mol of phosphate/mol of GFAP by Ca(2+)-CaM-dependent protein kinase II, and this phosphorylation did induce disassembly of the filament. Sequential analysis of the purified phosphopeptides revealed that only Ser8 on GFAP was phosphorylated by cdc2 kinase, whereas Ser13, Ser17, Ser34, and Ser389 on GFAP were phosphorylated by Ca(2+)-CaM-dependent protein kinase II.

SIGNOR-250626

Q9BYP7

Q9UP95

1

phosphorylation

down-regulates activity

0.464

We have shown that with-no-lysine kinase 3 (WNK3) possesses several properties that suggest it could be the Cl−/volume-sensitive regulatory kinase that, in association with protein phosphatases, reciprocally modifies the phosphorylation/dephosphorylation states of the SLC12 proteins and thus their activities|WNK3 activates NKCC1/2 and NCC and inhibits the KCCs

SIGNOR-264627

Q92993

Q01130

1

acetylation

down-regulates

0.466

In this study, we provide the first evidence that the acetyltransferase tip60 acetylates srsf2 on its lysine 52 residue inside the rna recognition motif, and promotes its proteasomal degradation.

SIGNOR-170594

Q07817

O60260

0

ubiquitination

down-regulates quantity by destabilization

0.2

In cells, we found BCL-XL levels were reduced by overexpression of PARK2, but this catalytic activity was blocked by the proteasome inhibitor MG132, suggesting degradation of BCL-XL protein by PARK2 is dependent on the proteasome system (XREF_FIG A).|PARK2 directly binds to and ubiquitinates BCL-XL.

SIGNOR-278661

P23470

P53667

1

dephosphorylation

down-regulates activity

0.26

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

SIGNOR-254711

P05067

P53355

0

phosphorylation

up-regulates quantity

0.287

DAPK1, but not its kinase deficient mutant (K42A), significantly increased human AŒ≤ secretion in neuronal cell culture models. Moreover, knockdown of DAPK1 expression or inhibition of DAPK1 catalytic activity significantly decreased AŒ≤ secretion. Furthermore, DAPK1, but not K42A, triggered Thr668 phosphorylation of APP, which may initiate and facilitate amyloidogenic APP processing leading to the generation of AŒ≤.|Furthermore, DAPK1, but not K42A, triggered Thr668 phosphorylation of APP, which may initiate and facilitate amyloidogenic APP processing leading to the generation of Abeta.

SIGNOR-279518

P18433

Q14721

1

dephosphorylation

down-regulates

0.2

Ptpalpha inhibits kv channels more strongly than ptpepsilon;this correlates with constitutive association of ptpalpha with kv2.1, driven by membranal localization of ptpalpha.

SIGNOR-148301

Q9UGK3

O60674

0

phosphorylation

up-regulates activity

0.343

To examine this possibility, STAP-2 was co-transfected with constitutively active tyrosine kinases in HEK-293 cells. STAP-2 was strongly phosphorylated by various tyrosine kinases, including v-Src (Fig.2 A-a), a JAK2 tyrosine kinase |On the other hand, the phosphorylation levels of Y22F, Y310F, and Y322F by GST-JH1 were reduced to 8060% of the levels of wild-type STAP-2, which suggests that these three are potential phosphorylation sites by activated JAK2.

SIGNOR-249372

Q96EB6

Q09472

1

deacetylation

down-regulates

0.835

Sirt1 induces deacetylation and repression of p300 itself (81). Mutational analysis demonstrated that sirt1 repression of p300 involves both lysine 1020 and lysine 1024

SIGNOR-182511

O00750

P14373

0

ubiquitination

down-regulates

0.402

We now show that trim27 functions as an e3 ligase and mediates lysine 48 polyubiquitination of pi3kc2_, leading to a decrease in pi3k enzyme activity.

SIGNOR-177935

P61586

Q70Z35

0

guanine nucleotide exchange factor

up-regulates activity

0.406

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-260570

Q13535

P30307

1

phosphorylation

up-regulates activity

0.643

We also found that activated ATR phosphorylates CDC25C (Cell Division Cycle 25C) at serine 216, which in turn inactivates the cyclin B1/Cyclin-Dependent Kinase 1(CDK1) complex and induces G2-phase arrest.

SIGNOR-279008

P37231

P18146

0

transcriptional regulation

down-regulates quantity by repression

0.62

Previous studies have reported that the PPARγ proximal promoter contains an overlapping binding site for Egr-1, which is involved in the down-regulation of PPARγ. In the present study, we have provided direct evidence that leptin causes PPARγ reduction in primary cultured PASMC; this effect is coupled to leptin-induced ERK1/2 activation and subsequent induction of Egr-1, which further down-regulates PPARγ expression and results in PASMC proliferation. The present study confirmed that ERK1/2 signaling cascade mediated leptin-induced PPARγ reduction by up-regulation of Egr-1 in PASMC.

SIGNOR-263508

P06493

Q9Y2I6

1

phosphorylation

down-regulates quantity by destabilization

0.422

In this study, we show that Nlp can be phosphorylated by cell cycle protein kinase Cdc2/cyclin B1. The phosphorylation sites of Nlp are mapped at Ser185 and Ser589. the phosphorylation at the site Ser589 by Cdc2/cyclin B1 plays an important role in Nlp protein stability probably due to its effect on protein degradation.

SIGNOR-259831

P27361

Q15046

1

phosphorylation

up-regulates

0.2

Lysrs serves as a key signaling molecule in the immune response by regulating gene expression. Lysrs was phosphorylated on serine 207 in a mapk-dependent manner, released from the multisynthetase complex, and translocated into the nucleus.

SIGNOR-186125

Q9NRS4

P0DTC2

1

cleavage

up-regulates activity

0.2

TMPRSS2 and TMPRSS4 serine proteases mediate this process by inducing cleavage of the S protein and enhancing membrane fusion.

SIGNOR-262306

O95644

P27361

0

phosphorylation

down-regulates

0.532

We show that jnk, erk, and p38 physically associate with the nfatc n-terminal regulatory domain and can directly phosphorylate functionally important residues involved in regulating nfatc subcellular localization, namely ser(172) and the conserved nfatc ser-pro repeats.

SIGNOR-74564

Q9UGL1

P06493

0

phosphorylation

down-regulates activity

0.258

Phosphorylation of the histone demethylase KDM5B and regulation of the phenotype of triple negative breast cancer|Here, we demonstrate that KDM5B is phosphorylated at Ser1456 by the cyclin-dependent kinase 1 (CDK1). Phosphorylation of KDM5B at Ser1456 attenuated the occupancy of KDM5B on the promoters of pluripotency genes.

SIGNOR-273435

O43791

Q9UBN7

1

ubiquitination

down-regulates quantity

0.2

Cullin3 SPOP ubiquitin E3 ligase promotes the poly-ubiquitination and degradation of HDAC6

SIGNOR-268862

Q9BQ95

Q9Y4K3

0

ubiquitination

down-regulates activity

0.79

Here we demonstrate that engagement of a subset of Toll-like receptors (TLR1, TLR2 and TLR4) results in the recruitment of mitochondria to macrophage phagosomes and augments mROS production. This response involves translocation of a TLR signalling adaptor, tumour necrosis factor receptor-associated factor 6 (TRAF6), to mitochondria, where it engages the protein ECSIT (evolutionarily conserved signalling intermediate in Toll pathways), which is implicated in mitochondrial respiratory chain assembly. Interaction with TRAF6 leads to ECSIT ubiquitination and enrichment at the mitochondrial periphery, resulting in increased mitochondrial and cellular ROS generation

SIGNOR-260370

Q6PHR2

P10071

1

phosphorylation

up-regulates activity

0.561

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

SIGNOR-260799

P24666

P12931

1

dephosphorylation

up-regulates activity

0.438

LMWPTP dephosphorylated pY(527)-Src and pY(416)-Src in vitro, with greater specificity for pY(527)Src. Activation of LMWPTP produced strong activation of Src mediated by fast dephosphorylation of pY(527)-Src, followed by slower deactivation of this kinase via dephosphorylation of pY(416)Src.

SIGNOR-248454

Q9NVW2

P01106

1

ubiquitination

down-regulates quantity by destabilization

0.37

This suggests that RLIM negatively regulates the transcriptional activity of c-Myc.|We further showed that RLIM can promote polyubiquitination of c-Myc in cells.

SIGNOR-278551

Q07869

Q7LBC6

0

transcriptional regulation

up-regulates quantity by expression

0.2

We show that Jhdm2a expression is induced by beta-adrenergic stimulation, and that Jhdm2a directly regulates peroxisome proliferator-activated receptor alpha (Ppara) and Ucp1 expression.

SIGNOR-266637

P17252

P21731-2

1

phosphorylation

down-regulates activity

0.521

These data suggest a model whereby agonist-induced PKC phosphorylation of Ser(145) partially impairs TPbeta signalling while GRK2/3 phosphorylation at both Ser(239) and Ser(357) within its IC(3) and C-tail domains, respectively, sterically inhibits G-protein coupling, profoundly desensitizing signalling, and promotes beta-arrestin association and, in turn, facilitates TPbeta internalization.

SIGNOR-274092

Q99878

Q86Y13

0

monoubiquitination

up-regulates activity

0.2

2A-HUB catalyzes monoubiquitination of H2A at lysine 119, functioning as a combinatoric component of the repression machinery required for specific gene regulation programs. Thus, 2A-HUB mediates a selective repression of a specific set of chemokine genes in macrophages, critically modulating migratory responses to TLR activation. H2A monoubiquitination acts to prevent FACT recruitment at the transcriptional promoter region, blocking RNA polymerase II release at the early stage of elongation.

SIGNOR-271762

Q9UBN7

P49841

0

phosphorylation

up-regulates activity

0.381

GSK3beta was found to co-localize with HDAC6 in hippocampal neurons, and inhibition of GSK3beta resulted in decreased binding of antibody to phosphoserine-22, a potential GSK3beta phosphorylation site in HDAC6.|This suggests that GSK3\u03b2 may directly phosphorylate HDAC6 at this site, although further work with purified proteins is needed to determine whether this is the case.|The fact that HDAC6 is the predominant cytoplasmic deacetylase in neurons suggests that GSK3beta dependent phosphorylation may enhance HDAC6 activity, resulting in a decrease in acetylation of tubulin and an inhibition of both mitochondrial motility and the transport of other kinesin-1 dependent cargoes.

SIGNOR-278941

O00141

Q92542

1

phosphorylation

down-regulates quantity

0.337

Furthermore, SGK1 directly bound to and phosphorylated Nicastrin on Ser437, thereby promoting protein degradation.|We showed that SGK1 downregulates Nicastrin protein levels.

SIGNOR-280122

P09917

P49137

0

phosphorylation

up-regulates activity

0.546

Arachidonic acid promotes phosphorylation of 5-lipoxygenase at Ser-271 by MAPK-activated protein kinase 2 (MK2). when stimulated with only exogenous arachidonic acid, activity for the S271A mutant was significantly lower as compared with wild type 5-LO.

SIGNOR-250143

P15311

P25098

0

phosphorylation

up-regulates

0.2

Grk2 phosphorylates glutathione s-transferase (gst)-ezrin, but not an ezrin fusion protein lacking threonine 567 (t567), in vitro. These results suggest that t567, the regulatory phosphorylation site responsible for maintaining ezrin in its active conformation, represents the principle site of grk2-mediated phosphorylation.

SIGNOR-135622

Q12913

P28482

1

dephosphorylation

down-regulates

0.406

In this study we show that one of these potential targets, the erk1/2, is indeed a direct dep-1 substrate in vivo.

SIGNOR-161536

O43474

P42226

0

transcriptional regulation

up-regulates quantity by expression

0.345

STAT6 coordinates and synergizes with both PPAR? and Krppel-like factor 4 (KLF4), a member of a family of proteins that contribute to macrophage function.

SIGNOR-249568

P15336

Q99986

0

phosphorylation

up-regulates

0.371

Vrk1 phosphorylates atf2 mainly on thr-73, stabilizing the atf2 protein and increasing its intracellular level.

SIGNOR-124330

P68400

Q13144

1

phosphorylation

up-regulates activity

0.386

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

SIGNOR-250859

Q15831

O43524

0

transcriptional regulation

down-regulates quantity

0.634

SGK-1 Negatively Regulates LKB1 Expression via FOXO3 Transcription Factor

SIGNOR-255758

Q5T447

Q9H2D6

1

polyubiquitination

down-regulates quantity by destabilization

0.438

Here, we identify a novel Tara-binding protein HECTD3, a putative member of HECT E3 ubiquitin ligases. HECTD3 directly binds Tara in vitro and forms a complex with Tara in vivo. Overexpression of HECTD3 enhances the ubiquitination of Tara in vivo and promotes the turnover of Tara, whereas depletion of HECTD3 by small interfering RNA decreases Tara degradation.

SIGNOR-271770

O95405

Q15796

1

relocalization

up-regulates activity

0.908

Smad anchor for receptor activation (SARA) is known as Smad cofactor that interacts directly with Smad2/3 and functions to recruit Smad2/3 to the TGF-beta receptor.

SIGNOR-165786

Q9H6E5

P48729

0

phosphorylation

up-regulates activity

0.267

We identified a phosphorylated residue (serine 6, S6) on Star-PAP in the zinc finger region, the domain required for PIPKIα interaction. We show that S6 is phosphorylated by CKIα within the nucleus which is required for Star-PAP nuclear retention and interaction with PIPKIα.

SIGNOR-273619

P46531

P53350

0

phosphorylation

down-regulates quantity by destabilization

0.402

As shown in Fig. S4D, the C-terminal NOTCH1 fragment was readily phosphorylated by PLK1. Additionally, when the two putative phosphorylation sites, Ser-1791 and Ser-2349, were replaced by Ala, WT NOTCH1-IC but not the mutant was efficiently phosphorylated (Fig. S4E). We found that mutation of Ser-1791/2349 promotes NOTCH1-IC stabilization (Fig. S4F).

SIGNOR-277491

P98155

Q8WY64

0

ubiquitination

down-regulates quantity by destabilization

0.698

Here we demonstrate that Idol also targets two closely related LDLR family members, VLDLR and ApoE receptor 2 (ApoER2), proteins implicated in both neuronal development and lipid metabolism. Idol triggers ubiquitination of the VLDLR and ApoER2 on their cytoplasmic tails, leading to their degradation.

SIGNOR-271487

P48730

Q13315

0

phosphorylation

up-regulates activity

0.34

These results elucidated the specificity of this in vivo degradation assay, and further implicated that CKI\u03b4-dependent phosphorylation events is the major signaling route through which DNA damage-dependent activation of ATM might control timely turnover of Mdm2 during genotoxic stress. (A) ATM-mediated phosphorylation of CK1\u03b4 promotes CK1\u03b4 nuclear localization.|We further demonstrated that DNA damage-induced activation of ATM directly phosphorylated CKI\u03b4 at two well-conserved S/TQ sites, which promotes CKI\u03b4 nuclear localization to increase CKI\u03b4-mediated phosphorylation of Mdm2, thereby facilitating subsequent Mdm2 ubiquitination by SCF\u03b2-TRCP.

SIGNOR-279504

Q16665

P15692

1

transcriptional regulation

up-regulates quantity

0.773

Transcription of the human erythropoietin (EPO) gene is activated in Hep3B cells exposed to hypoxia. Hypoxia-inducible factor 1 (HIF-1) is a nuclear factor whose DNA binding activity is induced by hypoxia in Hep3B cells, and HIF-1 binds at a site in the EPO gene enhancer that is required for hypoxic activation of transcription.

SIGNOR-256592

Q99814

O60341

1

transcriptional regulation

down-regulates quantity by repression

0.28

To this end, we confirm that KDM3A, KDM4B, KDM4C, KDM5B, KDM5C, and KDM62 are direct targets of HIF-1a while extent the list of known targets to KDM2A, KDM2B, KDM4D, KDM5A, and KDM6A. The results demonstrated that majority of the KDMs were similarly induced (KDM2A, KDM2B, KDM3A, KDM4B, KDM4C, KDM4D, KDM5A, KDM5B, KDM5C, KDM6B, and KDM7A) or repressed (KDM NO66 and KDM1A) by both HIF-1a and HIF-2a.

SIGNOR-271588

P17252

P09758

1

phosphorylation

down-regulates activity

0.2

Analyses using HCT116 cells expressing WT Trop-2 (HCT116/WT) or Trop-2 alanine-substituted at Ser-303 (HCT116/S303A) or Ser-322 (HCT116/S322A) revealed that Trop-2 is phosphorylated at Ser-322. sing protein kinase C (PKC) inhibitors and PKC-specific siRNAs, we found that PKCα and PKCδ are responsible for Trop-2 phosphorylation.

SIGNOR-273821

P52945

O43791

0

ubiquitination

down-regulates quantity

0.326

Pdx1 C terminus-interacting factor-1 (Pcif1, also known as SPOP) is a nuclear protein that inhibits Pdx1 transactivation. Here, we show that Pcif1 targets Pdx1 for ubiquitination and proteasomal degradation.

SIGNOR-268859

Q13501

P48729

0

phosphorylation

up-regulates activity

0.391

Mechanistically, CSNK1A1 interacted with STING1 upon the CGAS-STING1 pathway activation and promoted STING1 autophagic degradation by enhancing the phosphorylation of SQSTM1/p62 at serine 351 (serine 349 in human), which was critical for SQSTM1-mediated STING1 autophagic degradation.

SIGNOR-273769

P52630

P49840

0

phosphorylation

down-regulates quantity by destabilization

0.263

GSK3α/β are critical kinases to regulate STAT2 protein stability mediated by FBXW7.The 4-point mutant (STAT2-4A) of STAT2 at S381A/T385A/E389A/S393A inhibited GSK3α/β-mediated STAT2 phosphorylation.

SIGNOR-276761

P29972

P17252

0

phosphorylation

up-regulates

0.2

Activation of protein kinase c (pkc) by 1-oleoyl-2-acetyl-sn-glycerol (oag) induced a marked increase of aqp1-dependent water permeability. This regulation was abolished in mutated aqp1 channels lacking both consensus pkc phosphorylation sites thr(157) and thr(239) (termed aqp1 deltapkc).

SIGNOR-155106

Q7Z434

Q96J02

0

ubiquitination

down-regulates quantity by destabilization

0.646

These data collectively indicate that AIP4 is the E3 ligase for MAVS.|We generated single substitutions (K362A, K371A or K420A) and combined point substitutions of MAVS and tested their degradation. K371A or K420A MAVS showed partial resistance to PCBP2-induced degradation (data not shown), whereas MAVS with the combined substitutions K371A and K420A (KK-AA) completely withstood the degradation

SIGNOR-260362

Q9NR80

P61586

1

guanine nucleotide exchange factor

up-regulates activity

0.667

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-260531

P42345

Q15349

1

phosphorylation

up-regulates activity

0.392

Subsequently, mTOR phosphorylates and activates the 70-kDa ribosomal protein S6 kinase (p70S6K), which results in increased translation either directly or indirectly by activating initiation and elongation factors, eIF-2, eIF-4E (through 4E-BP) and eEF-2 (Bodine et al. xref

SIGNOR-279232

P48454

Q13469

1

dephosphorylation

up-regulates activity

0.408

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-248512

P42229

P23470

0

dephosphorylation

up-regulates activity

0.265

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

SIGNOR-254730

P49768

P42574

0

cleavage

up-regulates activity

0.454

Remarkably, the caspases acting on PS1 could be subdivided in two groups. One group, containing caspase-8, -6 and -11, cleaved PS1 after residues ENDD329 and to a lesser extent after residues AQRD341. A second group consisting of caspase-3, -7 and -1 acted uniquely on AQRD341. Importantly, these two cleavage sites were also recognized by caspases in the C-terminal PS1 fragment produced by constitutive proteolysis.

SIGNOR-261756

P28482

P36507

0

phosphorylation

up-regulates

0.744

Mapk1 is phosphorylated by map2k1/mek1 and map2k2/mek2 on thr-185 and tyr-187 in response to external stimuli like insulin or ngf. Both phosphorylations are required for activity.

SIGNOR-86709

P84022

P24941

0

phosphorylation

down-regulates activity

0.743

In the nucleus cdk2/4-mediated phosphorylation of smad3 occurs mostly at thr8, thr179, and ser213. Cdk-dependent phosphorylation of smad3 inhibits its transcriptional activity

SIGNOR-182971

P51812

P19634

1

phosphorylation

up-regulates activity

0.414

In pressured arteries, RSK2 dependent activation of NHE-1 was associated with increased intracellular Ca 2+ transients, which would be expected to increase MLCK activity, thereby contributing to basal tone and myogenic responses.|Together, these data indicate that Ser 703 in NHE-1 is phosphorylated by RSK2, that RSK2 is associated with NHE-1, and that the time course of NHE-1 phosphorylation in response to intraluminal pressure is fast enough for this phosphorylation event to contribute to myogenic vasoconstriction.

SIGNOR-280119

P17535

P15407

1

transcriptional regulation

up-regulates quantity by expression

0.817

Members of the AP1 family distinctly regulated the fra-1 promoter. In particular, coexpression of c-Jun, Jun-D, and Fra-2 up-regulated fra-1 transcription.

SIGNOR-261603

Q9Y5S9

Q96SB4

0

phosphorylation

down-regulates

0.261

We demonstrate that y14 is phosphorylated at its repeated arginine/serine (rs) dipeptides, likely by sr protein-specific kinases. Phosphorylation of y14 abolished its interaction with ejc components as well as factors that function downstream of the ejc.

SIGNOR-139555