GleghornLab/Signor_2class · Datasets at Hugging Face

IdA string	IdB string	labels int64	mechanism string	effect string	score float64	sentence string	signor_id string
P48023	O43638	0	transcriptional regulation	down-regulates quantity by repression	0.2	As we expected, Fkhl18 suppressed, dose-dependently,human and mouseFasLpromoter in bovine vascularsmooth muscle cells	SIGNOR-261612
Q92630	Q14195	1	phosphorylation	up-regulates activity	0.364	Together, these results suggest that crmp4 is able to increase neurite formation and elongation in neurons, although not as potently as crmp2, and that this process is regulated by ser522/ser518/thr514/thr509 phosphorylation in both cases. We demonstrate that cdk5 primes crmp2 and crmp4 for subsequent phosphorylation by gsk3, whereas dyrk2, phosphorylates and primes only crmp4 in vitro	SIGNOR-145987
Q96MT3	Q8N4C8	0	phosphorylation	up-regulates activity	0.293	We show that Mink1 phosphorylates Prickle on a conserved threonine residue and regulates its Rab5-dependent endosomal trafficking, a process required for the localized plasma membrane accumulation and function of Prickle.	SIGNOR-263095
Q13131	Q53ET0	1	phosphorylation	down-regulates	0.544	Collectively, these findings suggest ampk suppresses glucose production through two transcriptional effects:reduced expression of creb targets via crtc inactivation and reduced expression of foxo target genes via class iia hdac inactivation	SIGNOR-176426
Q6PIY7	P22612	0	phosphorylation	down-regulates activity	0.2	We found that Gld2 activity is regulated by site-specific phosphorylation in its disordered N-terminal domain. We identified two phosphorylation sites (S62, S110) where phosphomimetic substitutions increased Gld2 activity and one site (S116) that markedly reduced activity. Using mass spectrometry, we confirmed that HEK 293 cells readily phosphorylate the N-terminus of Gld2. We identified protein kinase A (PKA) and protein kinase B (Akt1) as the kinases that site-specifically phosphorylate Gld2 at S116, abolishing Gld2-mediated nucleotide addition.	SIGNOR-259404
Q86YJ5	Q96LA5	1	ubiquitination	down-regulates quantity by destabilization	0.2	MARCH9, a member of the RING-CH family of transmembrane E3 ubiquitin ligases, down-regulates CD4, major histocompatibility complex-I (MHC), and ICAM-1 in lymphoid cells. To identify novel MARCH9 substrates, we used high throughput flow cytometry and quantitative mass spectrometry by stable isotope labeling by amino acids in cell culture (SILAC) to determine the differential expression of plasma membrane proteins in a MARCH9-expressing B cell line. This combined approach identified 13 potential new MARCH9 targets.	SIGNOR-271543
O43474	P53350	0	phosphorylation	up-regulates quantity by stabilization	0.249	We further found that inhibition of polo-like kinase 1 could downregulate the expression of KLF4 and that PLK1 directly phosphorylated KLF4 at Ser234. Notably, phosphorylation of KLF4 by PLK1 caused the recruitment and binding of the E3 ligase TRAF6, which resulted in KLF4 K32 K63-linked ubiquitination and stabilization.	SIGNOR-277463
P17655	P12931	0	phosphorylation	up-regulates activity	0.525	CAPN2 itself was a bone fide substrate of SRC that was primarily phosphorylated at Y625 by SRC and exhibited increased proteolysis activity upon phosphorylation.	SIGNOR-277598
P12931	P41743	1	phosphorylation	up-regulates	0.533	Nerve growth factor stimulates multisite tyrosine phosphorylation and activation of the atypical protein kinase c's via a src kinase pathway. tyrosine 256, 271, and 325 were identified as major sites phosphorylated by src in the catalytic domain.	SIGNOR-111920
Q14457	P00533	0	phosphorylation	down-regulates activity	0.521	The mechanism by which EGFR suppresses Beclin 1 function involves EGFR interaction with two domains (BH3 and ECD) of Beclin 1; EGFR mediated multisite tyrosine phosphorylation of Beclin 1 on residues Y229, Y233 and Y352; and EGFR mediated alterations in the Beclin 1 interactome (increased binding to the negative regulators, Bcl-2 and Rubicon, and decreased binding to the VPS34 lipid kinase).\|Thus, EGFR signaling suppresses autophagy via its interaction with Beclin 1 during normal mitogenic signaling as well as during aberrant cell proliferation in cancer cells.	SIGNOR-278357
P35611	Q05513	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-43834
P46934	Q12809	1	ubiquitination	down-regulates quantity by destabilization	0.268	We have previously shown that the E3 ubiquitin (Ub) ligase Nedd4-2 (neural precursor cell expressed developmentally down-regulated protein 4-2) targets the PY motif of hERG channels to initiate channel degradation. Although both immature and mature hERG channels contain the PY motif, Nedd4-2 selectively mediates the degradation of mature hERG channels.	SIGNOR-260998
Q96SN8	Q38SD2	0	phosphorylation	up-regulates activity	0.505	Interestingly, LRRK1 in turn phosphorylates CDK5RAP2(Cep215), a human homologue of Drosophila Centrosomin (Cnn), in its gamma-tubulin-binding motif, thus promoting the interaction of CDK5RAP2 with gamma-tubulin. LRRK1 phosphorylation of CDK5RAP2 Ser 140 is necessary for CDK5RAP2-dependent microtubule nucleation.	SIGNOR-275468
P10415	P01241	0	transcriptional regulation	up-regulates quantity by expression	0.2	Autocrine hGH increased the transcription and subsequent mRNA level and protein expression of c-Myc, Cyclin D1, and Bcl-2 in human mammary epithelial cells	SIGNOR-261628
P12931	P25490	1	phosphorylation	down-regulates activity	0.284	YY1 phosphorylation is mediated by Src family kinases.	SIGNOR-276940
Q13882	P35222	1	phosphorylation	down-regulates quantity	0.305	PTK6 directly phosphorylates beta-catenin on Tyr64, Tyr142, Tyr331 and/or Tyr333, with the predominant site being Tyr64.\|The ability of PTK6 to negatively regulate beta-catenin and TCF transcription by modulating levels of TCF4 and TLE and Groucho could contribute to its growth-inhibitory activities in vivo.	SIGNOR-278289
P04792	Q9Y243	0	phosphorylation	down-regulates	0.286	First, the akt1, akt2, and akt3 isoforms can bind directly to hsp27 and can be found in a complex with p38 mapk, mk2, and hsp27 [98_100]. Second, rane and colleagues showed that akt could phosphorylate hsp27 at ser-82, but not ser-15 or ser-78, in vitro, while co-expression of an active akt mutant and hsp27 in hek cells resulted in hsp27 phosphorylation at the same residue.	SIGNOR-186780
Q96P20	Q8N4C8	0	phosphorylation	up-regulates activity	0.2	MINK1-mediated NLRP3 phosphorylation at Ser725 is critical for inflammasome activation.\|These results suggest that MINK1 promotes NLRP3 inflammasome activation via direct interaction with NLRP3.\|To determine whether MINK1 phosphorylated NLRP3 directly, we used Phos-tag SDS\u2013PAGE to detect the phosphorylation of NLRP3.	SIGNOR-280042
P19544	Q7RTT9	1	transcriptional regulation	up-regulates quantity by expression	0.274	ENT4 is transcriptionally activated by both isoforms of EWS/WT1 as evidenced by promoter-reporter and chromatin immunoprecipitation (ChIP) analyses.	SIGNOR-268985
P04637	Q9C0B5	1	transcriptional regulation	up-regulates quantity by expression	0.2	Mechanistic investigations revealed that mutant p53 transcriptionally upregulated ZDHHC5 along with the nuclear transcription factor NF-Y	SIGNOR-261150
P03372	P42345	0	phosphorylation	up-regulates activity	0.498	Thus our results indicate that the interaction between ER\u03b1 and raptor is necessary to recruit raptor to the nucleus, where mTOR phosphorylates and activates ER\u03b1.	SIGNOR-278295
P40763	P29074	0	dephosphorylation	down-regulates activity	0.255	In terms of molecular mechanisms, we revealed that PTPN4 dephosphorylates pSTAT3 at the Tyr705 residue with a direct interaction, which might provide novel targets for the therapy of CRC.\|Loss of PTPN4 Activates STAT3 to Promote the Tumor Growth in Rectal Cancer.	SIGNOR-277057
Q13131	P10636	1	phosphorylation	down-regulates activity	0.2	We have studied the relationship between the phosphorylation oftau by several kinases (MARK, PKA, MAPK, GSK3) and its assembly into PHFs. By contrast, MARK and PKA phosphorylate several sites within the repeats (notably theKXGS motifs including Ser262, Ser324, and Ser356, plus Ser320); in addition PKA phosphorylates somesites in the flanking domains, notably Ser214. This type of phosphorylation strongly reduces tau’s affinityfor microtubules, and at the same time inhibits tau’s assembly into PHFs.	SIGNOR-275439
Q00535	P53779	1	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
O15534	Q9Y297	0	ubiquitination	down-regulates	0.57	We have found that per1 interacts with both _-trcp1 and _-trcp2 in a manner that depends on casein kinase 1 activity, and depletion of both _-trcp1 and _-trcp2 by rnai leads to dramatic stabilization of per1	SIGNOR-137755
P27361	P49715	1	phosphorylation	down-regulates	0.371	Ccaat/enhancer-binding protein alpha (c/ebpalpha) is one of the key transcription factors that mediate lineage specification and differentiation of multipotent myeloid progenitors into mature granulocytes.Here we report that inducers of monocyte differentiation inhibit the alternate cell fate choice, that of granulopoiesis, through inhibition of c/ebpalpha. This inhibition is mediated by extracellular signal-regulated kinases 1 and/or 2 (erk1/2), which interact with c/ebpalpha through an fxfp docking site and phosphorylate serine 21.	SIGNOR-120570
Q14195	Q00535	0	phosphorylation	up-regulates activity	0.603	Together, these results suggest that crmp4 is able to increase neurite formation and elongation in neurons, although not as potently as crmp2, and that this process is regulated by ser522/ser518/thr514/thr509 phosphorylation in both cases. We demonstrate that cdk5 primes crmp2 and crmp4 for subsequent phosphorylation by gsk3, whereas dyrk2, phosphorylates and primes only crmp4 in vitro	SIGNOR-145963
Q9UNE7	P25815	1	polyubiquitination	down-regulates quantity by destabilization	0.292	S100 protein itself is ubiquitinated by CHIP in a Ca2+-dependent manner.Ubiquitylated S100 proteins are shown as (Ub)n-S100A2 and (Ub)n-S100P. The association of the S100 proteins with CHIP provides a Ca2+-dependent regulatory mechanism for the ubiquitination and degradation of intracellular proteins by the CHIP-proteasome pathway.	SIGNOR-272919
P45984	P52564	0	phosphorylation	up-regulates	0.473	A map kinase kinase kinase (mapkkk), termed ask1, was identified that activated two different subs of map kinase kinases (mapkk), sek1 (or mkk4) and mkk3/mapkk6 (or mkk6), which in turn activated stress-activated protein kinase (sapk, also known as jnk;c-jun amino-terminal kinase)	SIGNOR-45369
P05771	P21730	1	phosphorylation	down-regulates	0.2	Dynamics of protein kinase c-mediated phosphorylation of the complement c5a receptor on serine 334. Analysis of c5ar ser/ala mutants that possess a single intact serine residue either at position 334 or at neighboring positions 327, 332, or 338 revealed functional redundancy of c-terminal phosphorylation sites since all 4 serine residues could individually support c5ar internalization and desensitization	SIGNOR-151011
Q6NT76	P01579	1	transcriptional regulation	down-regulates quantity by repression	0.2	Additionally, by luciferase reporter assay, HMBOX1 displayed suppressive effect on the transcription activity of IFN-γ promoter.	SIGNOR-261625
P78352	Q05086	0	ubiquitination	down-regulates quantity by destabilization	0.349	E6-induced degradation of DLG4 depends on E6AP in vivo. Our findings as a whole indicate that E6AP is involved in E6-mediated ubiquitination and degradation of DLG4 both in vivo and in vitro.	SIGNOR-271397
Q15691	O95684	0	relocalization	up-regulates	0.2	Fop also binds to eb1 and is required for localizing eb1 to the centrosome	SIGNOR-142400
P12931	Q16825	0	dephosphorylation	up-regulates	0.643	Ptpd1 activates src tyrosine kinase and increases the magnitude and duration of epidermal growth factor (egf) signaling.	SIGNOR-124774
P08913	Q05655	0	phosphorylation	up-regulates activity	0.533	Taken together, these results indicate that S232 acts as a selective, PKC-sensitive, modulator of effector coupling of the alpha(2A)AR to inositol phosphate stimulation. This represents one mechanism by which cells route stimuli directed to multifunctional receptors to selected effectors so as to attain finely targeted signaling.	SIGNOR-249126
P36956	Q14703	0	cleavage	up-regulates activity	0.561	We present evidence that SKI-1 processes peptides mimicking the cleavage sites of the SKI-1 prosegment, pro-brain-derived neurotrophic factor, and the sterol regulatory element-binding protein SREBP-2	SIGNOR-267497
Q14119	P05305	1	transcriptional regulation	up-regulates quantity by expression	0.276	Vascular endothelial zinc finger 1 (Vezf1)/DB1 is a recently identified zinc finger-containing protein that is expressed specifically within endothelial cells during development. In this report, we demonstrate that Vezf1/DB1 is a nuclear localizing protein that potently and specifically activates transcription mediated by the human endothelin-1 promoter, in a Tax-independent manner, in transient transfection assays. Regulation of endothelin-1 promoter activity by Vezf1/DB1 provides a mechanism for endothelin-1 expression in the vascular endothelium during development and to maintain vascular tone	SIGNOR-266884
Q14493	Q6NXT2	1	translation regulation	up-regulates quantity by expression	0.2	Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA\|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control.	SIGNOR-265420
Q13315	Q9UBU7	1	phosphorylation	down-regulates	0.375	Dbf4/cdc7 (dbf4-dependent kinase (ddk)) is activated at the onset of s-phase, and its kinase activity is required for dna replication initiation from each origin. We identified novel atm/atr phosphorylation sites on dbf4 and showed that atm/atr-mediated phosphorylation of dbf4 is critical for the intra-s-phase checkpoint to inhibit dna replication.	SIGNOR-177793
P24941	Q9Y618	1	phosphorylation	down-regulates activity	0.429	Cdk2 and Pin1 negatively regulate the transcriptional corepressor SMRT.\|Cdk2 phosphorylates SMRT at consensus Cdk motifs to generate Pin1 binding sites and consequently targets SMRT for degradation, the latter also requiring the PPIase activity of Pin1 (XREF_FIG).	SIGNOR-278306
O43464	Q00535	0	phosphorylation	up-regulates	0.456	Here we report that cyclin-dependent kinase-5 (cdk5), a kinase implicated in the pathogenesis of several neurodegenerative diseases, is responsible for phosphorylating htra2 at s400.We have shown previously that phosphomimetic mutants of htra2 at s400 result in increased proteolytic activity and contribute to enhanced resistance to mitochondrial stress	SIGNOR-174598
P41743	P49757	1	phosphorylation	down-regulates	0.771	Numb is regulated by phosphorylation since the protein is released from ccss and no longer binds integrins when phosphorylated by atypical protein kinase c (apkc).	SIGNOR-156765
P31749	Q86V81	1	phosphorylation	up-regulates	0.449	Nuclear akt directly binds aly and phosphorylates it on the t219 residue. gfp-aly t219d displayed comparable activity to gfp control and wild-type aly, indicating that aly phosphorylation by akt is sufficient to enhance mrna export.	SIGNOR-252518
Q9UBF6	Q16665	1	ubiquitination	down-regulates activity	0.2	SAG (Sensitive to Apoptosis Gene), also known as RBX2 (RING box protein 2), ROC2 (Regulator of Cullins 2), or RNF7 (RING Finger Protein 7), was originally cloned in our laboratory as a redox inducible antioxidant protein and later characterized as the second member of the RBX/ROC RING component of the SCF (SKP1-CUL-F-box Proteins) E3 ubiquitin ligase. by forming a complex with other components of the SCF E3 ligase, SAG promotes ubiquitination and degradation of a number of protein substrates, including c-JUN, DEPTOR, HIF-1α, IκBα, NF1, NOXA, p27, and procaspase-3, thus regulating various signaling pathways and biological processes.	SIGNOR-271450
O95202	Q9BXM7	0	phosphorylation	up-regulates activity	0.358	Here we demonstrate that PINK1 directly interacts with and phosphorylates LETM1 at Thr192 in vitro.\|Phosphorylated LETM1 or the phospho-mimetic LETM1-T192E increase calcium release in artificial liposomes and facilitates calcium transport in intact mitochondria.	SIGNOR-262540
P05231	Q13469	0	transcriptional regulation	up-regulates quantity by expression	0.399	The calcineurin/nuclear factor of activated T cells (NFAT) signaling pathway has been found to play a role in regulating growth and differentiation in several cell types. However, the functional significance of NFAT in the vasculature is largely unclear. Here we show that NFATc1, NFATc3, and NFATc4 are expressed in human myometrial arteries. \|Chronic inhibition of NFAT significantly reduced IL-6 production in intact myometrial arteries and inhibited cell proliferation in vascular smooth muscle cells cultured from explants from the same arteries.	SIGNOR-251731
P23528	Q15569	0	phosphorylation	down-regulates activity	0.528	Like TESK1, TESK2 phosphorylated cofilin specifically at Ser-3 and induced formation of actin stress fibers and focal adhesionsExpression of cofilin or S3A-cofilin into HeLa cells induced marked decreases in rhodamine-phalloidin staining due to the actin binding and -depolymerizing activity of cofilin	SIGNOR-246723
P05787	P45983	0	phosphorylation	up-regulates	0.375	Kinase assays showed that c-jun n-terminal kinase (jnk) was also activated with activation kinetics corresponding to that of k8 phosphorylation. Furthermore, k8 was also phosphorylated on ser-73 by jnk in vitro. The ser-73 --> ala-associated filament reorganization defect is rescued by a ser-73 --> asp mutation. Also, disease-causing keratin mutations can modulate keratin phosphorylation and organization, which may affect disease pathogenesis.	SIGNOR-113645
Q02156	O14920	1	phosphorylation	up-regulates activity	0.547	Monoubiquitylated PKC\u03b5 interacts with a ubiquitin-binding domain in NEMO zinc finger and recruits the cytosolic IKK complex to the plasma membrane, where PKC\u03b5 phosphorylates IKK\u03b2 at Ser177 and activates IKK\u03b2.\|These results indicate that PKCepsilon phosphorylates IKKbeta at S177 and activates IKKbeta, which in turn induces PKM2 upregulation.	SIGNOR-278323
P10721	O96017	0	phosphorylation	up-regulates	0.286	In this report, we characterize the binding of sh2(chk) to specific phosphotyrosine sites on the c-kit protein sequence. the sh2(chk) binding to the two sites is direct and not through phosphorylated intermediates such as fyn or shc. this indicates that chk binds to the same site on c-kit to which fyn binds, possibly bringing the two into proximity on associated c-kit subunits and leading to the down-regulation of fyn by chk.	SIGNOR-197281
P31749	P84243	1	phosphorylation	down-regulates activity	0.2	Additionally, active akt1 kinase strongly phosphorylates histone h3 at serine 10 in vitro	SIGNOR-98285
Q9Y6Q9	O43781	0	phosphorylation	down-regulates activity	0.2	Mechanistically, Dyrk3 directly phosphorylated NCOA3 at Ser-1330, disrupting its binding to ATF4 and thereby causing the inhibition of ATF4 transcriptional activity.	SIGNOR-275451
P49675	P49715	0	transcriptional regulation	up-regulates quantity by expression	0.335	Electrophoretic mobility shift assay demonstrated that this region of the StAR promoter was bound by C/EBPalpha, C/EBPbeta, and CREB. Forced expression of either C/EBPalpha or C/EBPbeta alone was sufficient to up-regulate StAR promoter activity whereas PGE(2) was needed to induce StAR promoter activity in CREB-overexpressed cells.	SIGNOR-254043
P13807	P49841	0	phosphorylation	down-regulates activity	0.686	Glycogen synthase kinase-3 phosphorylates three serine residues on glycogen synthase (sites 3a, 3b and 3c) which are all located in the same nine-amino-acid segment of the polypeptide chain. The sequence in this region is: Arg-Tyr-Pro-Arg-Pro-Ala-Ser(P)-Val-Pro-Pro-Ser(P)-Pro-Ser-Leu-Ser(P)-Arg-.	SIGNOR-253007
P12931	P04083	1	phosphorylation	up-regulates	0.389	The authors identified several phosphorylated residues by a combination of peptide mapping and sequence analysis and showed that recombinant pp60c-src phosphorylates annexin a1 near its amino terminus, at tyrosine 21 (tyr21). Also polyoma virus middle t/pp60c-src complex, recombinant pp50v-abl, and the egf receptor/kinase phosphorylated the same tyrosine residue. It was also shown that serine 27 residue of anxa1 is the primary site phosphorylated by protein kinase c (pkc). In the same study, the threonine 41 residue has been identified as a pkc substrate as well. The adenosine cyclic 3_,5_-phosphate dependent protein kinase a (pka) phosphorylates anxa1 in its carboxyl-terminal core at the threonine 216 residue (thr216) [2].Finally in 2013 caron et al. showed the relevance of y21 phosphorylation for the anxa1 stability. In fact the authors demonstrated that the tyrosine 21 phosphorylation is crucial for anxa1 sumoylation induced by egf	SIGNOR-202796
P38936	P19174	0	phosphorylation	up-regulates quantity by stabilization	0.262	Phosphorylation at Ser-146 by PKCδ increases p21 stability	SIGNOR-262962
O60260	Q8IXI1	1	polyubiquitination	down-regulates quantity by destabilization	0.2	PINK1 phosphorylates Miro, a component of the primary motor/adaptor complex that anchors kinesin to the mitochondrial surface. The phosphorylation of Miro activates proteasomal degradation of Miro in a Parkin-dependent manner.	SIGNOR-272726
Q8TDY2	Q8IYT8	0	phosphorylation	up-regulates activity	0.747	When mTOR is inhibited, ULK1 and ULK2 activate and phosphorylate ATG13 and FIP200.	SIGNOR-280159
Q8IW41	P04637	1	phosphorylation	up-regulates	0.76	Furthermore, we show that prak activates p53 by direct phosphorylation. prak phosphorylates p53 at ser37	SIGNOR-152847
P42229	Q06609	1	transcriptional regulation	up-regulates quantity by expression	0.263	FLT3-ITD-TKD dual mutants induce hyperactivation of STAT5 and up-regulation of its downstream targets Bcl-x(L) and RAD51 in Ba/F3 cells	SIGNOR-261552
P01236	P31270	0	transcriptional regulation	up-regulates quantity by expression	0.351	HoxA-11 enhanced upregulation of PRL only in differentiated cells.	SIGNOR-261630
O14920	O43524	1	phosphorylation	down-regulates	0.692	Ikkbeta phosphorylates foxo3a at ser644. Ikappab kinase (ikk) physically interacts with, phosphorylates, and inhibits foxo3a independent of akt and causes proteolysis of foxo3a via the ub-dependent proteasome pathway	SIGNOR-124207
Q9UGK3	P12931	0	phosphorylation	up-regulates activity	0.406	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 Tyr-22 and Tyr-322 are the major tyrosine phosphorylation sites by v-Src.	SIGNOR-247337
P28482	Q92574	1	phosphorylation	down-regulates	0.49	Here, we show that erk may play a critical role in tsc progression through posttranslational inactivation of tsc2. Erk-dependent phosphorylation leads to tsc1-tsc2 dissociation and markedly impairs tsc2 ability to inhibit mtor signalin.	SIGNOR-157162
Q9UQM7	P23677	1	phosphorylation	up-regulates	0.329	D-myo-inositol 1,4,5-trisphosphate 3-kinase a is activated by receptor activation through a calcium:calmodulin-dependent protein kinase ii phosphorylation mechanism. the phosphorylated residue was thr311.	SIGNOR-48387
P53667	Q9Y281	1	phosphorylation	down-regulates activity	0.703	Cofilin is known to be a potent regulator of actin filament dynamics, and its ability to bind and depolymerize actin is abolished by phosphorylation of serine residue at 3;. Here we show that lim-kinase 1 (limk-1), a serine/threonine kinase containing lim and pdz domains, phosphorylates cofilin at ser 3, both in vitro and in vivo	SIGNOR-58596
P00533	P42224	1	phosphorylation	up-regulates	0.738	The transcription factors stat1, stat3, and stat5 are directly phosphorylated by erbb-1, subsequent to which they dimerize through phosphotyrosine-sh2 domain interactions and translocate to the nucleus to activate gene trascription critical for proliferation	SIGNOR-235689
Q92569	Q9UM73	0	phosphorylation	up-regulates activity	0.379	Subsequent studies revealed that ALK promoted cell migration through the P3K-AKT pathway via the p55γ regulatory subunit of PI3K.	SIGNOR-253217
P52757	P63000	1	gtpase-activating protein	down-regulates activity	0.64	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-260500
Q8N2W9	O15033	0	ubiquitination	down-regulates quantity by destabilization	0.403	In this study, we discovered a new protein isoform encoded by KIAA0317, termed fibrosis-inducing E3 ligase 1 (FIEL1), which potently stimulates the TGFβ signaling pathway through the site-specific ubiquitination of PIAS4.FIEL1 targets PIAS4 using a double locking mechanism that is facilitated by the kinases PKCζ and GSK3β. Specifically, PKCζ phosphorylation of PIAS4 and GSK3β phosphorylation of FIEL1 are both essential for the degradation of PIAS4.	SIGNOR-275575
Q8WUI4	Q9UPG8	1	deacetylation	down-regulates	0.258	Plag1 and plagl2 are also regulated by acetylation. They are acetylated and activated by p300 and deacetylated and repressed by hdac7.	SIGNOR-140953
P68400	P33527	1	phosphorylation	up-regulates	0.374	Casein kinase 2_ regulates multidrug resistance-associated protein 1 function via phosphorylation of thr249. This study supports a model in which ck2_ potentiates mrp1 function via direct phosphorylation of thr249.	SIGNOR-197844
O15273	P49841	0	phosphorylation	down-regulates quantity by destabilization	0.2	GSK-3beta phosphorylates FBXL21 and TCAP to activate FBXL21-mediated, phosphodegron-dependent TCAP degradation.\|These results show direct GSK-3beta phosphorylation of TCAP S157 and FBXL21 T33 sites.	SIGNOR-264852
P35568	P17252	0	phosphorylation	down-regulates activity	0.386	We show that pkcalpha is likely to be directly involved in ser24 phosphorylation...These observations are entirely consistent with a recent independent study demonstrating that the IRS1-S24D mutant shows impaired insulin-stimulated IR-IRS-1 interactions, tyrosine phosphorylation of IRS-1, recruitment/activation of PI 3-Kinase, and insulin-stimulated Glut4 translocation	SIGNOR-145398
P24723	P28482	1	phosphorylation	up-regulates activity	0.506	Protein kinase C-eta regulates Mcl-1 level via ERK1. knockdown of PKCη but not PKCα, -δ or -ε caused a significant decrease in ERK (extracellular signal-regulated kinase) phosphorylation. Knockdown of ERK1 but not ERK2 decreased Mcl-1 level, and the decrease in Mcl-1 caused by PKCη knockdown was restored by ERK1 overexpression. These results suggest that PKCη utilizes the ERK signaling pathway to protect against ubiquitin-mediated proteasomal degradation of Mcl-1.	SIGNOR-261910
P36897	P61586	1	null	up-regulates activity	0.64	Thus, TGF-_1 rapidly stimulates activity of both RhoA and Rac1 and this activation requires ALK5/T_RI kinase activity.	SIGNOR-227499
Q96CN5	P51955	0	phosphorylation	down-regulates activity	0.37	Moreover, LRRC45 interacts with both C-Nap1 and rootletin and is phosphorylated by Nek2A at S661 during mitosis. After phosphorylation, both LRRC45 centrosomal localization and fiber-like structures are significantly reduced, which subsequently leads to centrosome separation.	SIGNOR-273707
Q92630	P46531	1	phosphorylation	down-regulates quantity by destabilization	0.288	We demonstrate that DYRK2 phosphorylates Notch1-IC in response to chemotherapeutic agents and facilitates its proteasomal degradation by FBXW7 ubiquitin ligase through a Thr-2512 phosphorylation-dependent mechanism.	SIGNOR-279035
Q05086	O43324	1	ubiquitination	down-regulates quantity	0.2	These results strongly suggest that Ube3a decreases p18 levels via ubiquitination followed by proteasomal degradation.\|We demonstrate that Ube3a directly ubiquitinates p18 and targets it for proteasomal degradation, which normally limits mTORC1 signaling and activity dependent synaptic remodeling.	SIGNOR-278680
P17612	Q7Z434	1	phosphorylation	down-regulates activity	0.283	Mutagenesis indicated that PKACalpha phosphorylated wild-type VISA and the VISA mutants VISA (S100A), VISA (T234A) and VISA (S238A) but not VISA (T54A) (XREF_FIG, panel C).\|We found that PKACalpha caused degradation of wild-type VISA but not VISA (T54A) or VISA (K7/500R), in which either the PKACs mediated phosphorylation or MARCH5 mediated K48 linked polyubiquitination residues are mutated (XREF_FIG, panel G).	SIGNOR-279649
P19784	Q14005	1	phosphorylation	up-regulates activity	0.326	We now show that N-terminal to the NLS domain of pro-IL-16 are protein kinase CK2 substrate and cdc2 kinase substrate sites which, along with the NLS, constitute a dual phosphorylation-regulated CcN motif which regulates nuclear localization of pro-IL-16. In addition, we demonstrate that mutation of either site is associated with impairment of the N-terminal domain's ability to induce G(0)/G(1) cell cycle arrest. \| Thus, we confirm that the N-terminal (42SLNEE46) sequence of pro-IL-16 is in fact a site for protein kinase CK2 phosphorylation.	SIGNOR-251009
P00558	Q15118	1	phosphorylation	up-regulates activity	0.428	Mitochondrial PGK1 acts as a protein kinase to phosphorylate pyruvate dehydrogenase kinase 1 (PDHK1) at T338, which activates PDHK1 to phosphorylate and inhibit the pyruvate dehydrogenase (PDH) complex.	SIGNOR-278365
P56915	Q15375	1	transcriptional regulation	down-regulates quantity by repression	0.2	We demonstrate that Goosecoid can act as a repressor of its own promoter activity in transient co-transfection experiments in mouse P19 cells and in Xenopus embryos. Autorepression depends on the presence of the homeodomain and is mediated through the prd element more proximal to the transcriptional start site.	SIGNOR-261613
Q86Y01	P46531	1	ubiquitination	up-regulates activity	0.781	The human Deltex (DTX1) gene encodes a cytoplasmic protein that functions as a positive regulator of the Notch signaling pathway.	SIGNOR-85942
Q9NR19	P11279	1	transcriptional regulation	up-regulates quantity by expression	0.2	Nucleus-Translocated ACSS2 Promotes Gene Transcription for Lysosomal Biogenesis and Autophagy\|A chromatin immunoprecipitation (ChIP) assay with antibodies against TFEB or ACSS2 demonstrated that glucose deprivation results in the binding of TFEB (Figure 3D) and ACSS2 (Figure 3E) to the promoter regions of CTSA, GBA, GUSB, and LAMP1\|These results indicated that TFEB and ACSS2 are mutually required for their binding to the promoter regions of lysosomal genes. In line with these findings, glucose deprivation induced mRNA (Figure 3F) and protein (Figure 3G) expression for these lysosomal genes, which was largely abrogated by knockin of ACSS2 mutants	SIGNOR-276556
Q4G0J3	Q13315	0	phosphorylation	down-regulates quantity by destabilization	0.2	Altogether, the results suggest that ATM-mediated T440 phosphorylation enhances LARP7-BARD1 interaction and facilitates BRCA1/BARD1-mediated LARP7 ubiquitination and degradation.	SIGNOR-275580
Q9Y6D9	Q13315	0	phosphorylation	up-regulates activity	0.2	ATM mediated Mad1 Serine 214 phosphorylation regulates Mad1 dimerization and the spindle assembly checkpoint.\|Together, these findings reveal an important role of ATM-mediated Mad1 Serine 214 phosphorylation in mitosis.	SIGNOR-278467
P15336	Q9Y297	0	ubiquitination	down-regulates quantity by destabilization	0.2	Our data suggest that mTORC1 promotes the binding of the E3 ligase, βTrCP, to CREB2 (Figure 4D), promoting CREB2 degradation by the proteasome (Figure 4E). Here, we show that mTORC1 promotes glutamine anaplerosis by activating glutamate dehydrogenase (GDH). This regulation requires transcriptional repression of SIRT4, the mitochondrial-localized sirtuin that inhibits GDH. Mechanistically, mTORC1 represses SIRT4 by promoting the proteasome-mediated destabilization of cAMP-responsive element binding 2 (CREB2).	SIGNOR-267830
Q13133	P68400	0	phosphorylation	down-regulates	0.2	Ck2? Also phosphorylated lxr? At s198 in vitro, suggesting that ck2 may be a bona fide s198 kinase. our results show that macrophage lxr? Phosphorylation at s198 affects the transcriptional activity of the receptor in a gene-specific manner (fig. ?(Fig.3a)3a) and restricts the repertoire of genes regulated by lxr?	SIGNOR-160640
P49674	P56645	1	phosphorylation	down-regulates activity	0.74	The CKI phosphorylation of mPer1 and mPer3 proteins results in their rapid degradation, which is dependent on the ubiquitin-proteasome pathway. Moreover, CKIepsilon and CKIdelta are able to induce nuclear translocation of mPer3, which requires its nuclear localization signal. The mutation in potential phosphorylation sites on mPer3 decreased the extent of both nuclear translocation and degradation of mPer3 that are stimulated by CKIepsilon. \| In mut7 in which all of the conserved serine and threonine residues in this region were mutated, the ratio of the shifted band was greatly reduced reproducibly.	SIGNOR-250816
P15941	Q05655	0	phosphorylation	up-regulates	0.336	We show that phosphorylation of muc1 by pkcdelta increases binding of muc1 and beta-catenin in vitro and in vivo. The functional significance of the muc1-pkcdelta interaction is further supported by the demonstration that mutation of the pkcdelta phosphorylation site abrogates muc1-mediated decreases in binding of beta-catenin to e-cadherin	SIGNOR-115501
Q07352	Q15418	0	phosphorylation	down-regulates activity	0.2	These results indicate that RSK1 directly phosphorylates the C-terminus of ZFP36L1 downstream of ERK, and inhibits the Messenger RNA destabilization activity of ZFP36L1.\|These results indicate that RSK1 directly phosphorylates the C-terminus of ZFP36L1 downstream of ERK, and inhibits the mRNA destabilization activity of ZFP36L1.	SIGNOR-279280
Q13224	Q06124	0	dephosphorylation	down-regulates activity	0.469	In addition, surface expression of GluN2B was not reduced in mutant mice and it remains to be investigated how the direct dephosphorylation of GluN2B Y1252 by Shp2 reduces GluN2B function.\|The increased GluN2B Y1472 phosphorylation was reversed by a Src family kinase inhibitor, suggesting that Shp2 may negatively regulate GluN2B Y1472 phosphorylation through suppressing Src activity .	SIGNOR-276950
Q06124	P35568	1	dephosphorylation	down-regulates	0.897	The specific activity of four candidate protein-tyrosine phosphatases (protein-tyrosine phosphatase 1b (ptp1b), sh2 domain-containing ptpase-2 (shp-2), leukocyte common antigen-related (lar), and leukocyte antigen-related phosphatase) (lrp) toward irs-1 dephosphorylation was studied using recombinant proteins in vitro. Ptp1b exhibited the highest specific activity these results provide new insight into novel molecular interactions involving ptp1b and grb2 that may influence the steady-state capacity of irs-1 to function as a phosphotyrosine scaffold and possibly affect the balance of postreceptor insulin signaling.	SIGNOR-74856
O14559	P06241	0	phosphorylation	down-regulates	0.461	Tcgap interacted with fyn and was phosphorylated by fyn, with tyr-406 in the gap domain as a major fyn-mediated phosphorylation site. Fyn suppressed the gap activity of wild-type tcgap	SIGNOR-147156
O14939	Q00535	0	phosphorylation	up-regulates activity	0.368	In this study, we suggest that the phosphorylation and activation of PLD2 by cyclin-dependent kinase 5 (Cdk5) is critical for EGF-dependent insulin secretion.\|We determined that Cdk5 phosphorylates PLD2 at Ser 134 of PLD2 and that this phosphorylation was suggested to be important for EGF-dependent insulin secretion.	SIGNOR-278395
P17252	Q16760	1	phosphorylation	down-regulates activity	0.366	The plasma membrane translocation of diacylglycerol kinase delta1 is negatively regulated by conventional protein kinase C-dependent phosphorylation at Ser-22 and Ser-26 within the pleckstrin homology domain.	SIGNOR-249265
Q9H2X6	P46527	1	phosphorylation	up-regulates	0.254	Homeodomain-interacting protein kinase-2 stabilizes p27(kip1) by its phosphorylation at serine 10 and contributes to cell motility	SIGNOR-174617
P16220	P31751	0	phosphorylation	up-regulates	0.514	Creb is a nuclear target for activation via the growth factor-dependent ser/thr kinase akt/pkb. When overexpressed in serum-stimulated cells, akt/pkb potently induced ser-133 phosphorylation of creb and promoted recruitment of cbp.	SIGNOR-62253
P16298	P19484	1	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

P48023

O43638

0

transcriptional regulation

down-regulates quantity by repression

0.2

As we expected, Fkhl18 suppressed, dose-dependently,human and mouseFasLpromoter in bovine vascularsmooth muscle cells

SIGNOR-261612

Q92630

Q14195

1

phosphorylation

up-regulates activity

0.364

Together, these results suggest that crmp4 is able to increase neurite formation and elongation in neurons, although not as potently as crmp2, and that this process is regulated by ser522/ser518/thr514/thr509 phosphorylation in both cases. We demonstrate that cdk5 primes crmp2 and crmp4 for subsequent phosphorylation by gsk3, whereas dyrk2, phosphorylates and primes only crmp4 in vitro

SIGNOR-145987

Q96MT3

Q8N4C8

0

phosphorylation

up-regulates activity

0.293

We show that Mink1 phosphorylates Prickle on a conserved threonine residue and regulates its Rab5-dependent endosomal trafficking, a process required for the localized plasma membrane accumulation and function of Prickle.

SIGNOR-263095

Q13131

Q53ET0

1

phosphorylation

down-regulates

0.544

Collectively, these findings suggest ampk suppresses glucose production through two transcriptional effects:reduced expression of creb targets via crtc inactivation and reduced expression of foxo target genes via class iia hdac inactivation

SIGNOR-176426

Q6PIY7

P22612

0

phosphorylation

down-regulates activity

0.2

We found that Gld2 activity is regulated by site-specific phosphorylation in its disordered N-terminal domain. We identified two phosphorylation sites (S62, S110) where phosphomimetic substitutions increased Gld2 activity and one site (S116) that markedly reduced activity. Using mass spectrometry, we confirmed that HEK 293 cells readily phosphorylate the N-terminus of Gld2. We identified protein kinase A (PKA) and protein kinase B (Akt1) as the kinases that site-specifically phosphorylate Gld2 at S116, abolishing Gld2-mediated nucleotide addition.

SIGNOR-259404

Q86YJ5

Q96LA5

1

ubiquitination

down-regulates quantity by destabilization

0.2

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

SIGNOR-271543

O43474

P53350

0

phosphorylation

up-regulates quantity by stabilization

0.249

We further found that inhibition of polo-like kinase 1 could downregulate the expression of KLF4 and that PLK1 directly phosphorylated KLF4 at Ser234. Notably, phosphorylation of KLF4 by PLK1 caused the recruitment and binding of the E3 ligase TRAF6, which resulted in KLF4 K32 K63-linked ubiquitination and stabilization.

SIGNOR-277463

P17655

P12931

0

phosphorylation

up-regulates activity

0.525

CAPN2 itself was a bone fide substrate of SRC that was primarily phosphorylated at Y625 by SRC and exhibited increased proteolysis activity upon phosphorylation.

SIGNOR-277598

P12931

P41743

1

phosphorylation

up-regulates

0.533

Nerve growth factor stimulates multisite tyrosine phosphorylation and activation of the atypical protein kinase c's via a src kinase pathway. tyrosine 256, 271, and 325 were identified as major sites phosphorylated by src in the catalytic domain.

SIGNOR-111920

Q14457

P00533

0

phosphorylation

down-regulates activity

0.521

The mechanism by which EGFR suppresses Beclin 1 function involves EGFR interaction with two domains (BH3 and ECD) of Beclin 1; EGFR mediated multisite tyrosine phosphorylation of Beclin 1 on residues Y229, Y233 and Y352; and EGFR mediated alterations in the Beclin 1 interactome (increased binding to the negative regulators, Bcl-2 and Rubicon, and decreased binding to the VPS34 lipid kinase).|Thus, EGFR signaling suppresses autophagy via its interaction with Beclin 1 during normal mitogenic signaling as well as during aberrant cell proliferation in cancer cells.

SIGNOR-278357

P35611

Q05513

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-43834

P46934

Q12809

1

ubiquitination

down-regulates quantity by destabilization

0.268

We have previously shown that the E3 ubiquitin (Ub) ligase Nedd4-2 (neural precursor cell expressed developmentally down-regulated protein 4-2) targets the PY motif of hERG channels to initiate channel degradation. Although both immature and mature hERG channels contain the PY motif, Nedd4-2 selectively mediates the degradation of mature hERG channels.

SIGNOR-260998

Q96SN8

Q38SD2

0

phosphorylation

up-regulates activity

0.505

Interestingly, LRRK1 in turn phosphorylates CDK5RAP2(Cep215), a human homologue of Drosophila Centrosomin (Cnn), in its gamma-tubulin-binding motif, thus promoting the interaction of CDK5RAP2 with gamma-tubulin. LRRK1 phosphorylation of CDK5RAP2 Ser 140 is necessary for CDK5RAP2-dependent microtubule nucleation.

SIGNOR-275468

P10415

P01241

0

transcriptional regulation

up-regulates quantity by expression

0.2

Autocrine hGH increased the transcription and subsequent mRNA level and protein expression of c-Myc, Cyclin D1, and Bcl-2 in human mammary epithelial cells

SIGNOR-261628

P12931

P25490

1

phosphorylation

down-regulates activity

0.284

YY1 phosphorylation is mediated by Src family kinases.

SIGNOR-276940

Q13882

P35222

1

phosphorylation

down-regulates quantity

0.305

PTK6 directly phosphorylates beta-catenin on Tyr64, Tyr142, Tyr331 and/or Tyr333, with the predominant site being Tyr64.|The ability of PTK6 to negatively regulate beta-catenin and TCF transcription by modulating levels of TCF4 and TLE and Groucho could contribute to its growth-inhibitory activities in vivo.

SIGNOR-278289

P04792

Q9Y243

0

phosphorylation

down-regulates

0.286

First, the akt1, akt2, and akt3 isoforms can bind directly to hsp27 and can be found in a complex with p38 mapk, mk2, and hsp27 [98_100]. Second, rane and colleagues showed that akt could phosphorylate hsp27 at ser-82, but not ser-15 or ser-78, in vitro, while co-expression of an active akt mutant and hsp27 in hek cells resulted in hsp27 phosphorylation at the same residue.

SIGNOR-186780

Q96P20

Q8N4C8

0

phosphorylation

up-regulates activity

0.2

MINK1-mediated NLRP3 phosphorylation at Ser725 is critical for inflammasome activation.|These results suggest that MINK1 promotes NLRP3 inflammasome activation via direct interaction with NLRP3.|To determine whether MINK1 phosphorylated NLRP3 directly, we used Phos-tag SDS\u2013PAGE to detect the phosphorylation of NLRP3.

SIGNOR-280042

P19544

Q7RTT9

1

transcriptional regulation

up-regulates quantity by expression

0.274

ENT4 is transcriptionally activated by both isoforms of EWS/WT1 as evidenced by promoter-reporter and chromatin immunoprecipitation (ChIP) analyses.

SIGNOR-268985

P04637

Q9C0B5

1

transcriptional regulation

up-regulates quantity by expression

0.2

Mechanistic investigations revealed that mutant p53 transcriptionally upregulated ZDHHC5 along with the nuclear transcription factor NF-Y

SIGNOR-261150

P03372

P42345

0

phosphorylation

up-regulates activity

0.498

Thus our results indicate that the interaction between ER\u03b1 and raptor is necessary to recruit raptor to the nucleus, where mTOR phosphorylates and activates ER\u03b1.

SIGNOR-278295

P40763

P29074

0

dephosphorylation

down-regulates activity

0.255

In terms of molecular mechanisms, we revealed that PTPN4 dephosphorylates pSTAT3 at the Tyr705 residue with a direct interaction, which might provide novel targets for the therapy of CRC.|Loss of PTPN4 Activates STAT3 to Promote the Tumor Growth in Rectal Cancer.

SIGNOR-277057

Q13131

P10636

1

phosphorylation

down-regulates activity

0.2

We have studied the relationship between the phosphorylation oftau by several kinases (MARK, PKA, MAPK, GSK3) and its assembly into PHFs. By contrast, MARK and PKA phosphorylate several sites within the repeats (notably theKXGS motifs including Ser262, Ser324, and Ser356, plus Ser320); in addition PKA phosphorylates somesites in the flanking domains, notably Ser214. This type of phosphorylation strongly reduces tau’s affinityfor microtubules, and at the same time inhibits tau’s assembly into PHFs.

SIGNOR-275439

Q00535

P53779

1

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

O15534

Q9Y297

0

ubiquitination

down-regulates

0.57

We have found that per1 interacts with both _-trcp1 and _-trcp2 in a manner that depends on casein kinase 1 activity, and depletion of both _-trcp1 and _-trcp2 by rnai leads to dramatic stabilization of per1

SIGNOR-137755

P27361

P49715

1

phosphorylation

down-regulates

0.371

Ccaat/enhancer-binding protein alpha (c/ebpalpha) is one of the key transcription factors that mediate lineage specification and differentiation of multipotent myeloid progenitors into mature granulocytes.Here we report that inducers of monocyte differentiation inhibit the alternate cell fate choice, that of granulopoiesis, through inhibition of c/ebpalpha. This inhibition is mediated by extracellular signal-regulated kinases 1 and/or 2 (erk1/2), which interact with c/ebpalpha through an fxfp docking site and phosphorylate serine 21.

SIGNOR-120570

Q14195

Q00535

0

phosphorylation

up-regulates activity

0.603

Together, these results suggest that crmp4 is able to increase neurite formation and elongation in neurons, although not as potently as crmp2, and that this process is regulated by ser522/ser518/thr514/thr509 phosphorylation in both cases. We demonstrate that cdk5 primes crmp2 and crmp4 for subsequent phosphorylation by gsk3, whereas dyrk2, phosphorylates and primes only crmp4 in vitro

SIGNOR-145963

Q9UNE7

P25815

1

polyubiquitination

down-regulates quantity by destabilization

0.292

S100 protein itself is ubiquitinated by CHIP in a Ca2+-dependent manner.Ubiquitylated S100 proteins are shown as (Ub)n-S100A2 and (Ub)n-S100P. The association of the S100 proteins with CHIP provides a Ca2+-dependent regulatory mechanism for the ubiquitination and degradation of intracellular proteins by the CHIP-proteasome pathway.

SIGNOR-272919

P45984

P52564

0

phosphorylation

up-regulates

0.473

A map kinase kinase kinase (mapkkk), termed ask1, was identified that activated two different subs of map kinase kinases (mapkk), sek1 (or mkk4) and mkk3/mapkk6 (or mkk6), which in turn activated stress-activated protein kinase (sapk, also known as jnk;c-jun amino-terminal kinase)

SIGNOR-45369

P05771

P21730

1

phosphorylation

down-regulates

0.2

Dynamics of protein kinase c-mediated phosphorylation of the complement c5a receptor on serine 334. Analysis of c5ar ser/ala mutants that possess a single intact serine residue either at position 334 or at neighboring positions 327, 332, or 338 revealed functional redundancy of c-terminal phosphorylation sites since all 4 serine residues could individually support c5ar internalization and desensitization

SIGNOR-151011

Q6NT76

P01579

1

transcriptional regulation

down-regulates quantity by repression

0.2

Additionally, by luciferase reporter assay, HMBOX1 displayed suppressive effect on the transcription activity of IFN-γ promoter.

SIGNOR-261625

P78352

Q05086

0

ubiquitination

down-regulates quantity by destabilization

0.349

E6-induced degradation of DLG4 depends on E6AP in vivo. Our findings as a whole indicate that E6AP is involved in E6-mediated ubiquitination and degradation of DLG4 both in vivo and in vitro.

SIGNOR-271397

Q15691

O95684

0

relocalization

up-regulates

0.2

Fop also binds to eb1 and is required for localizing eb1 to the centrosome

SIGNOR-142400

P12931

Q16825

0

dephosphorylation

up-regulates

0.643

Ptpd1 activates src tyrosine kinase and increases the magnitude and duration of epidermal growth factor (egf) signaling.

SIGNOR-124774

P08913

Q05655

0

phosphorylation

up-regulates activity

0.533

Taken together, these results indicate that S232 acts as a selective, PKC-sensitive, modulator of effector coupling of the alpha(2A)AR to inositol phosphate stimulation. This represents one mechanism by which cells route stimuli directed to multifunctional receptors to selected effectors so as to attain finely targeted signaling.

SIGNOR-249126

P36956

Q14703

0

cleavage

up-regulates activity

0.561

We present evidence that SKI-1 processes peptides mimicking the cleavage sites of the SKI-1 prosegment, pro-brain-derived neurotrophic factor, and the sterol regulatory element-binding protein SREBP-2

SIGNOR-267497

Q14119

P05305

1

transcriptional regulation

up-regulates quantity by expression

0.276

Vascular endothelial zinc finger 1 (Vezf1)/DB1 is a recently identified zinc finger-containing protein that is expressed specifically within endothelial cells during development. In this report, we demonstrate that Vezf1/DB1 is a nuclear localizing protein that potently and specifically activates transcription mediated by the human endothelin-1 promoter, in a Tax-independent manner, in transient transfection assays. Regulation of endothelin-1 promoter activity by Vezf1/DB1 provides a mechanism for endothelin-1 expression in the vascular endothelium during development and to maintain vascular tone

SIGNOR-266884

Q14493

Q6NXT2

1

translation regulation

up-regulates quantity by expression

0.2

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

SIGNOR-265420

Q13315

Q9UBU7

1

phosphorylation

down-regulates

0.375

Dbf4/cdc7 (dbf4-dependent kinase (ddk)) is activated at the onset of s-phase, and its kinase activity is required for dna replication initiation from each origin. We identified novel atm/atr phosphorylation sites on dbf4 and showed that atm/atr-mediated phosphorylation of dbf4 is critical for the intra-s-phase checkpoint to inhibit dna replication.

SIGNOR-177793

P24941

Q9Y618

1

phosphorylation

down-regulates activity

0.429

Cdk2 and Pin1 negatively regulate the transcriptional corepressor SMRT.|Cdk2 phosphorylates SMRT at consensus Cdk motifs to generate Pin1 binding sites and consequently targets SMRT for degradation, the latter also requiring the PPIase activity of Pin1 (XREF_FIG).

SIGNOR-278306

O43464

Q00535

0

phosphorylation

up-regulates

0.456

Here we report that cyclin-dependent kinase-5 (cdk5), a kinase implicated in the pathogenesis of several neurodegenerative diseases, is responsible for phosphorylating htra2 at s400.We have shown previously that phosphomimetic mutants of htra2 at s400 result in increased proteolytic activity and contribute to enhanced resistance to mitochondrial stress

SIGNOR-174598

P41743

P49757

1

phosphorylation

down-regulates

0.771

Numb is regulated by phosphorylation since the protein is released from ccss and no longer binds integrins when phosphorylated by atypical protein kinase c (apkc).

SIGNOR-156765

P31749

Q86V81

1

phosphorylation

up-regulates

0.449

Nuclear akt directly binds aly and phosphorylates it on the t219 residue. gfp-aly t219d displayed comparable activity to gfp control and wild-type aly, indicating that aly phosphorylation by akt is sufficient to enhance mrna export.

SIGNOR-252518

Q9UBF6

Q16665

1

ubiquitination

down-regulates activity

0.2

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

SIGNOR-271450

O95202

Q9BXM7

0

phosphorylation

up-regulates activity

0.358

Here we demonstrate that PINK1 directly interacts with and phosphorylates LETM1 at Thr192 in vitro.|Phosphorylated LETM1 or the phospho-mimetic LETM1-T192E increase calcium release in artificial liposomes and facilitates calcium transport in intact mitochondria.

SIGNOR-262540

P05231

Q13469

0

transcriptional regulation

up-regulates quantity by expression

0.399

The calcineurin/nuclear factor of activated T cells (NFAT) signaling pathway has been found to play a role in regulating growth and differentiation in several cell types. However, the functional significance of NFAT in the vasculature is largely unclear. Here we show that NFATc1, NFATc3, and NFATc4 are expressed in human myometrial arteries. |Chronic inhibition of NFAT significantly reduced IL-6 production in intact myometrial arteries and inhibited cell proliferation in vascular smooth muscle cells cultured from explants from the same arteries.

SIGNOR-251731

P23528

Q15569

0

phosphorylation

down-regulates activity

0.528

Like TESK1, TESK2 phosphorylated cofilin specifically at Ser-3 and induced formation of actin stress fibers and focal adhesionsExpression of cofilin or S3A-cofilin into HeLa cells induced marked decreases in rhodamine-phalloidin staining due to the actin binding and -depolymerizing activity of cofilin

SIGNOR-246723

P05787

P45983

0

phosphorylation

up-regulates

0.375

Kinase assays showed that c-jun n-terminal kinase (jnk) was also activated with activation kinetics corresponding to that of k8 phosphorylation. Furthermore, k8 was also phosphorylated on ser-73 by jnk in vitro. The ser-73 --> ala-associated filament reorganization defect is rescued by a ser-73 --> asp mutation. Also, disease-causing keratin mutations can modulate keratin phosphorylation and organization, which may affect disease pathogenesis.

SIGNOR-113645

Q02156

O14920

1

phosphorylation

up-regulates activity

0.547

Monoubiquitylated PKC\u03b5 interacts with a ubiquitin-binding domain in NEMO zinc finger and recruits the cytosolic IKK complex to the plasma membrane, where PKC\u03b5 phosphorylates IKK\u03b2 at Ser177 and activates IKK\u03b2.|These results indicate that PKCepsilon phosphorylates IKKbeta at S177 and activates IKKbeta, which in turn induces PKM2 upregulation.

SIGNOR-278323

P10721

O96017

0

phosphorylation

up-regulates

0.286

In this report, we characterize the binding of sh2(chk) to specific phosphotyrosine sites on the c-kit protein sequence. the sh2(chk) binding to the two sites is direct and not through phosphorylated intermediates such as fyn or shc. this indicates that chk binds to the same site on c-kit to which fyn binds, possibly bringing the two into proximity on associated c-kit subunits and leading to the down-regulation of fyn by chk.

SIGNOR-197281

P31749

P84243

1

phosphorylation

down-regulates activity

0.2

Additionally, active akt1 kinase strongly phosphorylates histone h3 at serine 10 in vitro

SIGNOR-98285

Q9Y6Q9

O43781

0

phosphorylation

down-regulates activity

0.2

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

SIGNOR-275451

P49675

P49715

0

transcriptional regulation

up-regulates quantity by expression

0.335

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

SIGNOR-254043

P13807

P49841

0

phosphorylation

down-regulates activity

0.686

Glycogen synthase kinase-3 phosphorylates three serine residues on glycogen synthase (sites 3a, 3b and 3c) which are all located in the same nine-amino-acid segment of the polypeptide chain. The sequence in this region is: Arg-Tyr-Pro-Arg-Pro-Ala-Ser(P)-Val-Pro-Pro-Ser(P)-Pro-Ser-Leu-Ser(P)-Arg-.

SIGNOR-253007

P12931

P04083

1

phosphorylation

up-regulates

0.389

The authors identified several phosphorylated residues by a combination of peptide mapping and sequence analysis and showed that recombinant pp60c-src phosphorylates annexin a1 near its amino terminus, at tyrosine 21 (tyr21). Also polyoma virus middle t/pp60c-src complex, recombinant pp50v-abl, and the egf receptor/kinase phosphorylated the same tyrosine residue. It was also shown that serine 27 residue of anxa1 is the primary site phosphorylated by protein kinase c (pkc). In the same study, the threonine 41 residue has been identified as a pkc substrate as well. The adenosine cyclic 3_,5_-phosphate dependent protein kinase a (pka) phosphorylates anxa1 in its carboxyl-terminal core at the threonine 216 residue (thr216) [2].Finally in 2013 caron et al. showed the relevance of y21 phosphorylation for the anxa1 stability. In fact the authors demonstrated that the tyrosine 21 phosphorylation is crucial for anxa1 sumoylation induced by egf

SIGNOR-202796

P38936

P19174

0

phosphorylation

up-regulates quantity by stabilization

0.262

Phosphorylation at Ser-146 by PKCδ increases p21 stability

SIGNOR-262962

O60260

Q8IXI1

1

polyubiquitination

down-regulates quantity by destabilization

0.2

PINK1 phosphorylates Miro, a component of the primary motor/adaptor complex that anchors kinesin to the mitochondrial surface. The phosphorylation of Miro activates proteasomal degradation of Miro in a Parkin-dependent manner.

SIGNOR-272726

Q8TDY2

Q8IYT8

0

phosphorylation

up-regulates activity

0.747

When mTOR is inhibited, ULK1 and ULK2 activate and phosphorylate ATG13 and FIP200.

SIGNOR-280159

Q8IW41

P04637

1

phosphorylation

up-regulates

0.76

Furthermore, we show that prak activates p53 by direct phosphorylation. prak phosphorylates p53 at ser37

SIGNOR-152847

P42229

Q06609

1

transcriptional regulation

up-regulates quantity by expression

0.263

FLT3-ITD-TKD dual mutants induce hyperactivation of STAT5 and up-regulation of its downstream targets Bcl-x(L) and RAD51 in Ba/F3 cells

SIGNOR-261552

P01236

P31270

0

transcriptional regulation

up-regulates quantity by expression

0.351

HoxA-11 enhanced upregulation of PRL only in differentiated cells.

SIGNOR-261630

O14920

O43524

1

phosphorylation

down-regulates

0.692

Ikkbeta phosphorylates foxo3a at ser644. Ikappab kinase (ikk) physically interacts with, phosphorylates, and inhibits foxo3a independent of akt and causes proteolysis of foxo3a via the ub-dependent proteasome pathway

SIGNOR-124207

Q9UGK3

P12931

0

phosphorylation

up-regulates activity

0.406

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 Tyr-22 and Tyr-322 are the major tyrosine phosphorylation sites by v-Src.

SIGNOR-247337

P28482

Q92574

1

phosphorylation

down-regulates

0.49

Here, we show that erk may play a critical role in tsc progression through posttranslational inactivation of tsc2. Erk-dependent phosphorylation leads to tsc1-tsc2 dissociation and markedly impairs tsc2 ability to inhibit mtor signalin.

SIGNOR-157162

Q9UQM7

P23677

1

phosphorylation

up-regulates

0.329

D-myo-inositol 1,4,5-trisphosphate 3-kinase a is activated by receptor activation through a calcium:calmodulin-dependent protein kinase ii phosphorylation mechanism. the phosphorylated residue was thr311.

SIGNOR-48387

P53667

Q9Y281

1

phosphorylation

down-regulates activity

0.703

Cofilin is known to be a potent regulator of actin filament dynamics, and its ability to bind and depolymerize actin is abolished by phosphorylation of serine residue at 3;. Here we show that lim-kinase 1 (limk-1), a serine/threonine kinase containing lim and pdz domains, phosphorylates cofilin at ser 3, both in vitro and in vivo

SIGNOR-58596

P00533

P42224

1

phosphorylation

up-regulates

0.738

The transcription factors stat1, stat3, and stat5 are directly phosphorylated by erbb-1, subsequent to which they dimerize through phosphotyrosine-sh2 domain interactions and translocate to the nucleus to activate gene trascription critical for proliferation

SIGNOR-235689

Q92569

Q9UM73

0

phosphorylation

up-regulates activity

0.379

Subsequent studies revealed that ALK promoted cell migration through the P3K-AKT pathway via the p55γ regulatory subunit of PI3K.

SIGNOR-253217

P52757

P63000

1

gtpase-activating protein

down-regulates activity

0.64

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-260500

Q8N2W9

O15033

0

ubiquitination

down-regulates quantity by destabilization

0.403

In this study, we discovered a new protein isoform encoded by KIAA0317, termed fibrosis-inducing E3 ligase 1 (FIEL1), which potently stimulates the TGFβ signaling pathway through the site-specific ubiquitination of PIAS4.FIEL1 targets PIAS4 using a double locking mechanism that is facilitated by the kinases PKCζ and GSK3β. Specifically, PKCζ phosphorylation of PIAS4 and GSK3β phosphorylation of FIEL1 are both essential for the degradation of PIAS4.

SIGNOR-275575

Q8WUI4

Q9UPG8

1

deacetylation

down-regulates

0.258

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

SIGNOR-140953

P68400

P33527

1

phosphorylation

up-regulates

0.374

Casein kinase 2_ regulates multidrug resistance-associated protein 1 function via phosphorylation of thr249. This study supports a model in which ck2_ potentiates mrp1 function via direct phosphorylation of thr249.

SIGNOR-197844

O15273

P49841

0

phosphorylation

down-regulates quantity by destabilization

0.2

GSK-3beta phosphorylates FBXL21 and TCAP to activate FBXL21-mediated, phosphodegron-dependent TCAP degradation.|These results show direct GSK-3beta phosphorylation of TCAP S157 and FBXL21 T33 sites.

SIGNOR-264852

P35568

P17252

0

phosphorylation

down-regulates activity

0.386

We show that pkcalpha is likely to be directly involved in ser24 phosphorylation...These observations are entirely consistent with a recent independent study demonstrating that the IRS1-S24D mutant shows impaired insulin-stimulated IR-IRS-1 interactions, tyrosine phosphorylation of IRS-1, recruitment/activation of PI 3-Kinase, and insulin-stimulated Glut4 translocation

SIGNOR-145398

P24723

P28482

1

phosphorylation

up-regulates activity

0.506

Protein kinase C-eta regulates Mcl-1 level via ERK1. knockdown of PKCη but not PKCα, -δ or -ε caused a significant decrease in ERK (extracellular signal-regulated kinase) phosphorylation. Knockdown of ERK1 but not ERK2 decreased Mcl-1 level, and the decrease in Mcl-1 caused by PKCη knockdown was restored by ERK1 overexpression. These results suggest that PKCη utilizes the ERK signaling pathway to protect against ubiquitin-mediated proteasomal degradation of Mcl-1.

SIGNOR-261910

P36897

P61586

1

null

up-regulates activity

0.64

Thus, TGF-_1 rapidly stimulates activity of both RhoA and Rac1 and this activation requires ALK5/T_RI kinase activity.

SIGNOR-227499

Q96CN5

P51955

0

phosphorylation

down-regulates activity

0.37

Moreover, LRRC45 interacts with both C-Nap1 and rootletin and is phosphorylated by Nek2A at S661 during mitosis. After phosphorylation, both LRRC45 centrosomal localization and fiber-like structures are significantly reduced, which subsequently leads to centrosome separation.

SIGNOR-273707

Q92630

P46531

1

phosphorylation

down-regulates quantity by destabilization

0.288

We demonstrate that DYRK2 phosphorylates Notch1-IC in response to chemotherapeutic agents and facilitates its proteasomal degradation by FBXW7 ubiquitin ligase through a Thr-2512 phosphorylation-dependent mechanism.

SIGNOR-279035

Q05086

O43324

1

ubiquitination

down-regulates quantity

0.2

These results strongly suggest that Ube3a decreases p18 levels via ubiquitination followed by proteasomal degradation.|We demonstrate that Ube3a directly ubiquitinates p18 and targets it for proteasomal degradation, which normally limits mTORC1 signaling and activity dependent synaptic remodeling.

SIGNOR-278680

P17612

Q7Z434

1

phosphorylation

down-regulates activity

0.283

Mutagenesis indicated that PKACalpha phosphorylated wild-type VISA and the VISA mutants VISA (S100A), VISA (T234A) and VISA (S238A) but not VISA (T54A) (XREF_FIG, panel C).|We found that PKACalpha caused degradation of wild-type VISA but not VISA (T54A) or VISA (K7/500R), in which either the PKACs mediated phosphorylation or MARCH5 mediated K48 linked polyubiquitination residues are mutated (XREF_FIG, panel G).

SIGNOR-279649

P19784

Q14005

1

phosphorylation

up-regulates activity

0.326

We now show that N-terminal to the NLS domain of pro-IL-16 are protein kinase CK2 substrate and cdc2 kinase substrate sites which, along with the NLS, constitute a dual phosphorylation-regulated CcN motif which regulates nuclear localization of pro-IL-16. In addition, we demonstrate that mutation of either site is associated with impairment of the N-terminal domain's ability to induce G(0)/G(1) cell cycle arrest. | Thus, we confirm that the N-terminal (42SLNEE46) sequence of pro-IL-16 is in fact a site for protein kinase CK2 phosphorylation.

SIGNOR-251009

P00558

Q15118

1

phosphorylation

up-regulates activity

0.428

Mitochondrial PGK1 acts as a protein kinase to phosphorylate pyruvate dehydrogenase kinase 1 (PDHK1) at T338, which activates PDHK1 to phosphorylate and inhibit the pyruvate dehydrogenase (PDH) complex.

SIGNOR-278365

P56915

Q15375

1

transcriptional regulation

down-regulates quantity by repression

0.2

We demonstrate that Goosecoid can act as a repressor of its own promoter activity in transient co-transfection experiments in mouse P19 cells and in Xenopus embryos. Autorepression depends on the presence of the homeodomain and is mediated through the prd element more proximal to the transcriptional start site.

SIGNOR-261613

Q86Y01

P46531

1

ubiquitination

up-regulates activity

0.781

The human Deltex (DTX1) gene encodes a cytoplasmic protein that functions as a positive regulator of the Notch signaling pathway.

SIGNOR-85942

Q9NR19

P11279

1

transcriptional regulation

up-regulates quantity by expression

0.2

Nucleus-Translocated ACSS2 Promotes Gene Transcription for Lysosomal Biogenesis and Autophagy|A chromatin immunoprecipitation (ChIP) assay with antibodies against TFEB or ACSS2 demonstrated that glucose deprivation results in the binding of TFEB (Figure 3D) and ACSS2 (Figure 3E) to the promoter regions of CTSA, GBA, GUSB, and LAMP1|These results indicated that TFEB and ACSS2 are mutually required for their binding to the promoter regions of lysosomal genes. In line with these findings, glucose deprivation induced mRNA (Figure 3F) and protein (Figure 3G) expression for these lysosomal genes, which was largely abrogated by knockin of ACSS2 mutants

SIGNOR-276556

Q4G0J3

Q13315

0

phosphorylation

down-regulates quantity by destabilization

0.2

Altogether, the results suggest that ATM-mediated T440 phosphorylation enhances LARP7-BARD1 interaction and facilitates BRCA1/BARD1-mediated LARP7 ubiquitination and degradation.

SIGNOR-275580

Q9Y6D9

Q13315

0

phosphorylation

up-regulates activity

0.2

ATM mediated Mad1 Serine 214 phosphorylation regulates Mad1 dimerization and the spindle assembly checkpoint.|Together, these findings reveal an important role of ATM-mediated Mad1 Serine 214 phosphorylation in mitosis.

SIGNOR-278467

P15336

Q9Y297

0

ubiquitination

down-regulates quantity by destabilization

0.2

Our data suggest that mTORC1 promotes the binding of the E3 ligase, βTrCP, to CREB2 (Figure 4D), promoting CREB2 degradation by the proteasome (Figure 4E). Here, we show that mTORC1 promotes glutamine anaplerosis by activating glutamate dehydrogenase (GDH). This regulation requires transcriptional repression of SIRT4, the mitochondrial-localized sirtuin that inhibits GDH. Mechanistically, mTORC1 represses SIRT4 by promoting the proteasome-mediated destabilization of cAMP-responsive element binding 2 (CREB2).

SIGNOR-267830

Q13133

P68400

0

phosphorylation

down-regulates

0.2

Ck2? Also phosphorylated lxr? At s198 in vitro, suggesting that ck2 may be a bona fide s198 kinase. our results show that macrophage lxr? Phosphorylation at s198 affects the transcriptional activity of the receptor in a gene-specific manner (fig. ?(Fig.3a)3a) and restricts the repertoire of genes regulated by lxr?

SIGNOR-160640

P49674

P56645

1

phosphorylation

down-regulates activity

0.74

The CKI phosphorylation of mPer1 and mPer3 proteins results in their rapid degradation, which is dependent on the ubiquitin-proteasome pathway. Moreover, CKIepsilon and CKIdelta are able to induce nuclear translocation of mPer3, which requires its nuclear localization signal. The mutation in potential phosphorylation sites on mPer3 decreased the extent of both nuclear translocation and degradation of mPer3 that are stimulated by CKIepsilon. | In mut7 in which all of the conserved serine and threonine residues in this region were mutated, the ratio of the shifted band was greatly reduced reproducibly.

SIGNOR-250816

P15941

Q05655

0

phosphorylation

up-regulates

0.336

We show that phosphorylation of muc1 by pkcdelta increases binding of muc1 and beta-catenin in vitro and in vivo. The functional significance of the muc1-pkcdelta interaction is further supported by the demonstration that mutation of the pkcdelta phosphorylation site abrogates muc1-mediated decreases in binding of beta-catenin to e-cadherin

SIGNOR-115501

Q07352

Q15418

0

phosphorylation

down-regulates activity

0.2

These results indicate that RSK1 directly phosphorylates the C-terminus of ZFP36L1 downstream of ERK, and inhibits the Messenger RNA destabilization activity of ZFP36L1.|These results indicate that RSK1 directly phosphorylates the C-terminus of ZFP36L1 downstream of ERK, and inhibits the mRNA destabilization activity of ZFP36L1.

SIGNOR-279280

Q13224

Q06124

0

dephosphorylation

down-regulates activity

0.469

In addition, surface expression of GluN2B was not reduced in mutant mice and it remains to be investigated how the direct dephosphorylation of GluN2B Y1252 by Shp2 reduces GluN2B function.|The increased GluN2B Y1472 phosphorylation was reversed by a Src family kinase inhibitor, suggesting that Shp2 may negatively regulate GluN2B Y1472 phosphorylation through suppressing Src activity .

SIGNOR-276950

Q06124

P35568

1

dephosphorylation

down-regulates

0.897

The specific activity of four candidate protein-tyrosine phosphatases (protein-tyrosine phosphatase 1b (ptp1b), sh2 domain-containing ptpase-2 (shp-2), leukocyte common antigen-related (lar), and leukocyte antigen-related phosphatase) (lrp) toward irs-1 dephosphorylation was studied using recombinant proteins in vitro. Ptp1b exhibited the highest specific activity these results provide new insight into novel molecular interactions involving ptp1b and grb2 that may influence the steady-state capacity of irs-1 to function as a phosphotyrosine scaffold and possibly affect the balance of postreceptor insulin signaling.

SIGNOR-74856

O14559

P06241

0

phosphorylation

down-regulates

0.461

Tcgap interacted with fyn and was phosphorylated by fyn, with tyr-406 in the gap domain as a major fyn-mediated phosphorylation site. Fyn suppressed the gap activity of wild-type tcgap

SIGNOR-147156

O14939

Q00535

0

phosphorylation

up-regulates activity

0.368

In this study, we suggest that the phosphorylation and activation of PLD2 by cyclin-dependent kinase 5 (Cdk5) is critical for EGF-dependent insulin secretion.|We determined that Cdk5 phosphorylates PLD2 at Ser 134 of PLD2 and that this phosphorylation was suggested to be important for EGF-dependent insulin secretion.

SIGNOR-278395

P17252

Q16760

1

phosphorylation

down-regulates activity

0.366

The plasma membrane translocation of diacylglycerol kinase delta1 is negatively regulated by conventional protein kinase C-dependent phosphorylation at Ser-22 and Ser-26 within the pleckstrin homology domain.

SIGNOR-249265

Q9H2X6

P46527

1

phosphorylation

up-regulates

0.254

Homeodomain-interacting protein kinase-2 stabilizes p27(kip1) by its phosphorylation at serine 10 and contributes to cell motility

SIGNOR-174617

P16220

P31751

0

phosphorylation

up-regulates

0.514

Creb is a nuclear target for activation via the growth factor-dependent ser/thr kinase akt/pkb. When overexpressed in serum-stimulated cells, akt/pkb potently induced ser-133 phosphorylation of creb and promoted recruitment of cbp.

SIGNOR-62253

P16298

P19484

1

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