GleghornLab/Signor_2class · Datasets at Hugging Face

IdA string	IdB string	labels int64	mechanism string	effect string	score float64	sentence string	signor_id string
P53611	P20339	1	lipidation	up-regulates activity	0.491	Prenylation (or geranylgeranylation) of Rab GTPases is catalysed by RGGT (Rab geranylgeranyl transferase) and requires REP (Rab escort protein). In the classical pathway, REP associates first with unprenylated Rab, which is then prenylated by RGGT. In the alternative pathway, REP associates first with RGGT; this complex then binds and prenylates Rab proteins. Rab GTPases need to be geranylgeranylated on either one or two cysteine residues in their Ctermini in order to localize to the correct intracellular membrane and be functional	SIGNOR-265573
Q15256	P49023	1	dephosphorylation	down-regulates activity	0.2	Here, we show that paxillin is a direct substrate of PTPRT and that PTPRT specifically regulates paxillin phosphorylation at tyrosine residue 88 (Y88) in colorectal cancer (CRC) cells. We engineered CRC cells homozygous for a paxillin Y88F knock-in mutant and found that these cells exhibit significantly reduced cell migration and impaired anchorage-independent growth,	SIGNOR-248720
Q00613	Q92630	0	phosphorylation	up-regulates activity	0.318	To test whether in a similar way DYRK2 phosphorylates and activates HSF1 in human cancer cells, we overexpressed DYRK2 and, by use of phosphospecific antibodies, we observed that the levels of endogenous HSF1 phosphorylated at S326 and S320 (two main phosphorylation events linked to HSF1 activation) were increased (Fig.\u00a0 xref ).\|Together, these results show that DYRK2 phosphorylates HSF1 in cells and in vitro at S320 and also at S326, which is critical for HSF1 activation.Next, to test whether endogenous DYRK2 plays a role in HSF1 activation by proteotoxic stress, we used the prototypical HSF1 inducer heat shock (HS), in the absence or in the presence of harmine, observing that the inhibitor clearly impaired the phosphorylation of HSF1 upon HS (Fig S1F).	SIGNOR-278355
Q2M1Z3	P49841	0	phosphorylation	up-regulates activity	0.302	We show that GSK-3alpha and -beta interact with CdGAP in mammalian cells. We also demonstrate that GSK-3 phosphorylates CdGAP both in vitro and in vivo on Thr-776, which we have previously shown to be an ERK 1/2 phosphorylation site involved in CdGAP regulation.	SIGNOR-262879
Q13464	Q2V2M9	1	phosphorylation	up-regulates activity	0.275	In addition we were able to throw light on the mechanism of activation of FHOD3 by ROCK1 and could demonstrate the effects of constitutively active FHOD3 on actin filament synthesis in cardiomyocytes.\|ROCK1 can directly phosphorylate FHOD3 and FHOD3 seems to be the downstream mediator of the exaggerated actin filament formation phenotype that is induced in cardiomyocytes upon the overexpression of constitutively active ROCK1.	SIGNOR-278903
O95863	P49841	0	phosphorylation	down-regulates	0.557	Snail is a well-known zn-finger transcription factor that promotes emt by repressing e-cadherin expression. It is known that snail is phosphorylated by gsk3beta and degraded by beta-trcp-mediated ubiquitination. A variant of snail (snail-6sa), which abolishes these phosphorylations, is much more stable and resides exclusively in the nucleus to induce emt	SIGNOR-129402
O43474	P04637	1	transcriptional regulation	down-regulates quantity by repression	0.56	Previous work has shown that the Kruppel-like factor 4 (KLF4) transcription factor represses p53 transcription by binding to the PE21 element.	SIGNOR-270544
P00533	Q92529-2	1	phosphorylation	up-regulates activity	0.617	We also obtained tryptic phosphopeptide maps of N-Shc protein phosphorylated in vitro by other tyrosine kinases, TrkB, v-Src and EGFR. The overall patterns of the phosphopeptide maps generated by these tyrosine kinases were similar, although there were some differences among these maps (Figure 4a–d).We performed phosphopeptide mapping analysis using GST-fused N-Shc protein, and found that N-Shc phosphorylated by TrkA in vitro was resolved into at least seven phosphopeptides (Y1 through Y7, Figure 4a). Phosphopeptide mapping revealed that N-Shc has novel tyrosine-phosphorylation sites at Y259/Y260 and Y286; in vivo-phosphorylation of these tyrosines was demonstrated by site-specific anti-pTyr antibodies. Phosphorylated Y286 bound to several proteins, of which one was Crk. The pY221/pY222 site, corresponding to one of the Grb2-binding sites of Shc, also preferentially bound to Crk. The phosphorylation-dependent interaction between N-Shc and Crk was demonstrated in vitro and in vivo.	SIGNOR-273922
Q9Y2H1	P21333	1	phosphorylation	up-regulates activity	0.2	Activated Ndr2 Promotes FLNa Release From LFA-1.\|Taken together the data depicted in Figures xref and xref indicate that Ndr2 phosphorylates FLNa at S2152 both in vitro and in vivo .	SIGNOR-278501
Q9BQL6	Q8IWT3	0	ubiquitination	down-regulates quantity by destabilization	0.2	M-phase-specific CDK1–cyclin B1 complex directly binds KIND1 and KIND2 and phosphorylates a conserved proline-directed CDK1 consensus motif in the flexible and intrinsically disordered loop of the F1 domain. This then results in the recruitment of the CUL9–FBXL10 complex, modification with K48-linked polyubiquitin chains and proteasomal degradation of KIND1 and KIND2.	SIGNOR-276718
Q16539	Q12948	1	phosphorylation	up-regulates quantity by stabilization	0.2	P38 interacts with and phosphorylates the Ser241 and ser272 sites of FOXC1 to maintain its stability by inhibiting ubiquitination and degradation.	SIGNOR-275913
P08311	P55085	1	cleavage	down-regulates activity	0.526	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-263585
P23769	P31749	0	phosphorylation	down-regulates	0.524	We show that insulin induces gata2 phosphorylation on serine 401 in a pi-3k/akt-dependent manner. Insulin-dependent phosphorylation of serine 401 impairs gata2 translocation to the nucleus and its dna binding activity	SIGNOR-135614
P80370	Q9Y261	0	transcriptional regulation	up-regulates quantity by expression	0.332	Taken together, these data suggest that Foxa-2 is a direct transcriptional activator of the Pref-1 gene.	SIGNOR-254971
P13051	P49841	0	phosphorylation	down-regulates quantity by destabilization	0.2	Here we show that glycogen synthase kinase 3 (GSK-3) interacts with and phosphorylates UNG2 at Thr60 and that Thr60 phosphorylation requires a Ser64 priming phosphorylation event.\|phosphorylation of Thr60 and Ser64 creates a cyclin E/c-Myc-like phosphodegron that promotes polyubiquitylation and proteasome-mediated degradation	SIGNOR-264885
P48730	P35222	1	phosphorylation	down-regulates	0.626	However, ckiepsilon has been recently shown to interact with axin (sakanaka et al. 1999;rubinfeld et al. 2001), and it was proposed that this kinase mediates axin-induced apc phosphorylation, thereby stabilizing the -catenin degradation complex (rubinfeld et al. 2001). We have, therefore, evaluated cki as a candidate s45-kinase in several assays, both in vitro and in vivo.	SIGNOR-87441
Q14258	Q15911	1	polyubiquitination	down-regulates quantity by destabilization	0.451	In the present study we show that EFP (oestrogen-responsive finger protein) is an E3 ubiquitin ligase mediating oestrogen-induced ATBF1 protein degradation. Knockdown of EFP increases ATBF1 protein levels, whereas overexpression of EFP decreases ATBF1 protein levels.	SIGNOR-272048
Q9H3D4	P23443	0	phosphorylation	down-regulates	0.2	Atm kinase is a master switch for the delta np63 alpha phosphorylation/degradation in human head and neck squamous cell carcinoma cells upon dna damage. We previously found that the pro-apoptotic dna damaging agent, cisplatin, mediated the proteasome-dependent degradation of delta np63 alpha associated with its increased phosphorylated status. We found that delta np63 alpha is phosphorylated in the time-dependent fashion at the following positions: s385, t397 and s466, which were surrounded by recognition motifs for atm, cdk2 and p70s6k kinases, respectively	SIGNOR-180771
P23470	P24941	1	dephosphorylation	down-regulates activity	0.298	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-254695
Q05209	P12931	1	dephosphorylation	up-regulates activity	0.542	PTP-PEST increases dephosphorylation of Src at Y527 and activates it.\|The data presented here supports our hypothesis that PTP-PEST activates Src via dephosphorylating it at Y527 (Tyr530 in human c-Src equivalent to Tyr527 in chicken Src).	SIGNOR-277086
Q14469	P09471	0	null	down-regulates	0.2	GNAO1 overexpression enhances GSC differentiation by downregulating neural progenitor gene HES1	SIGNOR-278092
Q6NXT2	Q9NRC8	0	deacetylation	up-regulates activity	0.2	Besides confirming the previously reported histone H3K18 deacylation activity, our results revealed that SIRT7 has an astonishingly high activity to catalyze deacylation of H3K36 and is also catalytically active to deacylate H3K37.	SIGNOR-275879
Q16659	O95551	1	phosphorylation	up-regulates activity	0.377	ERK3 phosphorylates TDP2 and promotes its phosphodiesterase activity, thereby upregualting TDP2-mediated DNA damage response and desensitizing lung cancer cells to Top2 inhibitor-induced growth inhibition.\|In the current study, we have found that ERK3, an atypical MAPK, phosphorylates TDP2 at S60 and regulates TDP2 's phosphodiesterase activity, thereby cooperatively protecting lung cancer cells against Top2 inhibitors induced DNA damage and growth inhibition.	SIGNOR-278245
P28482	O94953	1	phosphorylation	up-regulates quantity by stabilization	0.2	In addition, the phosphorylation of JMJD2B via p-ERK at Thr305, Ser352, Ser566 and Thr1065 contribute to JMJD2B stability. p-ERK stabilizes the JMJD2B protein level by protecting JMJD2B from ubiquitination and proteasome degradation.	SIGNOR-276744
Q13635	P42574	0	cleavage	down-regulates	0.321	Like other dependence receptors, ptc1 contains a dependence-as-associated receptor c-terminal motif that is cleaved by caspases at a conserved aspartic acid (asp 1392) in the absence of shh, to expose a proapoptotic domain.	SIGNOR-199111
P35222	P04626	0	phosphorylation	down-regulates activity	0.766	Second, ErbB2 phosphorylates \u03b2-catenin at Tyr 654, leading to dissociation of the E-cadherin-\u03b2-catenin membrane complex and increased signaling to Wnt target genes such as cyclin D1 ( ).	SIGNOR-279041
Q9UKB1	P84022	1	ubiquitination	up-regulates	0.261	Here, we show that smad3 activated by tgf-beta is degraded by the ubiquitin-proteasome pathway. Smad3 interacts with a ring finger protein, roc1, through its c-terminal mh2 domain in a ligand-dependent manner. An e3 ubiquitin ligase complex roc1-scf(fbw1a) consisting of roc1, skp1, cullin1, and fbw1a (also termed betatrcp1) induces ubiquitination of smad3.	SIGNOR-108240
Q02156	Q92934	1	phosphorylation	down-regulates	0.34	Pkcs phosphorylate bad under in vitro conditions, and the association of phosphorylated bad with pkc-mu or pkc-epsilon, as shown by immunoprecipitation, indicated direct involvement of pkcs in bad phosphorylation. To confirm these results, cells overexpressing pegfp-n1, wt-bad, or bad with a single site mutated (ser112ala;ser136ala;ser155ala), two sites mutated (ser(112/136)ala;ser(112/155)ala;ser(136/155)ala), or the triple mutant were tested. Igf-i protected completely against rapamycin-induced apoptosis in cells overexpressing wt-bad and mutants having either one or two sites of phosphorylation mutated	SIGNOR-163908
P01019	P08246	0	cleavage	up-regulates activity	0.275	Cathepsin G, elastase, and proteinase 3 are serine proteinases released by activated neutrophils. Cathepsin G can cleave angiotensinogen to release angiotensin II, but this activity has not been previously reported for elastase or proteinase 3. In this study we show that elastase and proteinase 3 can release angiotensin I from angiotensinogen and release angiotensin II from angiotensin I and angiotensinogen.	SIGNOR-256313
Q5T447	Q9UNK0	1	polyubiquitination	down-regulates quantity by destabilization	0.44	Our co-immunoprecipitation experiments show that Syntaxin 8 directly interacts with HECTd3 and that the overexpression of HECTd3 promotes the ubiquitination of Syntaxin 8. Immunoprecipitates probed with the anti-ubiquitin (Santa Cruz) antibody could be recognized by the anti-ubiquin antibody (Fig. 3a), indicating that the shift of the His-syntaxin 8 protein bands were caused by polyubiquitin conjugations. Our data suggest that HECTd3 may function as an E3 ubiquitin-protein ligase to promote the ubiquitination and degradation of Syntaxin 8 through the proteasome pathway.	SIGNOR-271772
P16070	O14672	0	cleavage	up-regulates activity	0.346	The ADAM proteases are best known for their role in shedding the extracellular domain of transmembrane proteins. Among the transmembrane proteins shed by ADAM10 are notch, HER2, E-cadherin, CD44, L1 and the EGFR ligands, EGF and betacellulin.	SIGNOR-259847
O60674	Q92783	1	phosphorylation	up-regulates	0.617	Stam is associated with jak3 and jak2 tyrosine kinases via its itam region and phosphorylated by jak3 and jak2 upon stimulation with il-2.	SIGNOR-47834
Q13535	Q9Y253	1	phosphorylation	up-regulates	0.415	Atr-mediated phosphorylation of dna polymerase _ is needed for efficient recovery from uv damage. We show that, after uv irradiation, pol_ becomes phosphorylated at ser601 by the ataxia-telangiectasia mutated and rad3-related (atr) kinase. Atr-dependent phosphorylation of pol_ is necessary to restore normal survival and postreplication repair	SIGNOR-171290
P19174	P08631	0	phosphorylation	up-regulates activity	0.681	The phosphorylation of purified phospholipase C-gamma 1 (PLC-gamma 1) and PLC-gamma 2 by src-family-protein tyrosine kinases (PTKs) P56lck, p53/56lyn, p59hck, p59fyn, and p60src was studied in vitro. All five PTKs phosphorylated PLC-gamma 1 and PLC-gamma 2, suggesting that both PLC-gamma isozymes can be phosphorylated in cells by any of the src-family PTKs in response to the activation of cell surface receptors.	SIGNOR-249361
Q9Y4K3	O43561	1	ubiquitination	up-regulates activity	0.345	Interestingly, this study has demonstrated that the membrane-proximal region of linker for activation of T cells preceding tyrosine-132 mediates its association with TRAF6, which promotes the ubiquitination of linker for activation of T cells and, in turn, the phosphorylation of tyrosine residues on linker for activation of T cells.\|Moreover, LAT was ubiquitinated at Lysine 88 by TRAF6 via K63 linked chain.	SIGNOR-278675
Q16665	Q9UBF6	0	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
P35998	Q05086	0	ubiquitination	down-regulates quantity by destabilization	0.385	Our experiments collectively suggest that UBE3A stimulates Wnt pathway activation by interacting with, ubiquitinating, and reducing the levels of multiple (PSMB1, PSMC2, PSMD2, and PSMD7) proteasome subunits.	SIGNOR-265132
P17252	Q8TD43	1	phosphorylation	up-regulates	0.2	Phorbol ester-induced activation of protein kinase c (pkc) increased the ca(2+) sensitivity of wild-type trpm4 but not of two mutants mutated at putative pkc phosphorylation sites.	SIGNOR-132243
O00418	Q13131	0	phosphorylation	down-regulates activity	0.492	AMPK can phosphorylate three sites in eEF2 kinase in vitro. Of these, Ser-398 appears to be more efficiently phosphorylated than either Ser-78 or Ser-366. Ser-78 and Ser-366 do not appear to be phosphorylated by AMPK within cells. Ser-366 serves to decrease the activity of eEF2 kinase	SIGNOR-250314
P49840	O15084	1	phosphorylation	down-regulates activity	0.2	We provide evidence for a dual kinase-mediated regulation of the PITK holoenzyme whereby PITK phosphorylation at S1017 is catalyzed by calcium/calmodulin-dependent kinase II-delta (CaMKIIdelta), promoting the subsequent phosphorylation of S1013 by glycogen synthase kinase-3 (GSK3) in vitro.\|the phosphorylation of PITK at these specific residues altered PP1 binding and subsequent PITK-directed dephosphorylation of hnRNP K	SIGNOR-264792
Q05193	Q13627	0	phosphorylation	down-regulates	0.416	Mnb/dyrk1a was shown to phosphorylate dynamin 1 and alter its interactions with several sh3 domain-containing endocytic accessory proteins.Phosphorylation At s795 and s857 was confirmed in full-length dynamin 1, and s857 was subsequently determined to be the major mnb/dyrk1a phosphorylation site in vitro. Phosphorylation at s857 was demonstrated to be the basis for altering the binding of dynamin 1 to amphiphysin 1 and grb 2 by site-directed mutants mimicking phosphorylation.	SIGNOR-127440
P49716	P49841	0	phosphorylation	down-regulates quantity by destabilization	0.384	Phosphorylation of C/EBPdelta by GSK-3beta is required for its degradation by FBXW7alpha.	SIGNOR-279180
P08311	P05546	1	cleavage	down-regulates activity	0.444	Amino acid sequence analysis led to the conclusion that both neutrophil elastase and cathepsin G cleave HC at Ile66, which does not affect HC activity, and at Val439, near the reactive site Leu444, which inactivates HC.	SIGNOR-256509
P15172	P26651	0	post transcriptional regulation	down-regulates quantity by destabilization	0.292	The TTP binding site in the 3â€² UTR of MyoD would permit TTP-mediated mRNA decay	SIGNOR-253597
P12931	Q9UL51	1	phosphorylation	up-regulates activity	0.267	We identified a highly conserved tyrosine residue in the C-linker of HCN channels (Tyr476 in HCN2) that confers modulation by Src. Replacement of this tyrosine by phenylalanine in HCN2 or HCN4 abolished sensitivity to Src inhibitors. Mass spectrometry confirmed that Tyr476 is phosphorylated by Src. Our results have functional implications for HCN channel gating. Furthermore, they indicate that tyrosine phosphorylation contributes in vivo to the fine tuning of HCN channel activity.	SIGNOR-263199
P53041	Q16543	1	dephosphorylation	down-regulates activity	0.672	Activation of protein kinase clients by the Hsp90 system is mediated by the cochaperone protein Cdc37. Cdc37 requires phosphorylation at Ser13\|PP5/Ppt1 regulates phosphorylation of Ser13-Cdc37 in vivo, directly affecting activation of protein kinase clients by Hsp90-Cdc37.	SIGNOR-248539
Q92769	P33076	1	deacetylation	down-regulates quantity by repression	0.413	We report that CIITA and histone deacetylase 2 (HDAC2) interact in smooth muscle cells and macrophages as assayed by co-immunoprecipitations. HDAC2 deacetylates CIITA whereas both the HDAC inhibitor trichostatin A (TSA) and over-expression of HDAC2 interfering RNA increase CIITA acetylation. HDAC2 down-regulates CIITA recruitment to target promoters as evidenced by chromatin immunoprecipitation assays, and suppresses MHC II activation and collagen repression mediated by CIITA in luciferase reporter assays.	SIGNOR-254231
Q9Y577	Q07820	1	polyubiquitination	down-regulates quantity by destabilization	0.444	Here, we identified Trim17 as a novel E3 ubiquitin-ligase for Mcl-1. Indeed, Trim17 co-immunoprecipitated with Mcl-1. Trim17 ubiquitinated Mcl-1 in vitro. Overexpression of Trim17 decreased the protein level of Mcl-1 in a phosphorylation- and proteasome-dependent manner. Finally, knock down of Trim17 expression reduced both ubiquitination and degradation of Mcl-1 in neurons.	SIGNOR-272032
Q96FW1	P04637	1	deubiquitination	up-regulates quantity by stabilization	0.565	Furthermore, although OTUB1 dramatically induced p53 deubiquitination, its mutant (S16A) and deletion mutant did not have this effec	SIGNOR-276528
P41212	P27361	0	phosphorylation	down-regulates	0.317	Tel became phosphorylated by erk on two serine residues, ser213 and ser257, in the internal domain between the hlh and ets domains. Tel lost its abilities to repress transcription through the phosphorylation.	SIGNOR-123656
P54646	Q8IYT8	0	phosphorylation	down-regulates	0.304	We could prove that ulk1-mediated phosphorylation of ampk reduced its level of phosphorylation at t172 of the _-subunit and hence interferes with its catalytic activity. I	SIGNOR-173089
Q99558	Q13489	0	ubiquitination	down-regulates	0.65	Ciap1/2 (cellular inhibitor of apoptosis 1 and 2) ubiquitinate nik for degradation.	SIGNOR-167298
O43353	Q8WWF5	0	ubiquitination	down-regulates quantity by destabilization	0.2	Collectively, ZNRF4 degrades RIP2 protein by targeting the RIP2CARD domain in an E3-ubiquitin ligase activity dependent manner.\|Here we show that ZNRF4 induces K48-linked ubiquitination of RIP2 and promotes RIP2 degradation.	SIGNOR-278684
P28328	P28288	1	ubiquitination	up-regulates activity	0.401	PEX5 and PMP70 are ubiquitinated by PEX2 during amino acid starvation.	SIGNOR-278708
P35611	Q13464	0	phosphorylation	up-regulates	0.376	Rho-associated kinase (rho- kinase), which is activated by the small guanosine triphosphatase rho, phosphorylates alpha-adducin and thereby enhances the f-actin-binding activity of alpha-adducin in vitro. Here we identified the sites of phosphorylation of alpha-adducin by rho-kinase as thr445 and thr480	SIGNOR-66996
P35221	P68400	0	phosphorylation	down-regulates	0.39	We demonstrate here that egfr activation results in disruption of the complex of beta-catenin and alpha-catenin, thereby abrogating the inhibitory effect of alpha-catenin on beta-catenin transactivation via ck2alpha-dependent phosphorylation of alpha-catenin at s641.	SIGNOR-161847
Q9P0L2	P10636	1	phosphorylation	down-regulates activity	0.429	We have studied the relationship between the phosphorylation of tau by several kinases (MARK, PKA, MAPK, GSK3) and its assembly into PHFs. MARK and PKA phosphorylate several sites within the repeats (notably the KXGS motifs including Ser262, Ser324, and Ser356, plus Ser320). This type of phosphorylation strongly reduces tau's affinity for microtubules, and at the same time inhibits tau's assembly into PHFs.	SIGNOR-250173
P05412	P01112	0	phosphorylation	up-regulates activity	0.5	c-Jun was first shown to be phosphorylated in its transactivation domain (Ser-63 and Ser-73) by ERKs and p54-JNK. This is consistent with other studies which show that PD98059 inhibits up-regulation of c-Jun protein in Ras-transformed NIH-3T3 cells	SIGNOR-235522
Q02878	Q00987	0	ubiquitination	down-regulates quantity by destabilization	0.432	Furthermore, we also demonstrated that RPL6 is a substrate for HDM2-mediated ubiquitination and proteasomal degradation.\|The interaction of RPL6 and HDM2 drives HDM2 mediated RPL6 polyubiquitination and proteasomal degradation.	SIGNOR-278630
O15550	P31270	1	transcriptional regulation	up-regulates quantity by expression	0.263	Evidence for direct involvement of UTX in regulation of HOX gene activity was demonstrated through UTX knockdown experiments in HEK293T cells in which loss of UTX induced transcriptional repression of HOXA and HOXC clusters.	SIGNOR-260021
P27361	Q14247	1	phosphorylation	up-regulates	0.422	Cortactin is regulated by multiple phosphorylation events, including phosphorylation of s405 and s418 by extracellular regulated kinases (erk)1/2. Erk1/2 phosphorylation of cortactin has emerged as an important positive regulatory modification, enabling cortactin to bind and activate the arp2/3 regulator neuronal wiskott-aldrich syndrome protein (n-wasp), promoting actin polymerization and enhancing tumor cell movement.	SIGNOR-165212
Q12778	P24941	0	phosphorylation	down-regulates	0.652	Cdk2 specifically phosphorylated foxo1 at serine-249 (ser249) in vitro and in vivo. Phosphorylation of ser249 resulted in cytoplasmic localization and inhibition of foxo1.	SIGNOR-150028
Q9NPB6	P37173	0	phosphorylation	up-regulates	0.466	We demonstrate that Par6, a regulator of epithelial cell polarity and tight-junction assembly, interacts with TGFbeta receptors and is a substrate of the type II receptor, TbetaRII. [...] These data suggest that T_RII phosphorylates Par6 at its penultimate residue, Ser345.	SIGNOR-227484
Q15256	P17612	0	phosphorylation	down-regulates activity	0.343	The PKA phosphorylation site on PTP-SL was identified as the Ser(231) residue. treatment of COS-7 cells with PKA activators, or overexpression of the Calpha catalytic subunit of PKA, inhibited the cytoplasmic retention of ERK2 and p38alpha by wild-type PTP-SL, but not by a PTP-SL S231A mutant.‚	SIGNOR-250038
P00519	P15941	1	phosphorylation	up-regulates quantity by stabilization	0.455	The results demonstrate that ABL1 phosphorylates MUC1 on Tyr-60 and forms a complex with MUC1 by binding of the ABL1 SH2 domain to the pTyr-60 site.	SIGNOR-260830
O00139	Q6IQ55	0	phosphorylation	down-regulates activity	0.406	TTBK2 phosphorylates KIF2A primarily at growing MT ends and counteracts the depolymerization activity of KIF2A	SIGNOR-260926
P53350	Q9H2D6	1	phosphorylation	up-regulates	0.335	Here we show that tara is a novel polo-like kinase 1 (plk1) target protein. Plk1 interacts with and phosphorylates tara in vivo and in vitro. Actually, the thr-457 in tara was a bona fide in vivo phosphorylation site for plk1. Interestingly, we found that the centrosomal localization of tara depended on the thr-457 phosphorylation and the kinase activity of plk1	SIGNOR-198353
P49841	Q13237	0	phosphorylation	down-regulates activity	0.258	These data indicate that hypertrophic differentiation of growth plate chondrocytes during skeletal growth is promoted by phosphorylation and inactivation of GSK-3beta by cGKII.	SIGNOR-280095
Q13490	Q14249	1	ubiquitination	up-regulates activity	0.468	Alternatively, cIAP1 may mediate a vital function of EndoG other than cell death.\|Cellular inhibitor of apoptosis protein 1 ubiquitinates endonuclease G but does not affect endonuclease G-mediated cell death.	SIGNOR-278605
P23470	Q8WV28	1	dephosphorylation	up-regulates activity	0.2	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-254692
Q9GZQ8	Q9NR19	0	transcriptional regulation	up-regulates quantity by expression	0.2	As expected, we found that glucose deprivation induced the binding of TFEB (Figure S4C) and ACSS2 (Figure S4D) to the promoter regions of MAP1LC3B, ATG3, and WIPI-1 as well as mRNA (Figure 3H) and protein (Figure 3I) expression of these genes;	SIGNOR-276562
P23588	P23443	0	phosphorylation	up-regulates	0.776	S6k1/s6k2 specifically phosphorylate ser422 in vitro. Substitution of ser422 with ala results in a loss of activity in an in vivo translation assay, indicating that phosphorylation of this site plays an important role in eif4b function.	SIGNOR-123997
P53350	Q76N32	1	phosphorylation	down-regulates quantity by destabilization	0.44	We show that the intercentrosomal linker protein Cep68 is degraded in prometaphase through the SCF(βTrCP) (Skp1-Cul1-F-box protein) ubiquitin ligase complex. Cep68 degradation is initiated by PLK1 phosphorylation of Cep68 on Ser 332, allowing recognition by βTrCP.	SIGNOR-275621
P42229	Q07817	1	transcriptional regulation	up-regulates quantity by expression	0.653	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-261551
Q13315	Q9NZM5	1	phosphorylation	down-regulates quantity by destabilization	0.2	PICT-1 S233 and T289 were identified as the key phosphorylation sites in this pathway, as mutating both to alanine abolished UVB-induced increase of PICT-1 phosporylation. Inhibition of PIKKs or ATM (with wortmannin and KU55933, respectively) prevented the agglomeration and degradation of PICT-1, suggesting that ATM is a key regulator of PICT-1.	SIGNOR-273506
P25098	P41143	1	phosphorylation	down-regulates activity	0.2	Taken together, we have demonstrated that agonist-induced opioid receptor phosphorylation occurs exclusively at two phosphate acceptor sites (T358 and S363) of GRK2 at the DOR carboxyl terminus.	SIGNOR-249660
Q05655	Q16236	1	phosphorylation	up-regulates activity	0.371	Phosphorylation of Nrf2 at Ser-40 by protein kinase C regulates antioxidant response element-mediated transcription.	SIGNOR-249161
P78504	Q86YT6	0	ubiquitination	up-regulates activity	0.693	Mib1 is essential for the generation of functional notch ligands and regulates the classical notch ligands dll1, dll4, jag1, and jag2 in vertebrates mib1 is an essential e3 ubiquitin ligase for jag1 in the developing cerebellum.	SIGNOR-97388
P04637	P19525	0	phosphorylation	up-regulates	0.571	The double-stranded rna activated protein kinase pkr physically associates with the tumor suppressor p53 protein and phosphorylates human p53 on serine 392 in vitro.	SIGNOR-68033
P00519	P37840	1	phosphorylation	up-regulates quantity	0.424	C-Abl interacts with alpha-synuclein and phosphorylates alpha-synuclein at Y39 (XREF_FIG) .	SIGNOR-279582
P49841	Q99612	1	phosphorylation	up-regulates activity	0.2	Functionally, GSK3beta enhanced KLF6 mediated growth suppression, which was abrogated by the KLF6-4A phosphomutant.\|These data establish that GSK3\u03b2 directly phosphorylates KLF6, which augments its induction of p21 and resultant growth suppression.	SIGNOR-279373
Q00987	P98177	1	ubiquitination	down-regulates activity	0.63	Mdm2 Induces Mono-Ubiquitination of FOXO4.\|higher amounts of Mdm2 transfected resulted in reduced FOXO4 transcriptional activity.	SIGNOR-278656
O60496	P23470	0	dephosphorylation	up-regulates activity	0.2	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-254698
O15162	Q05655	0	phosphorylation	up-regulates	0.424	Following the induction of apoptosis, however, phosphorylation of serine residues decreased and it increased on threonine, consistent with the predicted pkc phosphorylation site at thr-161. Transfection of cho cells with scramblase and pkc_, but not scramblase or pkc_ alone, increased scramblase activity	SIGNOR-76904
P17706	P09619	1	dephosphorylation	down-regulates activity	0.564	The PDGF beta receptor is negatively regulated by protein tyrosine phosphatases (PTPs).\|In summary, our findings identify TC-PTP as a previously unrecognized negative regulator of PDGF beta receptor signaling and support the general notion that PTPs display site selectivity in their action on tyrosine kinase receptors.The fact that two of the investigated PDGF β receptor sites, Y1021 and Y771, displayed a larger increase in phosphorylation than Y579 and Y751 in TC-PTP ko MEFs indicated that these two sites are preferred substrates for TC-PTP.	SIGNOR-248389
P17612	Q92736	1	phosphorylation	up-regulates activity	0.478	PKA-mediated hyperphosphorylation of a conserved serine, Ser-2843 in skeletal RyR and Ser-2809 in cardiac RyR, results in an aberrant SR function during heart failure. hyperphosphorylated RyRs are leaky and therefore lead to a reduced SR Ca2+ load and impaired contractile function in heart failure	SIGNOR-250079
P07949	Q12913	0	dephosphorylation	down-regulates activity	0.277	The receptor-type protein tyrosine phosphatase J antagonizes the biochemical and biological effects of RET-derived oncoproteins.\|PTPRJ expression induces dephosphorylation of the RET(C634R) and, probably via an indirect mechanism, RET/PTC1 oncoproteins on two key RET autophosphorylation sites (Tyr1062 and Tyr905). This results in a significant decrease of RET-induced Shc and extracellular signal-regulated kinase 1/2 phosphorylation levels	SIGNOR-248701
P25963	O14965	0	phosphorylation	down-regulates activity	0.541	The results of the in vitro kinase assay, using purified human recombinant AURKA and IkappaBalpha proteins, confirmed that AURKA can directly phosphorylate IkappaBalpha (Ser32) at a concentration as low as 2.5 ng/mul (XREF_FIG).\|While an earlier study suggested that AURKA down-regulates IkappaBalpha indirectly through activation of the PI3K and AKT pathway 35, our data demonstrate, for the first time, that AURKA directly binds and phosphorylates the IkappaBalpha subunit, leading to activation of NF-kappaB.	SIGNOR-278912
O00213	P00519	0	phosphorylation	up-regulates	0.415	The c-abl tyrosine kinase phosphorylates the fe65 adaptor protein to stimulate fe65/amyloid precursor protein nuclear signaling. Here, we show that active c-abl stimulates app/fe65-mediated gene transcription and that this effect is mediated by phosphorylation of fe65 on tyrosine 547 within its second ptb domain.	SIGNOR-123476
P06493	Q16512	1	phosphorylation	up-regulates activity	0.436	CDK1 phosphorylates PKN1 at S533, S537, S562, and S916 in vitro and in cells during drug-induced mitotic arrest. Immunofluorescence staining further confirmed that PKN1 phosphorylation occurs during normal mitosis in a CDK1-dependent manner.Knockdown of PKN1 significantly inhibited anchorage-independent growth and migration without affecting proliferation in multiple cancer cell lines.	SIGNOR-276831
P36873	O15169	1	dephosphorylation	down-regulates activity	0.269	The data suggest that PP1 controls Wnt signaling through interaction with, and regulated dephosphorylation of, axin\| Axin phosphorylation markedly enhances the binding of glycogen synthase kinase 3, leading to a more active beta-catenin destruction complex. Wnt-regulated changes in axin phosphorylation, mediated by PP1, may therefore determine beta-catenin transcriptional activity\| Four sites, S80, S82, S222, and S473, were identified to be PP1 regulated	SIGNOR-248494
O00743	O43318	1	dephosphorylation	down-regulates activity	0.372	Protein phosphatase 6 down-regulates TAK1 kinase activation in the IL-1 signaling pathway\|From proteomic analysis of TAK1-binding proteins, we identified protein phosphatase 6 (PP6), a type-2A phosphatase, and demonstrated that PP6 associated with and inactivated TAK1 by dephosphorylation of Thr-187.	SIGNOR-248292
Q96PU5	P35498	1	ubiquitination	down-regulates quantity by destabilization	0.292	The control of Nav density at the cell membrane is crucial to ensuring normal neuronal excitability. Navs are subject to posttranslational modifications that may influence their cell membrane availability. Ubiquitylation is a key process that orchestrates the internalization and subsequent degradation or recycling of Navs. This is accomplished by ubiquitin protein ligases, such as NEDD4-2 (neuronal precursor cell expressed developmentally downregulated-4 type 2).	SIGNOR-253457
Q12948	Q16539	0	phosphorylation	up-regulates quantity by stabilization	0.2	P38 interacts with and phosphorylates the Ser241 and ser272 sites of FOXC1 to maintain its stability by inhibiting ubiquitination and degradation.	SIGNOR-275913
P08581	Q92990	1	relocalization	down-regulates	0.331	Significantly, nonphosphorylated hgf receptor prevents fap68 from stimulating p70s6k. fap68 binding to met requires the last 30 amino acids of the c-terminal tail, which are unique to the hgf receptor.	SIGNOR-110726
P53350	Q99741	1	phosphorylation	up-regulates	0.566	Binding between cdc6 and plk1 occurs through the polo-box domain of plk1, and cdc6 is phosphorylated by plk1 on t37. These results suggest that plk1-mediated phosphorylation of cdc6 promotes the interaction of cdc6 and cdk1, leading to the attenuation of cdk1 activity, release of separase, and subsequent anaphase progression.	SIGNOR-169184
P55010	P68400	0	phosphorylation	up-regulates	0.394	We find that eif5 is associated with ck2 when the kinase activity is at the highest level in vivo, and is phosphorylated at ser389 and ser390 by ck2.	SIGNOR-141159
O00311	P49736	1	phosphorylation	up-regulates	0.962	In this work, by in vitro kinase reactions and mass spectrometry analysis of the products, we have mapped phosphorylation sites in the n terminus of mcm2 by cdc7, cdk2, cdk1, and ck2	SIGNOR-143984
P49841	O75925	1	phosphorylation	down-regulates quantity by destabilization	0.332	We discovered a ubiquitin E3 ligase, HECTD2, which ubiquitinated and mediated the degradation of PIAS1, thus increasing inflammation in an experimental pneumonia model. We found that GSK3β phosphorylation of PIAS1 provided a phosphodegron for HECTD2 targeting.	SIGNOR-276923
Q9BXM7	P10636	1	phosphorylation	down-regulates activity	0.384	Simultaneously overexpressing PINK1 significantly reduced the levels of exogenous total and phosphorylated tau proteins (Figures 4A,B,E).\|Taken together, our data revealed that PINK1 overexpression promoted degradation of abnormal accumulated tau via the autophagy-lysosome pathway, indicating that PINK1 may be a potential target for AD treatment.	SIGNOR-279250

P53611

P20339

1

lipidation

up-regulates activity

0.491

Prenylation (or geranylgeranylation) of Rab GTPases is catalysed by RGGT (Rab geranylgeranyl transferase) and requires REP (Rab escort protein). In the classical pathway, REP associates first with unprenylated Rab, which is then prenylated by RGGT. In the alternative pathway, REP associates first with RGGT; this complex then binds and prenylates Rab proteins. Rab GTPases need to be geranylgeranylated on either one or two cysteine residues in their Ctermini in order to localize to the correct intracellular membrane and be functional

SIGNOR-265573

Q15256

P49023

1

dephosphorylation

down-regulates activity

0.2

Here, we show that paxillin is a direct substrate of PTPRT and that PTPRT specifically regulates paxillin phosphorylation at tyrosine residue 88 (Y88) in colorectal cancer (CRC) cells. We engineered CRC cells homozygous for a paxillin Y88F knock-in mutant and found that these cells exhibit significantly reduced cell migration and impaired anchorage-independent growth,

SIGNOR-248720

Q00613

Q92630

0

phosphorylation

up-regulates activity

0.318

To test whether in a similar way DYRK2 phosphorylates and activates HSF1 in human cancer cells, we overexpressed DYRK2 and, by use of phosphospecific antibodies, we observed that the levels of endogenous HSF1 phosphorylated at S326 and S320 (two main phosphorylation events linked to HSF1 activation) were increased (Fig.\u00a0 xref ).|Together, these results show that DYRK2 phosphorylates HSF1 in cells and in vitro at S320 and also at S326, which is critical for HSF1 activation.Next, to test whether endogenous DYRK2 plays a role in HSF1 activation by proteotoxic stress, we used the prototypical HSF1 inducer heat shock (HS), in the absence or in the presence of harmine, observing that the inhibitor clearly impaired the phosphorylation of HSF1 upon HS (Fig S1F).

SIGNOR-278355

Q2M1Z3

P49841

0

phosphorylation

up-regulates activity

0.302

We show that GSK-3alpha and -beta interact with CdGAP in mammalian cells. We also demonstrate that GSK-3 phosphorylates CdGAP both in vitro and in vivo on Thr-776, which we have previously shown to be an ERK 1/2 phosphorylation site involved in CdGAP regulation.

SIGNOR-262879

Q13464

Q2V2M9

1

phosphorylation

up-regulates activity

0.275

In addition we were able to throw light on the mechanism of activation of FHOD3 by ROCK1 and could demonstrate the effects of constitutively active FHOD3 on actin filament synthesis in cardiomyocytes.|ROCK1 can directly phosphorylate FHOD3 and FHOD3 seems to be the downstream mediator of the exaggerated actin filament formation phenotype that is induced in cardiomyocytes upon the overexpression of constitutively active ROCK1.

SIGNOR-278903

O95863

P49841

0

phosphorylation

down-regulates

0.557

Snail is a well-known zn-finger transcription factor that promotes emt by repressing e-cadherin expression. It is known that snail is phosphorylated by gsk3beta and degraded by beta-trcp-mediated ubiquitination. A variant of snail (snail-6sa), which abolishes these phosphorylations, is much more stable and resides exclusively in the nucleus to induce emt

SIGNOR-129402

O43474

P04637

1

transcriptional regulation

down-regulates quantity by repression

0.56

Previous work has shown that the Kruppel-like factor 4 (KLF4) transcription factor represses p53 transcription by binding to the PE21 element.

SIGNOR-270544

P00533

Q92529-2

1

phosphorylation

up-regulates activity

0.617

We also obtained tryptic phosphopeptide maps of N-Shc protein phosphorylated in vitro by other tyrosine kinases, TrkB, v-Src and EGFR. The overall patterns of the phosphopeptide maps generated by these tyrosine kinases were similar, although there were some differences among these maps (Figure 4a–d).We performed phosphopeptide mapping analysis using GST-fused N-Shc protein, and found that N-Shc phosphorylated by TrkA in vitro was resolved into at least seven phosphopeptides (Y1 through Y7, Figure 4a). Phosphopeptide mapping revealed that N-Shc has novel tyrosine-phosphorylation sites at Y259/Y260 and Y286; in vivo-phosphorylation of these tyrosines was demonstrated by site-specific anti-pTyr antibodies. Phosphorylated Y286 bound to several proteins, of which one was Crk. The pY221/pY222 site, corresponding to one of the Grb2-binding sites of Shc, also preferentially bound to Crk. The phosphorylation-dependent interaction between N-Shc and Crk was demonstrated in vitro and in vivo.

SIGNOR-273922

Q9Y2H1

P21333

1

phosphorylation

up-regulates activity

0.2

Activated Ndr2 Promotes FLNa Release From LFA-1.|Taken together the data depicted in Figures xref and xref indicate that Ndr2 phosphorylates FLNa at S2152 both in vitro and in vivo .

SIGNOR-278501

Q9BQL6

Q8IWT3

0

ubiquitination

down-regulates quantity by destabilization

0.2

M-phase-specific CDK1–cyclin B1 complex directly binds KIND1 and KIND2 and phosphorylates a conserved proline-directed CDK1 consensus motif in the flexible and intrinsically disordered loop of the F1 domain. This then results in the recruitment of the CUL9–FBXL10 complex, modification with K48-linked polyubiquitin chains and proteasomal degradation of KIND1 and KIND2.

SIGNOR-276718

Q16539

Q12948

1

phosphorylation

up-regulates quantity by stabilization

0.2

P38 interacts with and phosphorylates the Ser241 and ser272 sites of FOXC1 to maintain its stability by inhibiting ubiquitination and degradation.

SIGNOR-275913

P08311

P55085

1

cleavage

down-regulates activity

0.526

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-263585

P23769

P31749

0

phosphorylation

down-regulates

0.524

We show that insulin induces gata2 phosphorylation on serine 401 in a pi-3k/akt-dependent manner. Insulin-dependent phosphorylation of serine 401 impairs gata2 translocation to the nucleus and its dna binding activity

SIGNOR-135614

P80370

Q9Y261

0

transcriptional regulation

up-regulates quantity by expression

0.332

Taken together, these data suggest that Foxa-2 is a direct transcriptional activator of the Pref-1 gene.

SIGNOR-254971

P13051

P49841

0

phosphorylation

down-regulates quantity by destabilization

0.2

Here we show that glycogen synthase kinase 3 (GSK-3) interacts with and phosphorylates UNG2 at Thr60 and that Thr60 phosphorylation requires a Ser64 priming phosphorylation event.|phosphorylation of Thr60 and Ser64 creates a cyclin E/c-Myc-like phosphodegron that promotes polyubiquitylation and proteasome-mediated degradation

SIGNOR-264885

P48730

P35222

1

phosphorylation

down-regulates

0.626

However, ckiepsilon has been recently shown to interact with axin (sakanaka et al. 1999;rubinfeld et al. 2001), and it was proposed that this kinase mediates axin-induced apc phosphorylation, thereby stabilizing the -catenin degradation complex (rubinfeld et al. 2001). We have, therefore, evaluated cki as a candidate s45-kinase in several assays, both in vitro and in vivo.

SIGNOR-87441

Q14258

Q15911

1

polyubiquitination

down-regulates quantity by destabilization

0.451

In the present study we show that EFP (oestrogen-responsive finger protein) is an E3 ubiquitin ligase mediating oestrogen-induced ATBF1 protein degradation. Knockdown of EFP increases ATBF1 protein levels, whereas overexpression of EFP decreases ATBF1 protein levels.

SIGNOR-272048

Q9H3D4

P23443

0

phosphorylation

down-regulates

0.2

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

SIGNOR-180771

P23470

P24941

1

dephosphorylation

down-regulates activity

0.298

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-254695

Q05209

P12931

1

dephosphorylation

up-regulates activity

0.542

PTP-PEST increases dephosphorylation of Src at Y527 and activates it.|The data presented here supports our hypothesis that PTP-PEST activates Src via dephosphorylating it at Y527 (Tyr530 in human c-Src equivalent to Tyr527 in chicken Src).

SIGNOR-277086

Q14469

P09471

0

null

down-regulates

0.2

GNAO1 overexpression enhances GSC differentiation by downregulating neural progenitor gene HES1

SIGNOR-278092

Q6NXT2

Q9NRC8

0

deacetylation

up-regulates activity

0.2

Besides confirming the previously reported histone H3K18 deacylation activity, our results revealed that SIRT7 has an astonishingly high activity to catalyze deacylation of H3K36 and is also catalytically active to deacylate H3K37.

SIGNOR-275879

Q16659

O95551

1

phosphorylation

up-regulates activity

0.377

ERK3 phosphorylates TDP2 and promotes its phosphodiesterase activity, thereby upregualting TDP2-mediated DNA damage response and desensitizing lung cancer cells to Top2 inhibitor-induced growth inhibition.|In the current study, we have found that ERK3, an atypical MAPK, phosphorylates TDP2 at S60 and regulates TDP2 's phosphodiesterase activity, thereby cooperatively protecting lung cancer cells against Top2 inhibitors induced DNA damage and growth inhibition.

SIGNOR-278245

P28482

O94953

1

phosphorylation

up-regulates quantity by stabilization

0.2

In addition, the phosphorylation of JMJD2B via p-ERK at Thr305, Ser352, Ser566 and Thr1065 contribute to JMJD2B stability. p-ERK stabilizes the JMJD2B protein level by protecting JMJD2B from ubiquitination and proteasome degradation.

SIGNOR-276744

Q13635

P42574

0

cleavage

down-regulates

0.321

Like other dependence receptors, ptc1 contains a dependence-as-associated receptor c-terminal motif that is cleaved by caspases at a conserved aspartic acid (asp 1392) in the absence of shh, to expose a proapoptotic domain.

SIGNOR-199111

P35222

P04626

0

phosphorylation

down-regulates activity

0.766

Second, ErbB2 phosphorylates \u03b2-catenin at Tyr 654, leading to dissociation of the E-cadherin-\u03b2-catenin membrane complex and increased signaling to Wnt target genes such as cyclin D1 ( ).

SIGNOR-279041

Q9UKB1

P84022

1

ubiquitination

up-regulates

0.261

Here, we show that smad3 activated by tgf-beta is degraded by the ubiquitin-proteasome pathway. Smad3 interacts with a ring finger protein, roc1, through its c-terminal mh2 domain in a ligand-dependent manner. An e3 ubiquitin ligase complex roc1-scf(fbw1a) consisting of roc1, skp1, cullin1, and fbw1a (also termed betatrcp1) induces ubiquitination of smad3.

SIGNOR-108240

Q02156

Q92934

1

phosphorylation

down-regulates

0.34

Pkcs phosphorylate bad under in vitro conditions, and the association of phosphorylated bad with pkc-mu or pkc-epsilon, as shown by immunoprecipitation, indicated direct involvement of pkcs in bad phosphorylation. To confirm these results, cells overexpressing pegfp-n1, wt-bad, or bad with a single site mutated (ser112ala;ser136ala;ser155ala), two sites mutated (ser(112/136)ala;ser(112/155)ala;ser(136/155)ala), or the triple mutant were tested. Igf-i protected completely against rapamycin-induced apoptosis in cells overexpressing wt-bad and mutants having either one or two sites of phosphorylation mutated

SIGNOR-163908

P01019

P08246

0

cleavage

up-regulates activity

0.275

Cathepsin G, elastase, and proteinase 3 are serine proteinases released by activated neutrophils. Cathepsin G can cleave angiotensinogen to release angiotensin II, but this activity has not been previously reported for elastase or proteinase 3. In this study we show that elastase and proteinase 3 can release angiotensin I from angiotensinogen and release angiotensin II from angiotensin I and angiotensinogen.

SIGNOR-256313

Q5T447

Q9UNK0

1

polyubiquitination

down-regulates quantity by destabilization

0.44

Our co-immunoprecipitation experiments show that Syntaxin 8 directly interacts with HECTd3 and that the overexpression of HECTd3 promotes the ubiquitination of Syntaxin 8. Immunoprecipitates probed with the anti-ubiquitin (Santa Cruz) antibody could be recognized by the anti-ubiquin antibody (Fig. 3a), indicating that the shift of the His-syntaxin 8 protein bands were caused by polyubiquitin conjugations. Our data suggest that HECTd3 may function as an E3 ubiquitin-protein ligase to promote the ubiquitination and degradation of Syntaxin 8 through the proteasome pathway.

SIGNOR-271772

P16070

O14672

0

cleavage

up-regulates activity

0.346

The ADAM proteases are best known for their role in shedding the extracellular domain of transmembrane proteins. Among the transmembrane proteins shed by ADAM10 are notch, HER2, E-cadherin, CD44, L1 and the EGFR ligands, EGF and betacellulin.

SIGNOR-259847

O60674

Q92783

1

phosphorylation

up-regulates

0.617

Stam is associated with jak3 and jak2 tyrosine kinases via its itam region and phosphorylated by jak3 and jak2 upon stimulation with il-2.

SIGNOR-47834

Q13535

Q9Y253

1

phosphorylation

up-regulates

0.415

Atr-mediated phosphorylation of dna polymerase _ is needed for efficient recovery from uv damage. We show that, after uv irradiation, pol_ becomes phosphorylated at ser601 by the ataxia-telangiectasia mutated and rad3-related (atr) kinase. Atr-dependent phosphorylation of pol_ is necessary to restore normal survival and postreplication repair

SIGNOR-171290

P19174

P08631

0

phosphorylation

up-regulates activity

0.681

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

SIGNOR-249361

Q9Y4K3

O43561

1

ubiquitination

up-regulates activity

0.345

Interestingly, this study has demonstrated that the membrane-proximal region of linker for activation of T cells preceding tyrosine-132 mediates its association with TRAF6, which promotes the ubiquitination of linker for activation of T cells and, in turn, the phosphorylation of tyrosine residues on linker for activation of T cells.|Moreover, LAT was ubiquitinated at Lysine 88 by TRAF6 via K63 linked chain.

SIGNOR-278675

Q16665

Q9UBF6

0

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

P35998

Q05086

0

ubiquitination

down-regulates quantity by destabilization

0.385

Our experiments collectively suggest that UBE3A stimulates Wnt pathway activation by interacting with, ubiquitinating, and reducing the levels of multiple (PSMB1, PSMC2, PSMD2, and PSMD7) proteasome subunits.

SIGNOR-265132

P17252

Q8TD43

1

phosphorylation

up-regulates

0.2

Phorbol ester-induced activation of protein kinase c (pkc) increased the ca(2+) sensitivity of wild-type trpm4 but not of two mutants mutated at putative pkc phosphorylation sites.

SIGNOR-132243

O00418

Q13131

0

phosphorylation

down-regulates activity

0.492

AMPK can phosphorylate three sites in eEF2 kinase in vitro. Of these, Ser-398 appears to be more efficiently phosphorylated than either Ser-78 or Ser-366. Ser-78 and Ser-366 do not appear to be phosphorylated by AMPK within cells. Ser-366 serves to decrease the activity of eEF2 kinase

SIGNOR-250314

P49840

O15084

1

phosphorylation

down-regulates activity

0.2

We provide evidence for a dual kinase-mediated regulation of the PITK holoenzyme whereby PITK phosphorylation at S1017 is catalyzed by calcium/calmodulin-dependent kinase II-delta (CaMKIIdelta), promoting the subsequent phosphorylation of S1013 by glycogen synthase kinase-3 (GSK3) in vitro.|the phosphorylation of PITK at these specific residues altered PP1 binding and subsequent PITK-directed dephosphorylation of hnRNP K

SIGNOR-264792

Q05193

Q13627

0

phosphorylation

down-regulates

0.416

Mnb/dyrk1a was shown to phosphorylate dynamin 1 and alter its interactions with several sh3 domain-containing endocytic accessory proteins.Phosphorylation At s795 and s857 was confirmed in full-length dynamin 1, and s857 was subsequently determined to be the major mnb/dyrk1a phosphorylation site in vitro. Phosphorylation at s857 was demonstrated to be the basis for altering the binding of dynamin 1 to amphiphysin 1 and grb 2 by site-directed mutants mimicking phosphorylation.

SIGNOR-127440

P49716

P49841

0

phosphorylation

down-regulates quantity by destabilization

0.384

Phosphorylation of C/EBPdelta by GSK-3beta is required for its degradation by FBXW7alpha.

SIGNOR-279180

P08311

P05546

1

cleavage

down-regulates activity

0.444

Amino acid sequence analysis led to the conclusion that both neutrophil elastase and cathepsin G cleave HC at Ile66, which does not affect HC activity, and at Val439, near the reactive site Leu444, which inactivates HC.

SIGNOR-256509

P15172

P26651

0

post transcriptional regulation

down-regulates quantity by destabilization

0.292

The TTP binding site in the 3â€² UTR of MyoD would permit TTP-mediated mRNA decay

SIGNOR-253597

P12931

Q9UL51

1

phosphorylation

up-regulates activity

0.267

We identified a highly conserved tyrosine residue in the C-linker of HCN channels (Tyr476 in HCN2) that confers modulation by Src. Replacement of this tyrosine by phenylalanine in HCN2 or HCN4 abolished sensitivity to Src inhibitors. Mass spectrometry confirmed that Tyr476 is phosphorylated by Src. Our results have functional implications for HCN channel gating. Furthermore, they indicate that tyrosine phosphorylation contributes in vivo to the fine tuning of HCN channel activity.

SIGNOR-263199

P53041

Q16543

1

dephosphorylation

down-regulates activity

0.672

Activation of protein kinase clients by the Hsp90 system is mediated by the cochaperone protein Cdc37. Cdc37 requires phosphorylation at Ser13|PP5/Ppt1 regulates phosphorylation of Ser13-Cdc37 in vivo, directly affecting activation of protein kinase clients by Hsp90-Cdc37.

SIGNOR-248539

Q92769

P33076

1

deacetylation

down-regulates quantity by repression

0.413

We report that CIITA and histone deacetylase 2 (HDAC2) interact in smooth muscle cells and macrophages as assayed by co-immunoprecipitations. HDAC2 deacetylates CIITA whereas both the HDAC inhibitor trichostatin A (TSA) and over-expression of HDAC2 interfering RNA increase CIITA acetylation. HDAC2 down-regulates CIITA recruitment to target promoters as evidenced by chromatin immunoprecipitation assays, and suppresses MHC II activation and collagen repression mediated by CIITA in luciferase reporter assays.

SIGNOR-254231

Q9Y577

Q07820

1

polyubiquitination

down-regulates quantity by destabilization

0.444

Here, we identified Trim17 as a novel E3 ubiquitin-ligase for Mcl-1. Indeed, Trim17 co-immunoprecipitated with Mcl-1. Trim17 ubiquitinated Mcl-1 in vitro. Overexpression of Trim17 decreased the protein level of Mcl-1 in a phosphorylation- and proteasome-dependent manner. Finally, knock down of Trim17 expression reduced both ubiquitination and degradation of Mcl-1 in neurons.

SIGNOR-272032

Q96FW1

P04637

1

deubiquitination

up-regulates quantity by stabilization

0.565

Furthermore, although OTUB1 dramatically induced p53 deubiquitination, its mutant (S16A) and deletion mutant did not have this effec

SIGNOR-276528

P41212

P27361

0

phosphorylation

down-regulates

0.317

Tel became phosphorylated by erk on two serine residues, ser213 and ser257, in the internal domain between the hlh and ets domains. Tel lost its abilities to repress transcription through the phosphorylation.

SIGNOR-123656

P54646

Q8IYT8

0

phosphorylation

down-regulates

0.304

We could prove that ulk1-mediated phosphorylation of ampk reduced its level of phosphorylation at t172 of the _-subunit and hence interferes with its catalytic activity. I

SIGNOR-173089

Q99558

Q13489

0

ubiquitination

down-regulates

0.65

Ciap1/2 (cellular inhibitor of apoptosis 1 and 2) ubiquitinate nik for degradation.

SIGNOR-167298

O43353

Q8WWF5

0

ubiquitination

down-regulates quantity by destabilization

0.2

Collectively, ZNRF4 degrades RIP2 protein by targeting the RIP2CARD domain in an E3-ubiquitin ligase activity dependent manner.|Here we show that ZNRF4 induces K48-linked ubiquitination of RIP2 and promotes RIP2 degradation.

SIGNOR-278684

P28328

P28288

1

ubiquitination

up-regulates activity

0.401

PEX5 and PMP70 are ubiquitinated by PEX2 during amino acid starvation.

SIGNOR-278708

P35611

Q13464

0

phosphorylation

up-regulates

0.376

Rho-associated kinase (rho- kinase), which is activated by the small guanosine triphosphatase rho, phosphorylates alpha-adducin and thereby enhances the f-actin-binding activity of alpha-adducin in vitro. Here we identified the sites of phosphorylation of alpha-adducin by rho-kinase as thr445 and thr480

SIGNOR-66996

P35221

P68400

0

phosphorylation

down-regulates

0.39

We demonstrate here that egfr activation results in disruption of the complex of beta-catenin and alpha-catenin, thereby abrogating the inhibitory effect of alpha-catenin on beta-catenin transactivation via ck2alpha-dependent phosphorylation of alpha-catenin at s641.

SIGNOR-161847

Q9P0L2

P10636

1

phosphorylation

down-regulates activity

0.429

We have studied the relationship between the phosphorylation of tau by several kinases (MARK, PKA, MAPK, GSK3) and its assembly into PHFs. MARK and PKA phosphorylate several sites within the repeats (notably the KXGS motifs including Ser262, Ser324, and Ser356, plus Ser320). This type of phosphorylation strongly reduces tau's affinity for microtubules, and at the same time inhibits tau's assembly into PHFs.

SIGNOR-250173

P05412

P01112

0

phosphorylation

up-regulates activity

0.5

c-Jun was first shown to be phosphorylated in its transactivation domain (Ser-63 and Ser-73) by ERKs and p54-JNK. This is consistent with other studies which show that PD98059 inhibits up-regulation of c-Jun protein in Ras-transformed NIH-3T3 cells

SIGNOR-235522

Q02878

Q00987

0

ubiquitination

down-regulates quantity by destabilization

0.432

Furthermore, we also demonstrated that RPL6 is a substrate for HDM2-mediated ubiquitination and proteasomal degradation.|The interaction of RPL6 and HDM2 drives HDM2 mediated RPL6 polyubiquitination and proteasomal degradation.

SIGNOR-278630

O15550

P31270

1

transcriptional regulation

up-regulates quantity by expression

0.263

Evidence for direct involvement of UTX in regulation of HOX gene activity was demonstrated through UTX knockdown experiments in HEK293T cells in which loss of UTX induced transcriptional repression of HOXA and HOXC clusters.

SIGNOR-260021

P27361

Q14247

1

phosphorylation

up-regulates

0.422

Cortactin is regulated by multiple phosphorylation events, including phosphorylation of s405 and s418 by extracellular regulated kinases (erk)1/2. Erk1/2 phosphorylation of cortactin has emerged as an important positive regulatory modification, enabling cortactin to bind and activate the arp2/3 regulator neuronal wiskott-aldrich syndrome protein (n-wasp), promoting actin polymerization and enhancing tumor cell movement.

SIGNOR-165212

Q12778

P24941

0

phosphorylation

down-regulates

0.652

Cdk2 specifically phosphorylated foxo1 at serine-249 (ser249) in vitro and in vivo. Phosphorylation of ser249 resulted in cytoplasmic localization and inhibition of foxo1.

SIGNOR-150028

Q9NPB6

P37173

0

phosphorylation

up-regulates

0.466

We demonstrate that Par6, a regulator of epithelial cell polarity and tight-junction assembly, interacts with TGFbeta receptors and is a substrate of the type II receptor, TbetaRII. [...] These data suggest that T_RII phosphorylates Par6 at its penultimate residue, Ser345.

SIGNOR-227484

Q15256

P17612

0

phosphorylation

down-regulates activity

0.343

The PKA phosphorylation site on PTP-SL was identified as the Ser(231) residue. treatment of COS-7 cells with PKA activators, or overexpression of the Calpha catalytic subunit of PKA, inhibited the cytoplasmic retention of ERK2 and p38alpha by wild-type PTP-SL, but not by a PTP-SL S231A mutant.‚

SIGNOR-250038

P00519

P15941

1

phosphorylation

up-regulates quantity by stabilization

0.455

The results demonstrate that ABL1 phosphorylates MUC1 on Tyr-60 and forms a complex with MUC1 by binding of the ABL1 SH2 domain to the pTyr-60 site.

SIGNOR-260830

O00139

Q6IQ55

0

phosphorylation

down-regulates activity

0.406

TTBK2 phosphorylates KIF2A primarily at growing MT ends and counteracts the depolymerization activity of KIF2A

SIGNOR-260926

P53350

Q9H2D6

1

phosphorylation

up-regulates

0.335

Here we show that tara is a novel polo-like kinase 1 (plk1) target protein. Plk1 interacts with and phosphorylates tara in vivo and in vitro. Actually, the thr-457 in tara was a bona fide in vivo phosphorylation site for plk1. Interestingly, we found that the centrosomal localization of tara depended on the thr-457 phosphorylation and the kinase activity of plk1

SIGNOR-198353

P49841

Q13237

0

phosphorylation

down-regulates activity

0.258

These data indicate that hypertrophic differentiation of growth plate chondrocytes during skeletal growth is promoted by phosphorylation and inactivation of GSK-3beta by cGKII.

SIGNOR-280095

Q13490

Q14249

1

ubiquitination

up-regulates activity

0.468

Alternatively, cIAP1 may mediate a vital function of EndoG other than cell death.|Cellular inhibitor of apoptosis protein 1 ubiquitinates endonuclease G but does not affect endonuclease G-mediated cell death.

SIGNOR-278605

P23470

Q8WV28

1

dephosphorylation

up-regulates activity

0.2

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-254692

Q9GZQ8

Q9NR19

0

transcriptional regulation

up-regulates quantity by expression

0.2

As expected, we found that glucose deprivation induced the binding of TFEB (Figure S4C) and ACSS2 (Figure S4D) to the promoter regions of MAP1LC3B, ATG3, and WIPI-1 as well as mRNA (Figure 3H) and protein (Figure 3I) expression of these genes;

SIGNOR-276562

P23588

P23443

0

phosphorylation

up-regulates

0.776

S6k1/s6k2 specifically phosphorylate ser422 in vitro. Substitution of ser422 with ala results in a loss of activity in an in vivo translation assay, indicating that phosphorylation of this site plays an important role in eif4b function.

SIGNOR-123997

P53350

Q76N32

1

phosphorylation

down-regulates quantity by destabilization

0.44

We show that the intercentrosomal linker protein Cep68 is degraded in prometaphase through the SCF(βTrCP) (Skp1-Cul1-F-box protein) ubiquitin ligase complex. Cep68 degradation is initiated by PLK1 phosphorylation of Cep68 on Ser 332, allowing recognition by βTrCP.

SIGNOR-275621

P42229

Q07817

1

transcriptional regulation

up-regulates quantity by expression

0.653

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-261551

Q13315

Q9NZM5

1

phosphorylation

down-regulates quantity by destabilization

0.2

PICT-1 S233 and T289 were identified as the key phosphorylation sites in this pathway, as mutating both to alanine abolished UVB-induced increase of PICT-1 phosporylation. Inhibition of PIKKs or ATM (with wortmannin and KU55933, respectively) prevented the agglomeration and degradation of PICT-1, suggesting that ATM is a key regulator of PICT-1.

SIGNOR-273506

P25098

P41143

1

phosphorylation

down-regulates activity

0.2

Taken together, we have demonstrated that agonist-induced opioid receptor phosphorylation occurs exclusively at two phosphate acceptor sites (T358 and S363) of GRK2 at the DOR carboxyl terminus.

SIGNOR-249660

Q05655

Q16236

1

phosphorylation

up-regulates activity

0.371

Phosphorylation of Nrf2 at Ser-40 by protein kinase C regulates antioxidant response element-mediated transcription.

SIGNOR-249161

P78504

Q86YT6

0

ubiquitination

up-regulates activity

0.693

Mib1 is essential for the generation of functional notch ligands and regulates the classical notch ligands dll1, dll4, jag1, and jag2 in vertebrates mib1 is an essential e3 ubiquitin ligase for jag1 in the developing cerebellum.

SIGNOR-97388

P04637

P19525

0

phosphorylation

up-regulates

0.571

The double-stranded rna activated protein kinase pkr physically associates with the tumor suppressor p53 protein and phosphorylates human p53 on serine 392 in vitro.

SIGNOR-68033

P00519

P37840

1

phosphorylation

up-regulates quantity

0.424

C-Abl interacts with alpha-synuclein and phosphorylates alpha-synuclein at Y39 (XREF_FIG) .

SIGNOR-279582

P49841

Q99612

1

phosphorylation

up-regulates activity

0.2

Functionally, GSK3beta enhanced KLF6 mediated growth suppression, which was abrogated by the KLF6-4A phosphomutant.|These data establish that GSK3\u03b2 directly phosphorylates KLF6, which augments its induction of p21 and resultant growth suppression.

SIGNOR-279373

Q00987

P98177

1

ubiquitination

down-regulates activity

0.63

Mdm2 Induces Mono-Ubiquitination of FOXO4.|higher amounts of Mdm2 transfected resulted in reduced FOXO4 transcriptional activity.

SIGNOR-278656

O60496

P23470

0

dephosphorylation

up-regulates activity

0.2

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-254698

O15162

Q05655

0

phosphorylation

up-regulates

0.424

Following the induction of apoptosis, however, phosphorylation of serine residues decreased and it increased on threonine, consistent with the predicted pkc phosphorylation site at thr-161. Transfection of cho cells with scramblase and pkc_, but not scramblase or pkc_ alone, increased scramblase activity

SIGNOR-76904

P17706

P09619

1

dephosphorylation

down-regulates activity

0.564

The PDGF beta receptor is negatively regulated by protein tyrosine phosphatases (PTPs).|In summary, our findings identify TC-PTP as a previously unrecognized negative regulator of PDGF beta receptor signaling and support the general notion that PTPs display site selectivity in their action on tyrosine kinase receptors.The fact that two of the investigated PDGF β receptor sites, Y1021 and Y771, displayed a larger increase in phosphorylation than Y579 and Y751 in TC-PTP ko MEFs indicated that these two sites are preferred substrates for TC-PTP.

SIGNOR-248389

P17612

Q92736

1

phosphorylation

up-regulates activity

0.478

PKA-mediated hyperphosphorylation of a conserved serine, Ser-2843 in skeletal RyR and Ser-2809 in cardiac RyR, results in an aberrant SR function during heart failure. hyperphosphorylated RyRs are leaky and therefore lead to a reduced SR Ca2+ load and impaired contractile function in heart failure

SIGNOR-250079

P07949

Q12913

0

dephosphorylation

down-regulates activity

0.277

The receptor-type protein tyrosine phosphatase J antagonizes the biochemical and biological effects of RET-derived oncoproteins.|PTPRJ expression induces dephosphorylation of the RET(C634R) and, probably via an indirect mechanism, RET/PTC1 oncoproteins on two key RET autophosphorylation sites (Tyr1062 and Tyr905). This results in a significant decrease of RET-induced Shc and extracellular signal-regulated kinase 1/2 phosphorylation levels

SIGNOR-248701

P25963

O14965

0

phosphorylation

down-regulates activity

0.541

The results of the in vitro kinase assay, using purified human recombinant AURKA and IkappaBalpha proteins, confirmed that AURKA can directly phosphorylate IkappaBalpha (Ser32) at a concentration as low as 2.5 ng/mul (XREF_FIG).|While an earlier study suggested that AURKA down-regulates IkappaBalpha indirectly through activation of the PI3K and AKT pathway 35, our data demonstrate, for the first time, that AURKA directly binds and phosphorylates the IkappaBalpha subunit, leading to activation of NF-kappaB.

SIGNOR-278912

O00213

P00519

0

phosphorylation

up-regulates

0.415

The c-abl tyrosine kinase phosphorylates the fe65 adaptor protein to stimulate fe65/amyloid precursor protein nuclear signaling. Here, we show that active c-abl stimulates app/fe65-mediated gene transcription and that this effect is mediated by phosphorylation of fe65 on tyrosine 547 within its second ptb domain.

SIGNOR-123476

P06493

Q16512

1

phosphorylation

up-regulates activity

0.436

CDK1 phosphorylates PKN1 at S533, S537, S562, and S916 in vitro and in cells during drug-induced mitotic arrest. Immunofluorescence staining further confirmed that PKN1 phosphorylation occurs during normal mitosis in a CDK1-dependent manner.Knockdown of PKN1 significantly inhibited anchorage-independent growth and migration without affecting proliferation in multiple cancer cell lines.

SIGNOR-276831

P36873

O15169

1

dephosphorylation

down-regulates activity

0.269

The data suggest that PP1 controls Wnt signaling through interaction with, and regulated dephosphorylation of, axin| Axin phosphorylation markedly enhances the binding of glycogen synthase kinase 3, leading to a more active beta-catenin destruction complex. Wnt-regulated changes in axin phosphorylation, mediated by PP1, may therefore determine beta-catenin transcriptional activity| Four sites, S80, S82, S222, and S473, were identified to be PP1 regulated

SIGNOR-248494

O00743

O43318

1

dephosphorylation

down-regulates activity

0.372

Protein phosphatase 6 down-regulates TAK1 kinase activation in the IL-1 signaling pathway|From proteomic analysis of TAK1-binding proteins, we identified protein phosphatase 6 (PP6), a type-2A phosphatase, and demonstrated that PP6 associated with and inactivated TAK1 by dephosphorylation of Thr-187.

SIGNOR-248292

Q96PU5

P35498

1

ubiquitination

down-regulates quantity by destabilization

0.292

The control of Nav density at the cell membrane is crucial to ensuring normal neuronal excitability. Navs are subject to posttranslational modifications that may influence their cell membrane availability. Ubiquitylation is a key process that orchestrates the internalization and subsequent degradation or recycling of Navs. This is accomplished by ubiquitin protein ligases, such as NEDD4-2 (neuronal precursor cell expressed developmentally downregulated-4 type 2).

SIGNOR-253457

Q12948

Q16539

0

phosphorylation

up-regulates quantity by stabilization

0.2

P38 interacts with and phosphorylates the Ser241 and ser272 sites of FOXC1 to maintain its stability by inhibiting ubiquitination and degradation.

SIGNOR-275913

P08581

Q92990

1

relocalization

down-regulates

0.331

Significantly, nonphosphorylated hgf receptor prevents fap68 from stimulating p70s6k. fap68 binding to met requires the last 30 amino acids of the c-terminal tail, which are unique to the hgf receptor.

SIGNOR-110726

P53350

Q99741

1

phosphorylation

up-regulates

0.566

Binding between cdc6 and plk1 occurs through the polo-box domain of plk1, and cdc6 is phosphorylated by plk1 on t37. These results suggest that plk1-mediated phosphorylation of cdc6 promotes the interaction of cdc6 and cdk1, leading to the attenuation of cdk1 activity, release of separase, and subsequent anaphase progression.

SIGNOR-169184

P55010

P68400

0

phosphorylation

up-regulates

0.394

We find that eif5 is associated with ck2 when the kinase activity is at the highest level in vivo, and is phosphorylated at ser389 and ser390 by ck2.

SIGNOR-141159

O00311

P49736

1

phosphorylation

up-regulates

0.962

In this work, by in vitro kinase reactions and mass spectrometry analysis of the products, we have mapped phosphorylation sites in the n terminus of mcm2 by cdc7, cdk2, cdk1, and ck2

SIGNOR-143984

P49841

O75925

1

phosphorylation

down-regulates quantity by destabilization

0.332

We discovered a ubiquitin E3 ligase, HECTD2, which ubiquitinated and mediated the degradation of PIAS1, thus increasing inflammation in an experimental pneumonia model. We found that GSK3β phosphorylation of PIAS1 provided a phosphodegron for HECTD2 targeting.

SIGNOR-276923

Q9BXM7

P10636

1

phosphorylation

down-regulates activity

0.384

Simultaneously overexpressing PINK1 significantly reduced the levels of exogenous total and phosphorylated tau proteins (Figures 4A,B,E).|Taken together, our data revealed that PINK1 overexpression promoted degradation of abnormal accumulated tau via the autophagy-lysosome pathway, indicating that PINK1 may be a potential target for AD treatment.

SIGNOR-279250