GleghornLab/Signor_2class · Datasets at Hugging Face

IdA string	IdB string	labels int64	mechanism string	effect string	score float64	sentence string	signor_id string
Q14498	P00519	0	phosphorylation	up-regulates activity	0.322	In this paper, we report that RBM39 interacts with the nonreceptor tyrosine kinase c-Abl. Both the Src homology (SH) 2 and SH3 domains of c-Abl interact with RBM39. The major tyrosine phosphorylation sites on RBM39 that are phosphorylated by c-Abl are Y95 and Y99, as demonstrated by liquid chromatography coupled with tandem mass spectrometry (LC/MS/MS) and mutational analysis. c-Abl was shown boost the transcriptional coactivation activity of RBM39 for ERα and PRβ in a tyrosine kinase-dependent manner.	SIGNOR-262609
P18031	P49760	0	phosphorylation	up-regulates activity	0.322	The clk family kinases, clk1 and clk2, phosphorylate and activate the tyrosine phosphatase, ptp-1b.\|Phosphorylation of PTP-1B at Ser(50) by CLK1 or CLK2 is responsible for its enzymatic activation.	SIGNOR-70603
P31749	Q99683	1	phosphorylation	down-regulates activity	0.729	Akt phosphorylates and negatively regulates apoptosis signal-regulating kinase 1 akt decreased ask1 kinase activity stimulated by both oxidative stress and overexpression in 293 cells by phosphorylating a consensus akt site at serine 83 of ask1.	SIGNOR-252465
P49841	P35869	1	phosphorylation	up-regulates activity	0.25	A proposed model of GSK3β role on AHR function and degradation. AHR is phosphorylated by GSK3β in a p23-dependent manner in HeLa cells. This phosphorylation is required for optimal activation of the ligand-dependent AHR target gene transcription. After phosphorylation, AHR is K63-ubiquitinated and is targeted for the LC3-mediated selective autophagy. When the p23 content is compromised in HeLa cells, AHR is more prone to degradation via autophagy, bypassing the GSK3β phosphorylation of AHR.	SIGNOR-276664
P63000	O14559	0	gtpase-activating protein	down-regulates activity	0.444	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-260491
Q16236	Q13131	0	phosphorylation	up-regulates activity	0.2	MS-based analysis of immunoprecipitated Nrf2 revealed serine 374, 408 and 433 in human Nrf2 to be hyperphosphorylated as a function of activated AMPK. A direct phosphate-transfer by AMPK to those sites was indicated by in vitro kinase assays with recombinant proteins as well as interaction of AMPK and Nrf2 in cells, evident by co-immunoprecipitation. Mutation of serine 374, 408 and 433 to alanine did not markedly affect half-life, nuclear accumulation or induction of reporter gene expression upon Nrf2 activation with sulforaphane. However, some selected endogenous Nrf2 target genes responded with decreased induction when the identified phosphosites were mutated, whereas others remained unaffected.	SIGNOR-277496
P14780	P01137	1	cleavage	up-regulates	0.592	We also demonstrate that mmp-9, as well as its relative, mmp-2, cleave latent transforming growth factor-_ (tgf-_), which constitutes a novel mechanism of tgf-_ activation.	SIGNOR-74461
Q5JU85	P48058	1	relocalization	up-regulates quantity	0.2	BRAG1 increases the synaptic recycling pool of AMPARs.these data suggest that the BRAG1 enhancement of AMPAR transmission is mediated by the increased expression of the recycling pool of synaptic GluA2/3 receptors.	SIGNOR-264915
O00311	Q8TEA8	1	phosphorylation	up-regulates activity	0.321	Here we show that DUE-B is de-phosphorylated in M phase and phosphorylated in G1/S phase. Phosphorylated DUE-B forms homodimers, whereas de-phosphorylated DUE-B interacts with the Mcm2–7 complex and aminoacyl-tRNA synthetases. We find that CKII can prime DUE-B for Cdc7 phosphorylation. Confirming the importance of DUE-B phosphorylation in replication initiation, a C-terminal Ser/Thr to Ala mutant blocks Cdc45 and RPA loading on sperm chromatin and inhibits DNA replication. DUE-B C-terminal phosphorylation sites (serine 179, 181, 182, 194, 196, 197, 204, 205, and threonine 187) were mutated to unphosphorylatable alanine (DUE-B(S/T)-A) or phosphomimic aspartic acid (DUE-B(S/T)-D).	SIGNOR-273967
Q9Y261	P80370	1	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
Q8NFJ5	P00533	0	phosphorylation	down-regulates activity	0.387	EGFR phosphorylates and inhibits lung tumor suppressor GPRC5A in lung cancer.\|Together, these results indicate that endogenous EGFR can phosphorylate GPRC5A at four identified tyrosine residues (Y317, Y320, Y347 and Y350) in response to EGF stimulation in the lung cancer H1792 cells.	SIGNOR-278336
O14827	P63000	1	guanine nucleotide exchange factor	up-regulates activity	0.498	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-260574
Q99496	Q9C0C7	1	ubiquitination	down-regulates quantity by destabilization	0.359	RNF2 ubiquitinates AMBRA1 at lysine 45.\|These data indicate that RNF2 directly accelerates the degradation of AMBRA1.	SIGNOR-278596
O15111	Q9Y6Q9	1	phosphorylation	up-regulates	0.395	Herein, we report the successful identification of six functional in vivo src-3 phosphorylation sites.	SIGNOR-196953
P68400	Q04724	1	phosphorylation	up-regulates	0.32	These results suggest that ck2 phosphorylation of serine 239 of gro/tle1 is important for its function during neuronal differentiation.	SIGNOR-129026
Q9UBK2	P49841	0	phosphorylation	down-regulates quantity	0.476	GSK3\u03b2 is an important serine/threonine kinase to regulate PPAR\u03b3 coactivator-1\u03b1 degradation. , GSK3\u03b2 reduces PPAR\u03b3 coactivator-1\u03b1 levels by phosphorylating PPAR\u03b3 coactivator-1\u03b1 and subsequently stimulating PPAR\u03b3 coactivator-1\u03b1 degradation by the ubiquitin-proteasomal system.\|Within them, GSK3beta, which can phosphorylate PGC-1alpha and promote its ubiquitin mediated degradation , , was upregulated significantly in mnd2 mouse brain and spinal cord compared with that in wide-type mice (XREF_FIG).	SIGNOR-279723
Q13094	P42681	0	phosphorylation	up-regulates	0.728	Resting lymphocyte kinase (rlk/txk) targets lymphoid adaptor slp-76 in the cooperative activation of interleukin-2 transcription in t-cells. In this study, we report that rlk phosphorylates slp-76 at its n-terminal yesp/yepp sites. A third tyrosine within the amino-terminal region (y145) appears to be the most important for optimal slp-76 function	SIGNOR-44669
P68400	P27695	1	phosphorylation	up-regulates activity	0.485	Here we demonstrate that APE/Ref-1 is phosphorylated by casein kinase II (CKII). This was shown for both the recombinant APE/Ref-1 protein (Km=0.55 mM) and for APE/Ref-1 expressed in COS cells. Phosphorylation of APE/Ref-1 did not alter the repair activity of the enzyme, whereas it stimulated its redox capability towards AP-1, thus promoting DNA binding activity of AP-1.	SIGNOR-250825
O14920	Q13233	0	phosphorylation	up-regulates activity	0.595	These results suggested that IKK\u03b2 was a likely substrate for MEKK1 and that MEKK1 phosphorylation of IKK\u03b2 increased its kinase activity.	SIGNOR-279339
O43353	P28482	1	phosphorylation	up-regulates activity	0.295	RIP2 directly phosphorylates and activates ERK2 in vivo and in vitro.	SIGNOR-279106
Q6ZN28	P08581	1	transcriptional regulation	up-regulates quantity by expression	0.394	Human colon carcinoma SW480 cells express virtually no MACC1. MACC1 cDNA transfection led not only to strong increases in MACC1 mRNA expression (Fig. 3a), but also to a 40-fold upregulation of the HGF receptor MET mRNA expression (Fig. 3b). This was confirmed on the protein level	SIGNOR-266058
Q9UHD2	P11908	1	phosphorylation	up-regulates activity	0.2	Here, we show that ionizing radiation results in TBK1-mediated phosphorylation of phosphoribosyl pyrophosphate synthetase (PRPS)1/2 at T228, thereby enhancing PRPS1/2 catalytic activity and promoting deoxyribonucleotide synthesis.	SIGNOR-277317
Q8WV28	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-254692
P61586	Q9Y3M8	0	gtpase-activating protein	down-regulates activity	0.645	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-260521
P63167	Q13153	0	phosphorylation	down-regulates	0.378	Dlc1 phosphorylation on ser(88) by p21-activated kinase 1 (pak1), a signaling nodule, promotes mammalian cell survival by regulating its interaction with bim and the stability of bim. Here we discovered that phosphorylation of ser(88), which juxtapose each other at the interface of the dlc dimer, disrupts dlc1 dimer formation and consequently impairs its interaction with bim	SIGNOR-159995
P17252	P10415	1	phosphorylation	up-regulates	0.349	Purified pkca can efficiently and directly phosphorylate bcl2 at serine 70	SIGNOR-60120
Q15910	P31260	1	transcriptional regulation	down-regulates quantity by repression	0.438	These data support the proposed regulatory impact of particular PRC2-proteins in expression of HOXA9 and HOXA10 in NK/T-cells. In mammalian cells knockdown of PRC2 components EZH2 or PHF1 led to upregulated HOXA gene expression.	SIGNOR-260070
O60610	P06493	0	phosphorylation	down-regulates activity	0.2	In this study, we found that Cdk1 phosphorylated DIAPH1, which inhibited the interaction between DIAPH1 and profilin1 (PFN1) during metaphase.\|Thus, the results suggest that the level of cortical F-actin has to be finely maintained by Cdk1 mediated positive and negative regulation of DIAPH1.	SIGNOR-279598
P08575	Q86WV1	1	dephosphorylation	up-regulates activity	0.361	Mutational analysis demonstrated the pivotal role of Tyr-232 in SKAP55 in the association with CD45. In Jurkat cells, anti-CD3 antibody stimulation promoted SKAP55 tyrosine phosphorylation and translocation from the cytoplasm to the membrane. Overexpression of SKAP55 in these cells induced transcriptional activation of the IL-2 promoter, while mutant SKAP55-Y232F totally suppressed the promoter activity. Furthermore, overexpression of SKAP55-Y232F also caused the tyrosine hyperphosphorylation of Fyn with a decreased kinase activity. Thus, SKAP55 is an essential adapter to couple CD45 with the Src family kinases for dephosphorylation and, thus, positively regulates TCR signaling.	SIGNOR-248360
P17252	P35240	1	phosphorylation	down-regulates activity	0.328	PKC\u03b1\nnormally phosphorylates and inactivates NF2.\|PKCalpha normally phosphorylates and inactivates NF2.	SIGNOR-280081
P10415	P06493	0	phosphorylation	up-regulates activity	0.345	Using synthetic peptides and mutant cell lines, we identified threonine 56, one of two consensus sites for cdc2 within the bcl-2 sequence, as a residue phosphorylated by cdc2. Mutation at threonine 56 abrogated the cell cycle inhibitory effect of bcl-2 without affecting anti-apoptotic function.Taken together, our present findings indicate that phosphorylation of bcl-2 at threonine 56 by cdc2 is required for bcl-2-mediated cell cycle inhibition, which may have some roles during mitosis in the normal cell cycle.	SIGNOR-76837
P42345	Q8IYT8	1	phosphorylation	down-regulates	0.777	Mtor phosphorylates a mammalian homologue of atg13 and the mammalian atg1 homologues ulk1 and ulk2	SIGNOR-183961
Q86WV6	Q9BY78	0	ubiquitination	up-regulates activity	0.2	As a result, knockdown of RNF26 promoted degradation of MITA after viral infection and prevented degradation of IRF3.\|In addition, RNF26 could not induce polyubiquitination of MITA (K150R) in in vitro ubiquitination assays (XREF_FIG).	SIGNOR-278573
Q15835	O00254	1	phosphorylation	down-regulates activity	0.2	For example, RhoK phosphorylates and inhibits TIAM1, STEF, and PAR3; disrupts the polarity complex; and prevents Rac activation ( xref ).	SIGNOR-279993
Q13887	P49841	0	phosphorylation	down-regulates	0.368	Stability of the klf5 is mediated by proteasomal degradation via phosphorylation by glycogen synthase kinase 3_ (gsk3_) and recognition by f-box and wd repeat domain-containing 7 (fbw7) of a phosphodegron sequence surrounding serine 303 in klf5	SIGNOR-203627
Q14012	Q9NP62	1	phosphorylation	up-regulates activity	0.388	We show that Epac1 and Rap1, in response to cAMP, activate CaMKI to phosphorylate Ser47 in GCM1. This phosphorylation facilitates the interaction between GCM1 and the desumoylating enzyme SENP1 and thereby leads to GCM1 desumoylation and activation.	SIGNOR-262680
O60610	P61586	0	null	up-regulates activity	0.785	We find that the small GTPase Rho regulates R-cadherin adherens junction formation via Dia1 (also known as p140mDia) and profilin-1-mediated signaling pathway. The role played by Rho in regulating R-cadherin is underscored by the fact that constitutively active RhoA(Q63L) induces R-cadherin junction formation in MDA-MB-231 cells.\|Data presented thus far demonstrated that Rho, Dia1, and profilin-1 were required for R-cadherin junction formation in N480 cells.	SIGNOR-253108
P60953	Q70Z35	0	guanine nucleotide exchange factor	up-regulates activity	0.423	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-260572
Q13563	Q9BZL6	0	phosphorylation	up-regulates activity	0.2	Here, we report the identification of a previously unrecognized phosphorylation site within the polycystin-2 C terminus (Ser801), and we demonstrate that it is phosphorylated by protein kinase D. These results suggest that growth factor-stimulated, protein kinase D-mediated phosphorylation of polycystin-2 is essential for its ER channel function and links extracellular stimuli to its effects on cell growth and intracellular calcium regulation.	SIGNOR-276284
P05771	Q5JVS0	1	phosphorylation	down-regulates activity	0.29	We found a strong phosphorylation of Ki-1/57 by PKCalphabeta, PKCdelta, PKClambda/zeta, and especially by PKCsigma, however not by PKCmi. These data show that Ki-1/57 can serve in principal as a substrate for a wide variety of different PKC isoforms but also that its phosphorylation is strongest with PKCsigma. \| This suggests that the two threonine residues present in this fragment (Thr354 and Thr375) might be the main target residues for phosphorylation by PKC in vitro. \| Ki-1/57 Exits the Nucleus upon PMA Activation	SIGNOR-249247
P53350	Q14980	1	phosphorylation	down-regulates activity	0.534	Phosphorylation of NuMA by Plk1 at 1833/34 residue can impact its cortical localization.\|These data strongly suggest that Plk1 negatively regulate cortical NuMA localization and that this impact of Plk1 on NuMA is presumably independent of LGN, at least in the anaphase cells.	SIGNOR-279345
Q92783	O60674	0	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
P01100	Q15418	0	phosphorylation	up-regulates activity	0.529	We now provide evidence that two growth-regulated, nucleus- and cytoplasm-localized protein kinases, 90-kda ribosomal s6 kinase (rsk) and mitogen-activated protein kinase (map kinase), contribute to the serum-induced phosphorylation of c-fos. The major phosphopeptides derived from biosynthetically labeled c-fos correspond to phosphopeptides generated after phosphorylation of c-fos in vitro with both rsk and map kinase. The phosphorylation sites identified for rsk (ser-362) and map kinase (ser-374) are in the transrepression domain. Cooperative phosphorylation at these sites by both enzymes was observed in vitro and reflected in vivo by the predominance of the peptide phosphorylated on both sites, as opposed to singly phosphorylated peptides. This study suggests a role for nuclear rsk and map kinase in modulating newly synthesized c-fos phosphorylation and downstream signaling.	SIGNOR-37154
Q9UKV5	Q8IWA4	1	polyubiquitination	down-regulates quantity by destabilization	0.309	Gp78 induces ubiquitylation and proteasomal degradation of Mfn1 and Mfn2.	SIGNOR-272886
Q5FBB7	P51955	0	phosphorylation	up-regulates	0.2	Here we show that nek2a phosphorylates human sgo1 and such phosphorylation is essential for faithful chromosome congression in mitosis. phosphorylation sites were mapped to ser(14) and ser(507)	SIGNOR-156882
Q16539	P15336	1	phosphorylation	up-regulates	0.793	On the other hand, sapks such as jnks and p38 phosphorylate atf-2 at thr-69, thr-71, and ser-90 which lie close to the n-terminal transcriptional activation domain and stimulate itstrans-activating capacity our results indicate that atf-2 not only directly binds to smad3/4 hetero-oligomers but also that atf-2 is phosphorylated by tgf- signaling via tak1 and p38.	SIGNOR-65597
P23560	P16220	0	transcriptional regulation	up-regulates quantity	0.488	Brain-derived neurotrophic factor (BDNF) is a critical molecule for learning and memory. Brain BDNF levels correlate with cognitive status. Activation of CREB facilitates the transcription of crucial proteins for activity-dependent plasticity particularly BDNF.	SIGNOR-265062
P59595	P55212	0	cleavage	up-regulates activity	0.2	Caspase-6 is activated through the intrinsic pathway and mediates C-terminal cleavage of SARS-CoV N at residues 400 and 403	SIGNOR-260212
Q8TEM1	P06493	0	phosphorylation	up-regulates activity	0.549	In vitro phosphorylation of GST fusion protein containing the carboxyl-terminal domain of gp210 by cyclin B-p34cdc2 protein kinase generates a phosphopeptide that comigrates with a mitosis-specific phosphopeptide. Ser1880 Is the Mitotic Phosphorylation Site of Gp210.	SIGNOR-262699
Q16236	P09601	1	transcriptional regulation	up-regulates quantity by expression	0.679	In both models, the inducer-modified and Nrf2-bound Keap1 is inactivated and, consequently, newly synthesized Nrf2 proteins bypass Keap1 and translocate into the nucleus, bind to the ARE and drive the expression of Nrf2 target genes such as NAD(P)H quinone oxidoreductase 1 (NQO1), heme oxygenase 1 (HMOX1), glutamate-cysteine ligase (GCL) and glutathione S transferases (GSTs).	SIGNOR-256276
Q9GZY8	Q15139	0	phosphorylation	up-regulates activity	0.2	PKD directly phosphorylates MFF on serines 155, 172, and 275	SIGNOR-277559
P25490	O14763	1	transcriptional regulation	down-regulates quantity by repression	0.403	Depletion of FKBP51 impairs the acetylation status of YY1 and interferes with its binding on the DR5 promoter. The lack of the repressor activity of YY1 increases DR5 transcription and sensitizes melanoma cell to TRAIL-induced apoptosis.	SIGNOR-268793
O95551	Q16659	0	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
P02788	O60260	0	ubiquitination	down-regulates activity	0.2	We propose that Parkin ubiquitylation of LTF at K649 perturbs LTF\u2019s ability to accumulate intracellular iron levels and that depletion of Parkin, or substitution of K649 on LTF, allows LTF to accumulate intracellular iron levels.\|Parkin dependent ubiquitylation of LTF occurred most often on lysines (K) 182 and 649.	SIGNOR-278641
O43353	P98170	0	ubiquitination	up-regulates activity	0.628	XIAP is the essential E3 for RIPK2 ubiquitination and interacts with RIPK2 through its baculoviral IAP-repeat (BIR).	SIGNOR-280449
P17252	P02545	1	phosphorylation	up-regulates activity	0.362	Mutation of both Ser-403/Ser-404 within a PKC motif flanking the nuclear localization signal inhibits transport of mutant lamin A to the nucleus in 64% of the cells. It is proposed that phosphorylation of the motif in vivo positively regulates nuclear localization together with the nuclear localization sequence.	SIGNOR-248904
Q9NQS7	O14578	0	phosphorylation	up-regulates activity	0.426	Figure 5.CIT-K phosphorylates INCENP. (a) Schematic diagram of INCENP structure illustrating the phosphorylated sites identified by MS.	SIGNOR-280232
P01106	Q92995	0	deubiquitination	up-regulates quantity by stabilization	0.353	In this study, we demonstrate that the deubiquitinase USP13 stabilizes c-Myc by antagonizing FBXL14-mediated ubiquitination to maintain GSC self-renewal and tumorigenic potential. USP13 was preferentially expressed in GSCs, and its depletion potently inhibited GSC proliferation and tumor growth by promoting c-Myc ubiquitination and degradation.	SIGNOR-274124
P49336	P46531	1	phosphorylation	down-regulates	0.552	Purified recombinant cycc:cdk8 phosphorylates the notch icd within the tad and pest domains, and expression of cycc:cdk8 strongly enhances notch icd hyperphosphorylation and pest-dependent degradation by the fbw7/sel10 ubiquitin ligase in vivo.	SIGNOR-130640
P49841	P46531	1	phosphorylation	up-regulates	0.463	Here, we observed that gsk3beta was able to bind and phosphorylate notch1ic in vitro, and attenuation of gsk3beta activity reduced phosphorylation of notchic in vivo.Functionally, ligand-activated signaling through the endogenous notch1 receptor was reduced in gsk3beta fibroblasts, implying a positive role for gsk3beta in mammalian notch signaling.	SIGNOR-90608
Q9BY11	Q9P286	0	phosphorylation	up-regulates activity	0.2	We identified two novel Pak5 substrates, Pacsin1 and Synaptojanin1, proteins that directly interact with one another to regulate synaptic vesicle endocytosis and recycling. Pacsin1 and Synaptojanin1 were phosphorylated by Pak5 and the other group II Paks in vitro, and Pak5 phosphorylation promoted Pacsin1-Synaptojanin1 binding both in vitro and in vivo.	SIGNOR-263025
O43521	P31749	0	phosphorylation	down-regulates activity	0.567	Recombinant Akt could directly phosphorylate a GST-Bim(EL) fusion protein and identified the Akt phosphorylation site in the Bim(EL) domain as Ser(87). Further, we demonstrated that cytokine stimulation promotes Bim(EL) binding to 14-3-3 proteins. Finally, we show that mutation of Ser(87) dramatically increases the apoptotic potency of Bim(EL).	SIGNOR-252487
Q5XPI4	P19838	1	polyubiquitination	down-regulates quantity by destabilization	0.397	Here, we identify KPC1 as the Ub ligase (E3) that binds to the ankyrin repeats domain of p105, ubiquitinates it, and mediates its processing both under basal conditions and following signaling.	SIGNOR-272221
P03372	P49841	0	phosphorylation	up-regulates	0.34	The gsk-3 inhibitor lithium chloride was used to determine the role of gsk-3 in phosphorylation of ser-102, -104, and -106 and ser-118 in vivo and to explore the role of these serines in the regulation of eralpha function. Treatment of cells with lithium chloride resulted in dephosphorylation of ser-104 and -106 and ser-118, which suggests these serine residues as targets for gsk-3 in vivo. Our results further suggest that eralpha phosphorylation by gsk-3 stabilizes eralpha under resting conditions and modulates eralpha transcriptional activity upon ligand binding. Estradiol and phorbol ester cause phosphorylation of serine 118 in the human estrogen receptor. Potentiation of human estrogen receptor alpha transcriptional activation through phosphorylation of serines 104 and 106 by the cyclin a-cdk2 complex.	SIGNOR-139316
Q13043	Q9H2K8	0	phosphorylation	up-regulates	0.283	In addition, the thousand-and-one (tao) amino acids kinase or taok13 has been shown to directly phosphorylate and activate hpo or mst1/2	SIGNOR-192762
P16112	Q99542	0	cleavage	down-regulates quantity by destabilization	0.4	Matrix metalloproteinases 19 and 20 cleave aggrecan and cartilage oligomeric matrix protein (COMP)\|In this study we investigated the ability of MMP-19 and MMP-20 to cleave two of the macromolecules characterising the cartilage ECM, namely aggrecan and the cartilage oligomeric matrix protein (COMP). Both MMPs hydrolysed aggrecan efficiently at the well-described MMP cleavage site between residues Asn(341) and Phe(342), as shown by Western blotting using neo-epitope antibodies. Furthermore, the two enzymes cleaved COMP in a distinctive manner, generating a major proteolytic product of 60 kDa. Our results suggest that MMP-19 may participate in the degradation of aggrecan and COMP in arthritic disease, whereas MMP-20, due to its unique expression pattern, may primarily be involved in the turnover of these molecules during tooth development.	SIGNOR-266978
Q9Y294	Q00987	0	ubiquitination	down-regulates quantity by destabilization	0.267	We found that MDM2 overexpression also decreased the ASF1A half-life time, indicating an accelerated ASF1A degradation.\|We next examined whether the presence of RAD6 is essential for MDM2-induced ASF1A ubiquitination.	SIGNOR-278822
Q13315	Q96T60	1	phosphorylation	up-regulates	0.462	We demonstrate that pnkp is phosphorylated by the dna-dependent protein kinase (dna-pk) and ataxia-telangiectasia mutated (atm) in vitro. The major phosphorylation site for both kinases was serine 114, with serine 126 being a minor site. Purified pnkp protein with mutation of serines 114 and 126 had decreased dna kinase and dna phosphatase activities and reduced affinity for dna in vitro.	SIGNOR-176008
Q01860	P49137	0	phosphorylation	up-regulates activity	0.2	MK2 mediated OCT4 transcriptional activation is a novel mechanism for activating the MYC oncogene in progressive disease neuroblastoma that provides a therapeutic target.\|OCT4 phosphorylation at the S111 residue by MK2 was upstream of MYC transcriptional activation.	SIGNOR-279542
Q05397	P04626	0	phosphorylation	up-regulates activity	0.657	HER2, EGFR, and additional RTKs directly phosphorylate FAK FERM at Y397.\|To further confirm the mechanism of direct FAK activation by HER2, we performed a series of GST pull-down assays with purified recombinant proteins.	SIGNOR-278475
P46531	O00505	0	relocalization	up-regulates	0.324	Nicd binds via one of its four potential nuclear localization signals to importins alfa3, alfa4, and alfa7.	SIGNOR-165280
P14778	Q9Y4K3	0	ubiquitination	down-regulates quantity by destabilization	0.9	We found that of all TRAFs and E3 ligases examined, TRAF6 preferentially ubiquitinated IL-1R1.	SIGNOR-278576
P10645	P08047	0	transcriptional regulation	up-regulates quantity by expression	0.2	Recently, binding of specific protein 1 (Sp1) and cAMP response element binding protein (CREB) to a GC-rich element at -92/-62 has been identified as a critical step in gastrin-dependent regulation of the chromogranin A (CgA) gene in gastric epithelial cells. Here we demonstrate that binding of early growth response protein 1 (Egr-1) to the distal part of the -92/-62 site is also required for gastrin-dependent CgA transactivation.	SIGNOR-254273
Q13224	P17252	0	phosphorylation	up-regulates activity	0.469	These results indicate that PKC can directly phosphorylate S1303 and S1323 in the NR2B C terminus, leading to enhanced currents through NMDA receptor channels.	SIGNOR-249083
P12931	Q9UGK3	1	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
P49959	P23443	0	phosphorylation	down-regulates quantity by destabilization	0.2	MRE11 is highly unstable in PTEN-deficient cells but stability can be significantly restored by inhibiting mTORC1 or p70S6 kinase (p70S6K), downstream kinases whose activities are stimulated by AKT, or by mutating a residue in MRE11 that we show is phosphorylated by p70S6K in vitro.	SIGNOR-265944
Q8NG68	P68363	1	tyrosination	down-regulates	0.46	Tubulin tyrosine ligase (ttl) adds a c-terminal tyr to __tubulin as part of a tyrosination/detyrosination cycle present in most eukaryotic cells. / ttl inhibits spontaneous tubulin polymerization	SIGNOR-176915
P78527	O75030	1	phosphorylation	up-regulates activity	0.2	These results suggest that DNA-PK can target MITF-S325 for phosphorylation. In melanocytes and melanoma cells, MITF is rapidly phosphorylated by DNA-PK and interacts with NBS1–RAD50 but not MRE11, destabilizing the MRN complex.	SIGNOR-277899
Q9Y397	P01111	1	palmitoylation	up-regulates activity	0.404	Covalent lipid modifications mediate the membrane attachment and biological activity of Ras proteins. All Ras isoforms are farnesylated and carboxyl-methylated at the terminal cysteine; H-Ras and N-Ras are further modified by palmitoylation. Here we report that H- and N-Ras are palmitoylated by a human protein palmitoyltransferase encoded by the ZDHHC9 and GCP16 genes. DHHC9 is an integral membrane protein that contains a DHHC cysteine-rich domain. GCP16 encodes a Golgi-localized membrane protein.	SIGNOR-261355
P10912	P18031	0	dephosphorylation	down-regulates activity	0.501	PTPH1 only bound Tyr534, whereas PTP1B and TC-PTP bound multiple phosphopeptides. Earlier work suggests that Tyr332, Tyr487, Tyr534, Tyr566, and Tyr627 are all phosphorylated after GH stimulation (21). Apart from Tyr627, all of these also appear good PTP substrates	SIGNOR-248420
P00742	P02749	1	cleavage	down-regulates activity	0.386	In the previous study, we found that factor Xa can produce the nicked form by cleaving Lys 317-Thr 318, using recombinant human domain V (r-Domain V). \|The cleavage was completely inhibited by plasmin inhibitor (alpha2PI). The nicked form was demonstrated to show reduced affinity for CL with a dissociation constant of one order of magnitude larger than that of the intact beta2GPI.	SIGNOR-266997
Q8NBL1	P46531	1	glycosylation	up-regulates	0.606	O-glucosylation of epidermal growth factor-like (egf) repeats in the extracellular domain of notch is essential for notch function. A udp-glucose:protein o-glucosyltransferase (poglut/rumi) transfers o-glucose to serine within the o-glucose consensus.	SIGNOR-198713
P61978	P53779	0	phosphorylation	up-regulates activity	0.339	JNK Phosphorylation of HnRNP K Increases Its Transcriptional Activity. the primary site for JNK phosphorylation consists of serines 216 and 353 on the K protein.	SIGNOR-250083
P45983	P01106	1	phosphorylation	up-regulates activity	0.556	The jnk pathway is selectively involved in the c-myc-mediated apoptosis and that the apoptotic function of c-myc is directly regulated by jnk pathway through phosphorylation at ser-62 and ser-71.	SIGNOR-236018
P20823	Q9Y463	0	phosphorylation	up-regulates	0.502	Mirk phosphorylates hnf1 at amino acid 249mkk3 enhanced mirk kinase activity and the transcriptional activation of hnf1alpha by mirk	SIGNOR-86728
Q9BUB5	P06730	1	phosphorylation	up-regulates	0.779	Mnk1 and mnk2 regulate protein synthesis by phosphorylating the initiation factor eif4e.	SIGNOR-166646
Q16584	P24941	0	phosphorylation	up-regulates activity	0.2	Using in vitro kinase assays and phosphomutants, we determined that CDK1 phosphorylates MLK3 on Ser548 and decreases MLK3 activity during mitosis, whereas CDK2 phosphorylates MLK3 on Ser770 and increases MLK3 activity during G1/S and G2 phases.	SIGNOR-277604
Q02156	P21802	1	phosphorylation	up-regulates	0.2	Phosphorylation of serine 779 in fibroblast growth factor receptor 1 and 2 by protein kinase c(epsilon) regulates ras/mitogen-activated protein kinase signaling and neuronal differentiation	SIGNOR-201675
Q13363	O95471	1	transcriptional regulation	down-regulates quantity by repression	0.2	ChIP assays revealed that SNAI1P is recruited on the CLDN7 gene promoter along with the co-repressor CtBP1 and the effector HDAC1.	SIGNOR-254105
O43248	O15550	0	transcriptional regulation	up-regulates quantity by expression	0.302	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-260026
Q96BR1	Q66PJ3	1	phosphorylation	down-regulates activity	0.2	AIP4 is phosphorylated by CISK in vitro on WW domain residues, which may impact its ability to interact with and ubiquitinate substrate proteins.\|Expression of a constitutively active CISK inhibits CXCR4 degradation, possibly by attenuating CXCR4 binding to and ubiquitination by AIP4 and/or modulating the action of AIP4 on a protein involved in CXCR4 endosomal sorting .	SIGNOR-280124
O95644	P16298	0	relocalization	up-regulates	0.724	The ca2+ dependent phosphatase calcineurin induces cardiac and skeletal muscle hypertrophy by a process that involves nf-at nuclear translocation, and activation of mef2c.	SIGNOR-84047
Q9HCE7	Q13485	1	ubiquitination	down-regulates activity	0.745	Smurfs, which otherwise cannot directly bind to smad4, mediated poly-ubiquitination of smad4 in the presence of smad6 or smad7. Smad signaling is negatively regulated by inhibitory (i) smads and ubiquitin-mediated processes.	SIGNOR-236096
P35790	P35968	1	phosphorylation	down-regulates quantity by destabilization	0.249	Here, we show for the first time a possible mechanism by which CKI dependent phosphorylation of VEGFR2 at specific sites in its C-terminal tail triggers SCF beta-TRCP -mediated VEGFR2 ubiquitination and destruction.	SIGNOR-279029
O00192	Q9UDY2	0	relocalization	down-regulates activity	0.369	We identified ARVCF as a binding partner of ZO-1 and ZO-2 and characterized the role of PDZ-domain proteins in plasma membrane and nuclear localization of ARVCF. ZO-2, in contrast, relocated to the nucleus with ARVCF, and, given the interaction between the ZO-2 PDZ domains and ARVCF, raised the possibility that ZO-2 may play a role in nuclear localization of ARVCF. Such a role for ZO-2 is indeed supported by the ability of the ZO-2 PDZ domain to efficiently relocate ARVCF from the plasma membrane to the nucleus in a process that required the ability of the two proteins to interact and the presence of a functional NLS in the ZO-2 PDZ domains. Thus, ZO-2 could be involved in nuclear translocation and/or retention of ARVCF and play a role in regulating postulated functions of ARVCF in gene expression	SIGNOR-252122
P31749	A8MYZ6	1	phosphorylation	down-regulates	0.648	The phosphorylation of the two remaining akt-dependent sites inhibits foxo6 transcriptional activity	SIGNOR-252582
Q9Y5K5	Q15796	1	deubiquitination	up-regulates	0.378	Here, we report a novel interaction between smads and ubiquitin c-terminal hydrolase uch37, a deubiquitinating enzyme that could potentially reverse smurf-mediated ubiquitination. In gst pull down experiments, uch37 bound weakly to smad2 and smad3, and bound very strongly to smad7 in a region that is distinct from the -py- motif in smad7 that interacts with smurf ubiquitin ligases	SIGNOR-138876
Q13490	Q86VP3	1	polyubiquitination	down-regulates quantity by destabilization	0.303	Under basal conditions, PACS-2 underwent K48-linked poly-ubiquitination, resulting in PACS-2 proteasomal degradation. Biochemical assays showed cIAP-1 and cIAP-2 interacted with PACS-2 in vitro and co-immunoprecipitation studies demonstrated that the two cIAPs bound PACS-2 in vivo. More importantly, both cIAP-1 and cIAP-2 directly mediated PACS-2 ubiquitination in a cell-free assay.	SIGNOR-272851
P36956	P53350	0	phosphorylation	up-regulates activity	0.441	As illustrated in , the turnover of nuclear SREBP1a was attenuated in the presence of Plk1, confirming that Plk1 stabilizes nuclear SREBP1 by reducing its degradation.\|Figure 2.Plk1 phosphorylates threonine 424, serine 467 and serine 486 in nuclear SREBP1 during mitosis. (A) In vitro kinase assay with recombinant nuclear SREBP1a and Plk1.	SIGNOR-279382
Q9UBK2	Q96EB6	0	deacetylation	up-regulates activity	0.799	SIRT1 overexpression reduces muscle wasting by blocking the activation of FoxO1 and 3 SIRT1 activation has been reported to increase dramatically endurance exercise through the activation of PGC-1_ in muscle, which stimulates fatty acid oxidation	SIGNOR-217963

Q14498

P00519

0

phosphorylation

up-regulates activity

0.322

In this paper, we report that RBM39 interacts with the nonreceptor tyrosine kinase c-Abl. Both the Src homology (SH) 2 and SH3 domains of c-Abl interact with RBM39. The major tyrosine phosphorylation sites on RBM39 that are phosphorylated by c-Abl are Y95 and Y99, as demonstrated by liquid chromatography coupled with tandem mass spectrometry (LC/MS/MS) and mutational analysis. c-Abl was shown boost the transcriptional coactivation activity of RBM39 for ERα and PRβ in a tyrosine kinase-dependent manner.

SIGNOR-262609

P18031

P49760

0

phosphorylation

up-regulates activity

0.322

The clk family kinases, clk1 and clk2, phosphorylate and activate the tyrosine phosphatase, ptp-1b.|Phosphorylation of PTP-1B at Ser(50) by CLK1 or CLK2 is responsible for its enzymatic activation.

SIGNOR-70603

P31749

Q99683

1

phosphorylation

down-regulates activity

0.729

Akt phosphorylates and negatively regulates apoptosis signal-regulating kinase 1 akt decreased ask1 kinase activity stimulated by both oxidative stress and overexpression in 293 cells by phosphorylating a consensus akt site at serine 83 of ask1.

SIGNOR-252465

P49841

P35869

1

phosphorylation

up-regulates activity

0.25

A proposed model of GSK3β role on AHR function and degradation. AHR is phosphorylated by GSK3β in a p23-dependent manner in HeLa cells. This phosphorylation is required for optimal activation of the ligand-dependent AHR target gene transcription. After phosphorylation, AHR is K63-ubiquitinated and is targeted for the LC3-mediated selective autophagy. When the p23 content is compromised in HeLa cells, AHR is more prone to degradation via autophagy, bypassing the GSK3β phosphorylation of AHR.

SIGNOR-276664

P63000

O14559

0

gtpase-activating protein

down-regulates activity

0.444

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-260491

Q16236

Q13131

0

phosphorylation

up-regulates activity

0.2

MS-based analysis of immunoprecipitated Nrf2 revealed serine 374, 408 and 433 in human Nrf2 to be hyperphosphorylated as a function of activated AMPK. A direct phosphate-transfer by AMPK to those sites was indicated by in vitro kinase assays with recombinant proteins as well as interaction of AMPK and Nrf2 in cells, evident by co-immunoprecipitation. Mutation of serine 374, 408 and 433 to alanine did not markedly affect half-life, nuclear accumulation or induction of reporter gene expression upon Nrf2 activation with sulforaphane. However, some selected endogenous Nrf2 target genes responded with decreased induction when the identified phosphosites were mutated, whereas others remained unaffected.

SIGNOR-277496

P14780

P01137

1

cleavage

up-regulates

0.592

We also demonstrate that mmp-9, as well as its relative, mmp-2, cleave latent transforming growth factor-_ (tgf-_), which constitutes a novel mechanism of tgf-_ activation.

SIGNOR-74461

Q5JU85

P48058

1

relocalization

up-regulates quantity

0.2

BRAG1 increases the synaptic recycling pool of AMPARs.these data suggest that the BRAG1 enhancement of AMPAR transmission is mediated by the increased expression of the recycling pool of synaptic GluA2/3 receptors.

SIGNOR-264915

O00311

Q8TEA8

1

phosphorylation

up-regulates activity

0.321

Here we show that DUE-B is de-phosphorylated in M phase and phosphorylated in G1/S phase. Phosphorylated DUE-B forms homodimers, whereas de-phosphorylated DUE-B interacts with the Mcm2–7 complex and aminoacyl-tRNA synthetases. We find that CKII can prime DUE-B for Cdc7 phosphorylation. Confirming the importance of DUE-B phosphorylation in replication initiation, a C-terminal Ser/Thr to Ala mutant blocks Cdc45 and RPA loading on sperm chromatin and inhibits DNA replication. DUE-B C-terminal phosphorylation sites (serine 179, 181, 182, 194, 196, 197, 204, 205, and threonine 187) were mutated to unphosphorylatable alanine (DUE-B(S/T)-A) or phosphomimic aspartic acid (DUE-B(S/T)-D).

SIGNOR-273967

Q9Y261

P80370

1

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

Q8NFJ5

P00533

0

phosphorylation

down-regulates activity

0.387

EGFR phosphorylates and inhibits lung tumor suppressor GPRC5A in lung cancer.|Together, these results indicate that endogenous EGFR can phosphorylate GPRC5A at four identified tyrosine residues (Y317, Y320, Y347 and Y350) in response to EGF stimulation in the lung cancer H1792 cells.

SIGNOR-278336

O14827

P63000

1

guanine nucleotide exchange factor

up-regulates activity

0.498

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-260574

Q99496

Q9C0C7

1

ubiquitination

down-regulates quantity by destabilization

0.359

RNF2 ubiquitinates AMBRA1 at lysine 45.|These data indicate that RNF2 directly accelerates the degradation of AMBRA1.

SIGNOR-278596

O15111

Q9Y6Q9

1

phosphorylation

up-regulates

0.395

Herein, we report the successful identification of six functional in vivo src-3 phosphorylation sites.

SIGNOR-196953

P68400

Q04724

1

phosphorylation

up-regulates

0.32

These results suggest that ck2 phosphorylation of serine 239 of gro/tle1 is important for its function during neuronal differentiation.

SIGNOR-129026

Q9UBK2

P49841

0

phosphorylation

down-regulates quantity

0.476

GSK3\u03b2 is an important serine/threonine kinase to regulate PPAR\u03b3 coactivator-1\u03b1 degradation. , GSK3\u03b2 reduces PPAR\u03b3 coactivator-1\u03b1 levels by phosphorylating PPAR\u03b3 coactivator-1\u03b1 and subsequently stimulating PPAR\u03b3 coactivator-1\u03b1 degradation by the ubiquitin-proteasomal system.|Within them, GSK3beta, which can phosphorylate PGC-1alpha and promote its ubiquitin mediated degradation , , was upregulated significantly in mnd2 mouse brain and spinal cord compared with that in wide-type mice (XREF_FIG).

SIGNOR-279723

Q13094

P42681

0

phosphorylation

up-regulates

0.728

Resting lymphocyte kinase (rlk/txk) targets lymphoid adaptor slp-76 in the cooperative activation of interleukin-2 transcription in t-cells. In this study, we report that rlk phosphorylates slp-76 at its n-terminal yesp/yepp sites. A third tyrosine within the amino-terminal region (y145) appears to be the most important for optimal slp-76 function

SIGNOR-44669

P68400

P27695

1

phosphorylation

up-regulates activity

0.485

Here we demonstrate that APE/Ref-1 is phosphorylated by casein kinase II (CKII). This was shown for both the recombinant APE/Ref-1 protein (Km=0.55 mM) and for APE/Ref-1 expressed in COS cells. Phosphorylation of APE/Ref-1 did not alter the repair activity of the enzyme, whereas it stimulated its redox capability towards AP-1, thus promoting DNA binding activity of AP-1.

SIGNOR-250825

O14920

Q13233

0

phosphorylation

up-regulates activity

0.595

These results suggested that IKK\u03b2 was a likely substrate for MEKK1 and that MEKK1 phosphorylation of IKK\u03b2 increased its kinase activity.

SIGNOR-279339

O43353

P28482

1

phosphorylation

up-regulates activity

0.295

RIP2 directly phosphorylates and activates ERK2 in vivo and in vitro.

SIGNOR-279106

Q6ZN28

P08581

1

transcriptional regulation

up-regulates quantity by expression

0.394

Human colon carcinoma SW480 cells express virtually no MACC1. MACC1 cDNA transfection led not only to strong increases in MACC1 mRNA expression (Fig. 3a), but also to a 40-fold upregulation of the HGF receptor MET mRNA expression (Fig. 3b). This was confirmed on the protein level

SIGNOR-266058

Q9UHD2

P11908

1

phosphorylation

up-regulates activity

0.2

Here, we show that ionizing radiation results in TBK1-mediated phosphorylation of phosphoribosyl pyrophosphate synthetase (PRPS)1/2 at T228, thereby enhancing PRPS1/2 catalytic activity and promoting deoxyribonucleotide synthesis.

SIGNOR-277317

Q8WV28

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-254692

P61586

Q9Y3M8

0

gtpase-activating protein

down-regulates activity

0.645

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-260521

P63167

Q13153

0

phosphorylation

down-regulates

0.378

Dlc1 phosphorylation on ser(88) by p21-activated kinase 1 (pak1), a signaling nodule, promotes mammalian cell survival by regulating its interaction with bim and the stability of bim. Here we discovered that phosphorylation of ser(88), which juxtapose each other at the interface of the dlc dimer, disrupts dlc1 dimer formation and consequently impairs its interaction with bim

SIGNOR-159995

P17252

P10415

1

phosphorylation

up-regulates

0.349

Purified pkca can efficiently and directly phosphorylate bcl2 at serine 70

SIGNOR-60120

Q15910

P31260

1

transcriptional regulation

down-regulates quantity by repression

0.438

These data support the proposed regulatory impact of particular PRC2-proteins in expression of HOXA9 and HOXA10 in NK/T-cells. In mammalian cells knockdown of PRC2 components EZH2 or PHF1 led to upregulated HOXA gene expression.

SIGNOR-260070

O60610

P06493

0

phosphorylation

down-regulates activity

0.2

In this study, we found that Cdk1 phosphorylated DIAPH1, which inhibited the interaction between DIAPH1 and profilin1 (PFN1) during metaphase.|Thus, the results suggest that the level of cortical F-actin has to be finely maintained by Cdk1 mediated positive and negative regulation of DIAPH1.

SIGNOR-279598

P08575

Q86WV1

1

dephosphorylation

up-regulates activity

0.361

Mutational analysis demonstrated the pivotal role of Tyr-232 in SKAP55 in the association with CD45. In Jurkat cells, anti-CD3 antibody stimulation promoted SKAP55 tyrosine phosphorylation and translocation from the cytoplasm to the membrane. Overexpression of SKAP55 in these cells induced transcriptional activation of the IL-2 promoter, while mutant SKAP55-Y232F totally suppressed the promoter activity. Furthermore, overexpression of SKAP55-Y232F also caused the tyrosine hyperphosphorylation of Fyn with a decreased kinase activity. Thus, SKAP55 is an essential adapter to couple CD45 with the Src family kinases for dephosphorylation and, thus, positively regulates TCR signaling.

SIGNOR-248360

P17252

P35240

1

phosphorylation

down-regulates activity

0.328

PKC\u03b1\nnormally phosphorylates and inactivates NF2.|PKCalpha normally phosphorylates and inactivates NF2.

SIGNOR-280081

P10415

P06493

0

phosphorylation

up-regulates activity

0.345

Using synthetic peptides and mutant cell lines, we identified threonine 56, one of two consensus sites for cdc2 within the bcl-2 sequence, as a residue phosphorylated by cdc2. Mutation at threonine 56 abrogated the cell cycle inhibitory effect of bcl-2 without affecting anti-apoptotic function.Taken together, our present findings indicate that phosphorylation of bcl-2 at threonine 56 by cdc2 is required for bcl-2-mediated cell cycle inhibition, which may have some roles during mitosis in the normal cell cycle.

SIGNOR-76837

P42345

Q8IYT8

1

phosphorylation

down-regulates

0.777

Mtor phosphorylates a mammalian homologue of atg13 and the mammalian atg1 homologues ulk1 and ulk2

SIGNOR-183961

Q86WV6

Q9BY78

0

ubiquitination

up-regulates activity

0.2

As a result, knockdown of RNF26 promoted degradation of MITA after viral infection and prevented degradation of IRF3.|In addition, RNF26 could not induce polyubiquitination of MITA (K150R) in in vitro ubiquitination assays (XREF_FIG).

SIGNOR-278573

Q15835

O00254

1

phosphorylation

down-regulates activity

0.2

For example, RhoK phosphorylates and inhibits TIAM1, STEF, and PAR3; disrupts the polarity complex; and prevents Rac activation ( xref ).

SIGNOR-279993

Q13887

P49841

0

phosphorylation

down-regulates

0.368

Stability of the klf5 is mediated by proteasomal degradation via phosphorylation by glycogen synthase kinase 3_ (gsk3_) and recognition by f-box and wd repeat domain-containing 7 (fbw7) of a phosphodegron sequence surrounding serine 303 in klf5

SIGNOR-203627

Q14012

Q9NP62

1

phosphorylation

up-regulates activity

0.388

We show that Epac1 and Rap1, in response to cAMP, activate CaMKI to phosphorylate Ser47 in GCM1. This phosphorylation facilitates the interaction between GCM1 and the desumoylating enzyme SENP1 and thereby leads to GCM1 desumoylation and activation.

SIGNOR-262680

O60610

P61586

0

null

up-regulates activity

0.785

We find that the small GTPase Rho regulates R-cadherin adherens junction formation via Dia1 (also known as p140mDia) and profilin-1-mediated signaling pathway. The role played by Rho in regulating R-cadherin is underscored by the fact that constitutively active RhoA(Q63L) induces R-cadherin junction formation in MDA-MB-231 cells.|Data presented thus far demonstrated that Rho, Dia1, and profilin-1 were required for R-cadherin junction formation in N480 cells.

SIGNOR-253108

P60953

Q70Z35

0

guanine nucleotide exchange factor

up-regulates activity

0.423

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-260572

Q13563

Q9BZL6

0

phosphorylation

up-regulates activity

0.2

Here, we report the identification of a previously unrecognized phosphorylation site within the polycystin-2 C terminus (Ser801), and we demonstrate that it is phosphorylated by protein kinase D. These results suggest that growth factor-stimulated, protein kinase D-mediated phosphorylation of polycystin-2 is essential for its ER channel function and links extracellular stimuli to its effects on cell growth and intracellular calcium regulation.

SIGNOR-276284

P05771

Q5JVS0

1

phosphorylation

down-regulates activity

0.29

We found a strong phosphorylation of Ki-1/57 by PKCalphabeta, PKCdelta, PKClambda/zeta, and especially by PKCsigma, however not by PKCmi. These data show that Ki-1/57 can serve in principal as a substrate for a wide variety of different PKC isoforms but also that its phosphorylation is strongest with PKCsigma. | This suggests that the two threonine residues present in this fragment (Thr354 and Thr375) might be the main target residues for phosphorylation by PKC in vitro. | Ki-1/57 Exits the Nucleus upon PMA Activation

SIGNOR-249247

P53350

Q14980

1

phosphorylation

down-regulates activity

0.534

Phosphorylation of NuMA by Plk1 at 1833/34 residue can impact its cortical localization.|These data strongly suggest that Plk1 negatively regulate cortical NuMA localization and that this impact of Plk1 on NuMA is presumably independent of LGN, at least in the anaphase cells.

SIGNOR-279345

Q92783

O60674

0

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

P01100

Q15418

0

phosphorylation

up-regulates activity

0.529

We now provide evidence that two growth-regulated, nucleus- and cytoplasm-localized protein kinases, 90-kda ribosomal s6 kinase (rsk) and mitogen-activated protein kinase (map kinase), contribute to the serum-induced phosphorylation of c-fos. The major phosphopeptides derived from biosynthetically labeled c-fos correspond to phosphopeptides generated after phosphorylation of c-fos in vitro with both rsk and map kinase. The phosphorylation sites identified for rsk (ser-362) and map kinase (ser-374) are in the transrepression domain. Cooperative phosphorylation at these sites by both enzymes was observed in vitro and reflected in vivo by the predominance of the peptide phosphorylated on both sites, as opposed to singly phosphorylated peptides. This study suggests a role for nuclear rsk and map kinase in modulating newly synthesized c-fos phosphorylation and downstream signaling.

SIGNOR-37154

Q9UKV5

Q8IWA4

1

polyubiquitination

down-regulates quantity by destabilization

0.309

Gp78 induces ubiquitylation and proteasomal degradation of Mfn1 and Mfn2.

SIGNOR-272886

Q5FBB7

P51955

0

phosphorylation

up-regulates

0.2

Here we show that nek2a phosphorylates human sgo1 and such phosphorylation is essential for faithful chromosome congression in mitosis. phosphorylation sites were mapped to ser(14) and ser(507)

SIGNOR-156882

Q16539

P15336

1

phosphorylation

up-regulates

0.793

On the other hand, sapks such as jnks and p38 phosphorylate atf-2 at thr-69, thr-71, and ser-90 which lie close to the n-terminal transcriptional activation domain and stimulate itstrans-activating capacity our results indicate that atf-2 not only directly binds to smad3/4 hetero-oligomers but also that atf-2 is phosphorylated by tgf- signaling via tak1 and p38.

SIGNOR-65597

P23560

P16220

0

transcriptional regulation

up-regulates quantity

0.488

Brain-derived neurotrophic factor (BDNF) is a critical molecule for learning and memory. Brain BDNF levels correlate with cognitive status. Activation of CREB facilitates the transcription of crucial proteins for activity-dependent plasticity particularly BDNF.

SIGNOR-265062

P59595

P55212

0

cleavage

up-regulates activity

0.2

Caspase-6 is activated through the intrinsic pathway and mediates C-terminal cleavage of SARS-CoV N at residues 400 and 403

SIGNOR-260212

Q8TEM1

P06493

0

phosphorylation

up-regulates activity

0.549

In vitro phosphorylation of GST fusion protein containing the carboxyl-terminal domain of gp210 by cyclin B-p34cdc2 protein kinase generates a phosphopeptide that comigrates with a mitosis-specific phosphopeptide. Ser1880 Is the Mitotic Phosphorylation Site of Gp210.

SIGNOR-262699

Q16236

P09601

1

transcriptional regulation

up-regulates quantity by expression

0.679

In both models, the inducer-modified and Nrf2-bound Keap1 is inactivated and, consequently, newly synthesized Nrf2 proteins bypass Keap1 and translocate into the nucleus, bind to the ARE and drive the expression of Nrf2 target genes such as NAD(P)H quinone oxidoreductase 1 (NQO1), heme oxygenase 1 (HMOX1), glutamate-cysteine ligase (GCL) and glutathione S transferases (GSTs).

SIGNOR-256276

Q9GZY8

Q15139

0

phosphorylation

up-regulates activity

0.2

PKD directly phosphorylates MFF on serines 155, 172, and 275

SIGNOR-277559

P25490

O14763

1

transcriptional regulation

down-regulates quantity by repression

0.403

Depletion of FKBP51 impairs the acetylation status of YY1 and interferes with its binding on the DR5 promoter. The lack of the repressor activity of YY1 increases DR5 transcription and sensitizes melanoma cell to TRAIL-induced apoptosis.

SIGNOR-268793

O95551

Q16659

0

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

P02788

O60260

0

ubiquitination

down-regulates activity

0.2

We propose that Parkin ubiquitylation of LTF at K649 perturbs LTF\u2019s ability to accumulate intracellular iron levels and that depletion of Parkin, or substitution of K649 on LTF, allows LTF to accumulate intracellular iron levels.|Parkin dependent ubiquitylation of LTF occurred most often on lysines (K) 182 and 649.

SIGNOR-278641

O43353

P98170

0

ubiquitination

up-regulates activity

0.628

XIAP is the essential E3 for RIPK2 ubiquitination and interacts with RIPK2 through its baculoviral IAP-repeat (BIR).

SIGNOR-280449

P17252

P02545

1

phosphorylation

up-regulates activity

0.362

Mutation of both Ser-403/Ser-404 within a PKC motif flanking the nuclear localization signal inhibits transport of mutant lamin A to the nucleus in 64% of the cells. It is proposed that phosphorylation of the motif in vivo positively regulates nuclear localization together with the nuclear localization sequence.

SIGNOR-248904

Q9NQS7

O14578

0

phosphorylation

up-regulates activity

0.426

Figure 5.CIT-K phosphorylates INCENP. (a) Schematic diagram of INCENP structure illustrating the phosphorylated sites identified by MS.

SIGNOR-280232

P01106

Q92995

0

deubiquitination

up-regulates quantity by stabilization

0.353

In this study, we demonstrate that the deubiquitinase USP13 stabilizes c-Myc by antagonizing FBXL14-mediated ubiquitination to maintain GSC self-renewal and tumorigenic potential. USP13 was preferentially expressed in GSCs, and its depletion potently inhibited GSC proliferation and tumor growth by promoting c-Myc ubiquitination and degradation.

SIGNOR-274124

P49336

P46531

1

phosphorylation

down-regulates

0.552

Purified recombinant cycc:cdk8 phosphorylates the notch icd within the tad and pest domains, and expression of cycc:cdk8 strongly enhances notch icd hyperphosphorylation and pest-dependent degradation by the fbw7/sel10 ubiquitin ligase in vivo.

SIGNOR-130640

P49841

P46531

1

phosphorylation

up-regulates

0.463

Here, we observed that gsk3beta was able to bind and phosphorylate notch1ic in vitro, and attenuation of gsk3beta activity reduced phosphorylation of notchic in vivo.Functionally, ligand-activated signaling through the endogenous notch1 receptor was reduced in gsk3beta fibroblasts, implying a positive role for gsk3beta in mammalian notch signaling.

SIGNOR-90608

Q9BY11

Q9P286

0

phosphorylation

up-regulates activity

0.2

We identified two novel Pak5 substrates, Pacsin1 and Synaptojanin1, proteins that directly interact with one another to regulate synaptic vesicle endocytosis and recycling. Pacsin1 and Synaptojanin1 were phosphorylated by Pak5 and the other group II Paks in vitro, and Pak5 phosphorylation promoted Pacsin1-Synaptojanin1 binding both in vitro and in vivo.

SIGNOR-263025

O43521

P31749

0

phosphorylation

down-regulates activity

0.567

Recombinant Akt could directly phosphorylate a GST-Bim(EL) fusion protein and identified the Akt phosphorylation site in the Bim(EL) domain as Ser(87). Further, we demonstrated that cytokine stimulation promotes Bim(EL) binding to 14-3-3 proteins. Finally, we show that mutation of Ser(87) dramatically increases the apoptotic potency of Bim(EL).

SIGNOR-252487

Q5XPI4

P19838

1

polyubiquitination

down-regulates quantity by destabilization

0.397

Here, we identify KPC1 as the Ub ligase (E3) that binds to the ankyrin repeats domain of p105, ubiquitinates it, and mediates its processing both under basal conditions and following signaling.

SIGNOR-272221

P03372

P49841

0

phosphorylation

up-regulates

0.34

The gsk-3 inhibitor lithium chloride was used to determine the role of gsk-3 in phosphorylation of ser-102, -104, and -106 and ser-118 in vivo and to explore the role of these serines in the regulation of eralpha function. Treatment of cells with lithium chloride resulted in dephosphorylation of ser-104 and -106 and ser-118, which suggests these serine residues as targets for gsk-3 in vivo. Our results further suggest that eralpha phosphorylation by gsk-3 stabilizes eralpha under resting conditions and modulates eralpha transcriptional activity upon ligand binding. Estradiol and phorbol ester cause phosphorylation of serine 118 in the human estrogen receptor. Potentiation of human estrogen receptor alpha transcriptional activation through phosphorylation of serines 104 and 106 by the cyclin a-cdk2 complex.

SIGNOR-139316

Q13043

Q9H2K8

0

phosphorylation

up-regulates

0.283

In addition, the thousand-and-one (tao) amino acids kinase or taok13 has been shown to directly phosphorylate and activate hpo or mst1/2

SIGNOR-192762

P16112

Q99542

0

cleavage

down-regulates quantity by destabilization

0.4

Matrix metalloproteinases 19 and 20 cleave aggrecan and cartilage oligomeric matrix protein (COMP)|In this study we investigated the ability of MMP-19 and MMP-20 to cleave two of the macromolecules characterising the cartilage ECM, namely aggrecan and the cartilage oligomeric matrix protein (COMP). Both MMPs hydrolysed aggrecan efficiently at the well-described MMP cleavage site between residues Asn(341) and Phe(342), as shown by Western blotting using neo-epitope antibodies. Furthermore, the two enzymes cleaved COMP in a distinctive manner, generating a major proteolytic product of 60 kDa. Our results suggest that MMP-19 may participate in the degradation of aggrecan and COMP in arthritic disease, whereas MMP-20, due to its unique expression pattern, may primarily be involved in the turnover of these molecules during tooth development.

SIGNOR-266978

Q9Y294

Q00987

0

ubiquitination

down-regulates quantity by destabilization

0.267

We found that MDM2 overexpression also decreased the ASF1A half-life time, indicating an accelerated ASF1A degradation.|We next examined whether the presence of RAD6 is essential for MDM2-induced ASF1A ubiquitination.

SIGNOR-278822

Q13315

Q96T60

1

phosphorylation

up-regulates

0.462

We demonstrate that pnkp is phosphorylated by the dna-dependent protein kinase (dna-pk) and ataxia-telangiectasia mutated (atm) in vitro. The major phosphorylation site for both kinases was serine 114, with serine 126 being a minor site. Purified pnkp protein with mutation of serines 114 and 126 had decreased dna kinase and dna phosphatase activities and reduced affinity for dna in vitro.

SIGNOR-176008

Q01860

P49137

0

phosphorylation

up-regulates activity

0.2

MK2 mediated OCT4 transcriptional activation is a novel mechanism for activating the MYC oncogene in progressive disease neuroblastoma that provides a therapeutic target.|OCT4 phosphorylation at the S111 residue by MK2 was upstream of MYC transcriptional activation.

SIGNOR-279542

Q05397

P04626

0

phosphorylation

up-regulates activity

0.657

HER2, EGFR, and additional RTKs directly phosphorylate FAK FERM at Y397.|To further confirm the mechanism of direct FAK activation by HER2, we performed a series of GST pull-down assays with purified recombinant proteins.

SIGNOR-278475

P46531

O00505

0

relocalization

up-regulates

0.324

Nicd binds via one of its four potential nuclear localization signals to importins alfa3, alfa4, and alfa7.

SIGNOR-165280

P14778

Q9Y4K3

0

ubiquitination

down-regulates quantity by destabilization

0.9

We found that of all TRAFs and E3 ligases examined, TRAF6 preferentially ubiquitinated IL-1R1.

SIGNOR-278576

P10645

P08047

0

transcriptional regulation

up-regulates quantity by expression

0.2

Recently, binding of specific protein 1 (Sp1) and cAMP response element binding protein (CREB) to a GC-rich element at -92/-62 has been identified as a critical step in gastrin-dependent regulation of the chromogranin A (CgA) gene in gastric epithelial cells. Here we demonstrate that binding of early growth response protein 1 (Egr-1) to the distal part of the -92/-62 site is also required for gastrin-dependent CgA transactivation.

SIGNOR-254273

Q13224

P17252

0

phosphorylation

up-regulates activity

0.469

These results indicate that PKC can directly phosphorylate S1303 and S1323 in the NR2B C terminus, leading to enhanced currents through NMDA receptor channels.

SIGNOR-249083

P12931

Q9UGK3

1

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

P49959

P23443

0

phosphorylation

down-regulates quantity by destabilization

0.2

MRE11 is highly unstable in PTEN-deficient cells but stability can be significantly restored by inhibiting mTORC1 or p70S6 kinase (p70S6K), downstream kinases whose activities are stimulated by AKT, or by mutating a residue in MRE11 that we show is phosphorylated by p70S6K in vitro.

SIGNOR-265944

Q8NG68

P68363

1

tyrosination

down-regulates

0.46

Tubulin tyrosine ligase (ttl) adds a c-terminal tyr to __tubulin as part of a tyrosination/detyrosination cycle present in most eukaryotic cells. / ttl inhibits spontaneous tubulin polymerization

SIGNOR-176915

P78527

O75030

1

phosphorylation

up-regulates activity

0.2

These results suggest that DNA-PK can target MITF-S325 for phosphorylation. In melanocytes and melanoma cells, MITF is rapidly phosphorylated by DNA-PK and interacts with NBS1–RAD50 but not MRE11, destabilizing the MRN complex.

SIGNOR-277899

Q9Y397

P01111

1

palmitoylation

up-regulates activity

0.404

Covalent lipid modifications mediate the membrane attachment and biological activity of Ras proteins. All Ras isoforms are farnesylated and carboxyl-methylated at the terminal cysteine; H-Ras and N-Ras are further modified by palmitoylation. Here we report that H- and N-Ras are palmitoylated by a human protein palmitoyltransferase encoded by the ZDHHC9 and GCP16 genes. DHHC9 is an integral membrane protein that contains a DHHC cysteine-rich domain. GCP16 encodes a Golgi-localized membrane protein.

SIGNOR-261355

P10912

P18031

0

dephosphorylation

down-regulates activity

0.501

PTPH1 only bound Tyr534, whereas PTP1B and TC-PTP bound multiple phosphopeptides. Earlier work suggests that Tyr332, Tyr487, Tyr534, Tyr566, and Tyr627 are all phosphorylated after GH stimulation (21). Apart from Tyr627, all of these also appear good PTP substrates

SIGNOR-248420

P00742

P02749

1

cleavage

down-regulates activity

0.386

In the previous study, we found that factor Xa can produce the nicked form by cleaving Lys 317-Thr 318, using recombinant human domain V (r-Domain V). |The cleavage was completely inhibited by plasmin inhibitor (alpha2PI). The nicked form was demonstrated to show reduced affinity for CL with a dissociation constant of one order of magnitude larger than that of the intact beta2GPI.

SIGNOR-266997

Q8NBL1

P46531

1

glycosylation

up-regulates

0.606

O-glucosylation of epidermal growth factor-like (egf) repeats in the extracellular domain of notch is essential for notch function. A udp-glucose:protein o-glucosyltransferase (poglut/rumi) transfers o-glucose to serine within the o-glucose consensus.

SIGNOR-198713

P61978

P53779

0

phosphorylation

up-regulates activity

0.339

JNK Phosphorylation of HnRNP K Increases Its Transcriptional Activity. the primary site for JNK phosphorylation consists of serines 216 and 353 on the K protein.

SIGNOR-250083

P45983

P01106

1

phosphorylation

up-regulates activity

0.556

The jnk pathway is selectively involved in the c-myc-mediated apoptosis and that the apoptotic function of c-myc is directly regulated by jnk pathway through phosphorylation at ser-62 and ser-71.

SIGNOR-236018

P20823

Q9Y463

0

phosphorylation

up-regulates

0.502

Mirk phosphorylates hnf1 at amino acid 249mkk3 enhanced mirk kinase activity and the transcriptional activation of hnf1alpha by mirk

SIGNOR-86728

Q9BUB5

P06730

1

phosphorylation

up-regulates

0.779

Mnk1 and mnk2 regulate protein synthesis by phosphorylating the initiation factor eif4e.

SIGNOR-166646

Q16584

P24941

0

phosphorylation

up-regulates activity

0.2

Using in vitro kinase assays and phosphomutants, we determined that CDK1 phosphorylates MLK3 on Ser548 and decreases MLK3 activity during mitosis, whereas CDK2 phosphorylates MLK3 on Ser770 and increases MLK3 activity during G1/S and G2 phases.

SIGNOR-277604

Q02156

P21802

1

phosphorylation

up-regulates

0.2

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

SIGNOR-201675

Q13363

O95471

1

transcriptional regulation

down-regulates quantity by repression

0.2

ChIP assays revealed that SNAI1P is recruited on the CLDN7 gene promoter along with the co-repressor CtBP1 and the effector HDAC1.

SIGNOR-254105

O43248

O15550

0

transcriptional regulation

up-regulates quantity by expression

0.302

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-260026

Q96BR1

Q66PJ3

1

phosphorylation

down-regulates activity

0.2

AIP4 is phosphorylated by CISK in vitro on WW domain residues, which may impact its ability to interact with and ubiquitinate substrate proteins.|Expression of a constitutively active CISK inhibits CXCR4 degradation, possibly by attenuating CXCR4 binding to and ubiquitination by AIP4 and/or modulating the action of AIP4 on a protein involved in CXCR4 endosomal sorting .

SIGNOR-280124

O95644

P16298

0

relocalization

up-regulates

0.724

The ca2+ dependent phosphatase calcineurin induces cardiac and skeletal muscle hypertrophy by a process that involves nf-at nuclear translocation, and activation of mef2c.

SIGNOR-84047

Q9HCE7

Q13485

1

ubiquitination

down-regulates activity

0.745

Smurfs, which otherwise cannot directly bind to smad4, mediated poly-ubiquitination of smad4 in the presence of smad6 or smad7. Smad signaling is negatively regulated by inhibitory (i) smads and ubiquitin-mediated processes.

SIGNOR-236096

P35790

P35968

1

phosphorylation

down-regulates quantity by destabilization

0.249

Here, we show for the first time a possible mechanism by which CKI dependent phosphorylation of VEGFR2 at specific sites in its C-terminal tail triggers SCF beta-TRCP -mediated VEGFR2 ubiquitination and destruction.

SIGNOR-279029

O00192

Q9UDY2

0

relocalization

down-regulates activity

0.369

We identified ARVCF as a binding partner of ZO-1 and ZO-2 and characterized the role of PDZ-domain proteins in plasma membrane and nuclear localization of ARVCF. ZO-2, in contrast, relocated to the nucleus with ARVCF, and, given the interaction between the ZO-2 PDZ domains and ARVCF, raised the possibility that ZO-2 may play a role in nuclear localization of ARVCF. Such a role for ZO-2 is indeed supported by the ability of the ZO-2 PDZ domain to efficiently relocate ARVCF from the plasma membrane to the nucleus in a process that required the ability of the two proteins to interact and the presence of a functional NLS in the ZO-2 PDZ domains. Thus, ZO-2 could be involved in nuclear translocation and/or retention of ARVCF and play a role in regulating postulated functions of ARVCF in gene expression

SIGNOR-252122

P31749

A8MYZ6

1

phosphorylation

down-regulates

0.648

The phosphorylation of the two remaining akt-dependent sites inhibits foxo6 transcriptional activity

SIGNOR-252582

Q9Y5K5

Q15796

1

deubiquitination

up-regulates

0.378

Here, we report a novel interaction between smads and ubiquitin c-terminal hydrolase uch37, a deubiquitinating enzyme that could potentially reverse smurf-mediated ubiquitination. In gst pull down experiments, uch37 bound weakly to smad2 and smad3, and bound very strongly to smad7 in a region that is distinct from the -py- motif in smad7 that interacts with smurf ubiquitin ligases

SIGNOR-138876

Q13490

Q86VP3

1

polyubiquitination

down-regulates quantity by destabilization

0.303

Under basal conditions, PACS-2 underwent K48-linked poly-ubiquitination, resulting in PACS-2 proteasomal degradation. Biochemical assays showed cIAP-1 and cIAP-2 interacted with PACS-2 in vitro and co-immunoprecipitation studies demonstrated that the two cIAPs bound PACS-2 in vivo. More importantly, both cIAP-1 and cIAP-2 directly mediated PACS-2 ubiquitination in a cell-free assay.

SIGNOR-272851

P36956

P53350

0

phosphorylation

up-regulates activity

0.441

As illustrated in , the turnover of nuclear SREBP1a was attenuated in the presence of Plk1, confirming that Plk1 stabilizes nuclear SREBP1 by reducing its degradation.|Figure 2.Plk1 phosphorylates threonine 424, serine 467 and serine 486 in nuclear SREBP1 during mitosis. (A) In vitro kinase assay with recombinant nuclear SREBP1a and Plk1.

SIGNOR-279382

Q9UBK2

Q96EB6

0

deacetylation

up-regulates activity

0.799

SIRT1 overexpression reduces muscle wasting by blocking the activation of FoxO1 and 3 SIRT1 activation has been reported to increase dramatically endurance exercise through the activation of PGC-1_ in muscle, which stimulates fatty acid oxidation

SIGNOR-217963