GleghornLab/Signor_processed · Datasets at Hugging Face

IdA stringlengths 6 21	IdB stringlengths 6 21	mechanism stringclasses 40 values	effect stringclasses 10 values	score float64 0.1 0.99 ⌀	sentence stringlengths 10 1.63k ⌀	signor_id stringlengths 12 14
Q13635	P42574	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
P62166	Q9NP60	binding	up-regulates activity	0.321	IL1 receptor accessory protein like, a protein involved in X-linked mental retardation, interacts with Neuronal Calcium Sensor-1 and regulates exocytosis. our data show that IL1RAPL interacts only with NCS-1 through its specific C-terminal domain. The functional relevance of IL1RAPL activity was further supported by the inhibitory effect on exocytosis in PC12 cells overexpressing IL1RAPL. Taken together, our data suggest that IL1RAPL may regulate calcium-dependent exocytosis and provide insight into the understanding of physiopathological mechanisms underlying cognitive impairment resulting from IL1RAPL dysfunction.	SIGNOR-264476
Q16666	P68400	phosphorylation	up-regulates activity	0.321	Here we examine the functionality of the interferon-induced factor 16 (IFI 16) CcN motif, demonstrating its ability to target a heterologous protein to the nucleus, and to be phosphorylated specifically by the CcN-motif-phosphorylating protein kinase CK2 (CK2). \| Specific phosphorylation of IFI 16 Ser132 in HeLa cell extracts and by purified CK2 in vitro	SIGNOR-250902
Q99062	P09603	binding	up-regulates	0.321	A crystal structure of the signaling complex between human granulocyte colony-stimulating factor (gcsf) and a ligand binding region of gcsf receptor (gcsf-r), has been determined to 2.8 a resolution	SIGNOR-144737
P45983	Q92730	binding	up-regulates	0.321	In the non-canonical wnt pathway, frizzled uses galfaq or galfai and gbetagamma dimers to activate phospholipase c (plc), resulting in protein kinase c (pkc) activation and calcium mobilization that regulates the transcription factor nfat, and frizzled also signals through the small gtpases rho and rac to c-jun n-terminal kinase (jnk), which activates the ap1 transcription factor	SIGNOR-152811
O95319	P12931	phosphorylation	up-regulates activity	0.321	Site-directed mutagenesis of putative tyrosine phosphorylation sites in CUGBP2 identified tyrosine 39 as a c-Src target, and a CUGBP2 with a mutated tyrosine 39 displayed an attenuated ability to bind COX-2 mRNA.	SIGNOR-263195
P49810	P29466	cleavage	up-regulates activity	0.32	In decreasing order of activity, caspase-8, -3, -1, -6 and -7 proteolysed PS2 at the recognition site D326SYD329.	SIGNOR-261748
Q8NEG5	P51668	binding	up-regulates activity	0.32	MEX can act as an E3, Ub (ubiquitin) ligase, through the E2, Ub-conjugating enzymes UbcH5a, UbcH5c or UbcH6. A region of MEX that contains the RING fingers and the ZZ zinc finger was required for interaction with UbcH5a and MEX self-association, whereas the SWIM domain was critical for MEX ubiquitination. The expression of MEX promoted apoptosis that was induced through Fas, DR (death receptor) 3 and DR4 signalling, but not that mediated by the BH3 (Bcl-2 homology 3)-only protein BimEL or the chemotherapeutic drug adriamycin.	SIGNOR-271554
Q9NR30	Q92499	binding	up-regulates activity	0.32	We demonstrated here that DDX1-DDX21-DHX36 represents a dsRNA sensor that uses the adaptor molecule TRIF to activate the NF-ÎºB pathway and type I IFN responses in dendritic cells. Our study suggests that the DDX1-DDX21-DHX36 complex represents this missing poly I:C sensor, which uses DDX1 to bind poly I:C and uses DDX21 and DXH36 to bind TRIF. Poly I:C is a synthetic form of RNA that mimics double-stranded viral RNA.	SIGNOR-260191
Q92934	P41743	phosphorylation	down-regulates	0.32	In-vitro kinase activity assay showed that pkc-_ directly phosphorylated bad at phospho specific residues, ser-112, ser-136 and ser-155 which in turn induced inactivation of bad and disruption of bad/bcl-xl dimer	SIGNOR-172894
P51648	Q9NXK8	binding	down-regulates quantity by destabilization	0.32	We now show that SCFFBXL12 is an authentic E3 for the ALDH3 family of enzymes. We now show that the ubiquitin-dependent degradation of ALDH3 mediated by FBXL12 (F box and leucine-rich repeat protein 12) is essential for execution of the differentiation program of trophoblast stem cells (TSCs). FBXL12 is present only in eutherian mammals, and its expression is largely restricted to the placenta during mouse embryogenesis. FBXL12 was found to interact specifically with members of the ALDH3 family and to mediate their polyubiquitylation. Finally, coimmunoprecipitation analysis revealed that FBXL12 interacted efficiently only with members of the ALDH3 family (ALDH3A1, ALDH3A2, and ALDH3B1), showing little if any association with those of the ALDH1 family (ALDH1A1, ALDH1A2, and ALDH1A3) (Fig. 2H). Collectively, these results suggested that SCFFBXL12 is an authentic E3 specific for ALDH3 family members.	SIGNOR-272814
O95863	P52954	transcriptional regulation	up-regulates quantity by expression	0.32	Compared with the empty vector, LBX1 induced increased promoter activity of threefold to fourfold and fivefold to sixfold for ZEB1 and Snail1, respectively	SIGNOR-266053
Q16613	P17612	phosphorylation	up-regulates activity	0.32	AANAT1–207 was phosphorylated in vitro at both PKA sites, Thr-31 and Ser-205. regulation is achieved by binding to 14-3-3, which structurally modulates the substrate binding sites, leading to measurable effects on the affinity of AANAT for its substrates with an accompanying increase in activity at low substrate concentrations.	SIGNOR-250324
Q15468	P06493	phosphorylation	down-regulates activity	0.32	Importantly, we show that CDK1 and CyclinB phosphorylates the N-terminal domain of STIL, but not the region encompassing the CC or STAN motifs.	SIGNOR-279145
P51636	P68400	phosphorylation	up-regulates activity	0.32	We show that caveolin-2 is phosphorylated in vivo at two serine residues and that the phosphorylation of caveolin-2 is necessary for its actions as a positive regulator of caveolin-1 during organelle biogenesis in prostate cancer cells. Mutation of the primary phosphorylation sites on caveolin-2, serine 23 and 36, reduces the number of plasmalemma-attached caveolae	SIGNOR-101110
P10909	Q86TM6	polyubiquitination	down-regulates quantity by destabilization	0.32	We also report that the ER-associated ubiquitin ligase Hrd1/synoviolin can interact with, and ubiquitinate clusterin. The fact that cleaved endogenous clusterin appears, under certain conditions, to be subject to polyubiquitination (Figure 2C) and proteasomal degradation (1, 2) strongly suggests that it passed through the secretory pathway before reaching the cytosol.	SIGNOR-272629
Q7Z2E3	P05129	phosphorylation	up-regulates	0.32	We show the novel molecular consequences of increased kinase activities of mutants: aprataxin (aptx), a dna repair protein causative for autosomal recessive ataxia, was found to be a preferential substrate of mutant pkc gamma, and phosphorylation inhibited its nuclear entry. ollectively, phosphorylation occurred at thr111, reducing nuclear aptx.	SIGNOR-186409
P09086	P26583	binding	up-regulates activity	0.32	HMG2 and Oct2 interact via their HMG domains and POU homeodomains, respectively. This interaction is not restricted to Oct2, as other members of the octamer transcription factor family like Oct1 and Oct6 also interact with HMG2. The interaction with HMG2 results in a marked increase in the sequence-specific DNA binding activity of the Oct proteins	SIGNOR-240108
Q15797	P50750	phosphorylation	down-regulates	0.32	Phosphorylation of the linker region of smad1, a receptor-activated smad (r-smad), at serine 206 (s206) and s214 induced by bmp and mediated by cdk8/9 is critical for binding of the e3 ubiquitin ligase smurf1. Binding of smurf1 leads to polyubiquitination of smad1 and its degradation by the proteasome;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3.	SIGNOR-161569
Q04724	P68400	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
P30838	Q9NXK8	binding	down-regulates quantity by destabilization	0.32	We now show that SCFFBXL12 is an authentic E3 for the ALDH3 family of enzymes. We now show that the ubiquitin-dependent degradation of ALDH3 mediated by FBXL12 (F box and leucine-rich repeat protein 12) is essential for execution of the differentiation program of trophoblast stem cells (TSCs). FBXL12 is present only in eutherian mammals, and its expression is largely restricted to the placenta during mouse embryogenesis. FBXL12 was found to interact specifically with members of the ALDH3 family and to mediate their polyubiquitylation. Finally, coimmunoprecipitation analysis revealed that FBXL12 interacted efficiently only with members of the ALDH3 family (ALDH3A1, ALDH3A2, and ALDH3B1), showing little if any association with those of the ALDH1 family (ALDH1A1, ALDH1A2, and ALDH1A3) (Fig. 2H). Collectively, these results suggested that SCFFBXL12 is an authentic E3 specific for ALDH3 family members.	SIGNOR-272813
Q9BVN2	Q9Y4K3	polyubiquitination	down-regulates quantity by destabilization	0.32	We demonstrated that NESCA and NEMO interact by their N-terminal region. Beside to NEMO, we revealed that NESCA directly associates to the E3 ubiquitin ligase TRAF6, which in turn catalyzes NESCA polyubiquitination. Finally, we demonstrated that NESCA overexpression strongly inhibits TRAF6-mediated polyubiquitination of NEMO.	SIGNOR-272774
O60282	P53779	phosphorylation	down-regulates activity	0.32	Mass spectrometry identified a residue in the kinesin-1 motor domain that was phosphorylated by JNK3 and this modification reduced kinesin-1 binding to microtubules. JNK3 phosphorylates kinesin-1 at Ser176	SIGNOR-262950
Q9Y5Y9	Q96PU5	ubiquitination	down-regulates quantity by destabilization	0.32	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-253463
P14635	A6NLU0	ubiquitination	down-regulates quantity by destabilization	0.32	We conclude that, like many RING-finger containing proteins, RFPL4 is an E3 ubiquitin ligase. The specificity of its expression and these interactions suggest that RFPL4 targets cyclin B1 for proteasomal degradation, a key aspect of oocyte cell cycle control during meiosis and the crucial oocyte-to-embryo transition to mitosis.	SIGNOR-271476
P42680	P12931	phosphorylation	up-regulates activity	0.32	The proximal event following T cell-APC synapse formation is immediate activation of several signaling molecules: The Src kinase phosphorylates and activates Tec tyrosine kinases, which then activate PLC-\u03b3 that is required for IP 3 generation to sustain intracellular calcium flux.	SIGNOR-280135
P46531	Q00535	phosphorylation	up-regulates activity	0.32	An in vitro kinase reaction demonstrated that T2132, S2136, and S2141 were CDK5\u2010phosphorylated sites in the Notch1 peptide (Figure\u00a02B, C, and D).\|In conclusion, CDK5 positively regulates Notch1 function via phosphorylation, which in turn promotes cell proliferation and migration.	SIGNOR-279401
P11362	P27361	phosphorylation	down-regulates	0.32	Erk-mediated phosphorylation of fibroblast growth factor receptor 1 on ser777 inhibits signaling	SIGNOR-200884
Q9P253	P62837	binding	up-regulates activity	0.32	VPS18 Ubiquitylates SNK in Vitro and in Vivo. The ubiquitylation of proteins by hVPS18 was selectively mediated by UbcH4.	SIGNOR-271549
O43521	Q16539	phosphorylation	down-regulates quantity by destabilization	0.32	Ser69 can also be phosphorylated by JNK and p38MAPK at least in vitro. Phosphorylation of BimEL on Ser69 promotes its ubiquitination.	SIGNOR-260442
P0DP23	O43303	binding	up-regulates activity	0.32	We report that CP110 interacts with two different Ca2+-binding proteins, calmodulin (CaM) and centrin, in vivo. our data demonstrate a functional role for CaM binding to CP110 and suggest that CP110 cooperates with CaM and centrin to regulate progression through cytokinesis.	SIGNOR-265965
P43353	Q9NXK8	binding	down-regulates quantity by destabilization	0.32	We now show that SCFFBXL12 is an authentic E3 for the ALDH3 family of enzymes. We now show that the ubiquitin-dependent degradation of ALDH3 mediated by FBXL12 (F box and leucine-rich repeat protein 12) is essential for execution of the differentiation program of trophoblast stem cells (TSCs). FBXL12 is present only in eutherian mammals, and its expression is largely restricted to the placenta during mouse embryogenesis. FBXL12 was found to interact specifically with members of the ALDH3 family and to mediate their polyubiquitylation. Finally, coimmunoprecipitation analysis revealed that FBXL12 interacted efficiently only with members of the ALDH3 family (ALDH3A1, ALDH3A2, and ALDH3B1), showing little if any association with those of the ALDH1 family (ALDH1A1, ALDH1A2, and ALDH1A3) (Fig. 2H). Collectively, these results suggested that SCFFBXL12 is an authentic E3 specific for ALDH3 family members.	SIGNOR-272815
O14939	Q05397	phosphorylation	up-regulates activity	0.32	The kinase domain of FAK interacts with PLD2-PH and induces tyrosine phosphorylation and activation of PLD2.	SIGNOR-279480
P46531	P49840	phosphorylation	down-regulates	0.319	Taken together, our results indicate that gsk-3alfa is a negative regulator of notch1/nicd.	SIGNOR-183969
P08581	P08047	transcriptional regulation	up-regulates quantity by expression	0.319	Furthermore, in transient cotransfection assays, overexpression of Sp1 and/or Sp3 stimulated HGF promoter activity independently and additively through binding to the Sp1 binding site in the HGF gene promoter region.	SIGNOR-241490
Q9UBK2	Q969K3	ubiquitination	down-regulates quantity by destabilization	0.319	Mechanistically, PGC1α was phosphorylated at serine (S) 636 by DNA-dependent protein kinase in response to irradiation. Phosphorylation at S636 promoted the degradation of PGC1α by facilitating its binding to the E3 ligase RNF34.	SIGNOR-277912
Q96FW1	P68400	phosphorylation	up-regulates activity	0.319	Casein kinase 2 (CK2)-dependent phosphorylation of OTUB1 at Ser16 played a critical role in ODN- and cathepsin K siRNA-mediated p53 stabilization. \|Furthermore, although OTUB1 dramatically induced p53 deubiquitination, its mutant (S16A) and deletion mutant did not have this effec	SIGNOR-276527
Q9H6Z4	Q15418	phosphorylation	up-regulates quantity	0.319	RSK phosphorylates RanBP3 at Serine 58 residue in vitro and in vivo.RanBP3 phosphorylation increases its affinity towards Ran	SIGNOR-276149
Q9UKF7	P17252	phosphorylation	up-regulates activity	0.319	Only BIM-I caused a reduction in 14-3-3 binding (Figure 3B), suggesting that PKC could be responsible for one or both of the serine phosphorylations, pSer274 and pSer299.	SIGNOR-273801
P37840	Q9H4B4	phosphorylation	down-regulates activity	0.319	Polo-like kinase (plk) family (plk1, plk2, and plk3) phosphorylate alpha-syn and beta-syn specifically at ser-129 and ser-118, respectively. Polo-like kinase 2 (plk2) phosphorylates alpha-synuclein at serine 129 in central nervous system. The membrane association of pd-linked mutant alpha -synuclein, but not wild-type -synuclein, was increased by serine 129 phosphorylation.	SIGNOR-189053
P04637	Q9H0M0	ubiquitination	up-regulates activity	0.319	Unlike other E3 ligases, WWP1 increases p53 stability; inhibition of WWP1 expression or expression of a ligase-mutant form results in decreased p53 expression.\|WWP1 associates with p53 and induces p53 ubiquitylation.	SIGNOR-278649
P41180	P05771	phosphorylation	down-regulates activity	0.319	Expression of a mutant CaR in which the major PKC phosphorylation site is altered by substitution of alanine for threonine (T888A) eliminated oscillatory behavior, producing [Ca(2+)](i) responses almost identical to those produced by the wild type CaR exposed to PKC inhibitors. These results support a model in which phosphorylation of the CaR at the inhibitory threonine 888 by PKC provides the negative feedback needed to cause [Ca(2+)](i) oscillations mediated by this receptor.	SIGNOR-249176
P10275	P17844	binding	up-regulates	0.319	P68 is a nuclear protein and interacts with ar / p68 co-occupies the active psa promoter at are regions and enhances ar transcriptional activity	SIGNOR-181456
P50148	P34969	binding	up-regulates activity	0.319	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. \| We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. \| The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257381
Q96J02	P31749	phosphorylation	up-regulates quantity	0.319	AKT1-mediated phosphorylation of ITCH at Ser257 drives its nuclear translocation	SIGNOR-272922
O60934	Q13428	relocalization	up-regulates activity	0.319	We further identify TCOF1 (also known as Treacle), a nucleolar factor implicated in ribosome biogenesis and mutated in Treacher Collins syndrome, as an interaction partner of NBS1, and demonstrate that NBS1 translocation and accumulation in the nucleoli is Treacle dependent.	SIGNOR-265085
P04179	Q9P275	deubiquitination	up-regulates quantity by stabilization	0.319	Protein stability of mitochondrial superoxide dismutase SOD2 is regulated by USP36\|Finally, USP36 was shown to be a specific deubiquitinating enzyme that reduces the ubiquitination level of SOD2 and was involved in SOD2 protein stability by extending its half-life.	SIGNOR-272280
Q13547	Q9H4L7	binding	up-regulates activity	0.319	SMARCAD1 interacts with HDAC1 and KAP1 and is required for their binding to heterochromatin	SIGNOR-239835
P15976	Q03112	transcriptional regulation	up-regulates quantity by expression	0.319	We finally observed that the forced expression of Evi1 induced GATA-2 expression in a hematopoietic cell line, EML C1, along with GATA-1, Ang-1, Ang-2 and Tie2	SIGNOR-266061
P48736	Q15303	binding	up-regulates	0.319	Pi3k is the sole binding partner to six tyrosines of erbb3 and one in erbb4.	SIGNOR-146888
Q00613	Q92630	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
Q99683	Q5SGD2	dephosphorylation	down-regulates	0.318	Exogenous pp2cepsilon associated with exogenous ask1 in hek-293 cells under non-stressed conditions, inactivating ask1 by decreasing thr845 phosphorylation	SIGNOR-154554
P07550	Q9H6Z9	hydroxylation	up-regulates quantity by stabilization	0.318	We further show that the interaction of pVHL with beta(2)AR is dependent on proline hydroxylation (proline-382 and -395) and that the dioxygenase EGLN3 interacts directly with the beta(2)AR to serve as an endogenous beta(2)AR prolyl hydroxylase. Under hypoxic conditions, receptor hydroxylation and subsequent ubiquitylation decrease dramatically, thus attenuating receptor degradation and down-regulation.	SIGNOR-262007
P18084	O14713	binding	down-regulates activity	0.318	Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation	SIGNOR-257660
Q15366	P28482	phosphorylation	up-regulates quantity by stabilization	0.318	We also identified 4 hnRNP-E2 MAPKERK1/2 phosphorylation sites and demonstrated that hnRNP-E2 is a bona fide MAPKERK1/2 substrate and that MAPKERK1/2-dependent phosphorylation of hnRNP-E2 at these amino acid residues is essential for increased hnRNP-E2 expression in BCR/ABL-expressing cells. Serine/threonine to alanine substitution abolishes hnRNP-E2 phosphorylation and markedly decreases its stability in BCR/ABL-expressing myeloid precursors. Consistent with the existence of a BCR/ABL-MAPK pathway that posttranslationally regulates hnRNP-E2 expression, sequence analysis of hnRNP-E2 revealed the presence of 4 consensus ERK phosphorylation sites (S/T-P)35,36 at amino acid residues 173, 189, 213, and 272 (Figure 2B).	SIGNOR-262912
Q9H4A6	P78527	phosphorylation	up-regulates activity	0.318	In response to DNA damage, DNA-PK phosphorylates GOLPH3, resulting in increased interaction with MYO18A, which applies a tensile force to the Golgi. Interference with the Golgi DNA damage response by depletion of DNA-PK, GOLPH3, or MYO18A reduces survival after DNA damage, whereas overexpression of GOLPH3, as is observed frequently in human cancers, confers resistance to killing by DNA-damaging agents	SIGNOR-253558
P38936	Q9H0Z9	post transcriptional regulation	up-regulates quantity by stabilization	0.318	Here, we found that RNPC1, an RNA-binding protein and a target of the p53 family, is required for maintaining the stability of the basal and stress-induced p21 transcript.	SIGNOR-275391
P04637	P51955	phosphorylation	down-regulates	0.318	NEK2 Phosphorylates p53 at Ser315 and Reduces Its Stability.\|These results are consistent with NEK2 inhibiting p53 transcriptional activation functions.	SIGNOR-278488
Q13485	Q96JC1	relocalization	down-regulates activity	0.318	The data demonstrating binding of TLP to TGF-β and activin type II receptors and selective inhibition of Smad3/Smad4 complex formation by deregulated TLP suggest that TLP is involved in localizing these receptors and Smad4 to specific intracellular compartments, where it regulates formation of Smad3/Smad4 but not Smad2/Smad4 complexes.	SIGNOR-261377
P18846	P51812	phosphorylation	up-regulates activity	0.318	ATF1 and CREB can be phosphorylated by Rsk2 which is a protein kinase directly activated by Erk MAP kinase. These results suggest a signaling pathway in which Erk MAP kinase activates the c-fos enhancer by direct phosphorylation of p62TCF and by activation of Rsk related kinases that phosphorylate ATF1 and CREB.\|ATF1 and CREB can be phosphorylated by Rsk2 which is a protein kinase directly activated by Erk MAP kinases.	SIGNOR-280117
P50222	O60315	transcriptional regulation	down-regulates quantity by repression	0.318	ZEB2 represses GAX transcription through multiple up- stream consensus binding sites.	SIGNOR-268951
P04004	P17252	phosphorylation	up-regulates quantity by stabilization	0.318	Phosphorylation of vitronectin on Ser362 by protein kinase C attenuates its cleavage by plasmin.	SIGNOR-248962
Q13224	O15409	transcriptional regulation	up-regulates quantity by expression	0.318	By interacting with CASK, TBR1 regulates several ASD candidate genes, such as GRIN2B, AUTS2 and RELN—all of which are recurrently mutated in ASD. In areas of the brain with overlapping expression patterns, such as in glutamatergic layer 6 neurons, the TBR1–FOXP2 interaction may result in co-ordinated regulation of common downstream targets.	SIGNOR-266834
P29034	Q9UNE7	polyubiquitination	down-regulates quantity by destabilization	0.318	S100 protein itself is ubiquitinated by CHIP in a Ca2+-dependent manner.Ubiquitylated S100 proteins are shown as (Ub)n-S100A2 and (Ub)n-S100P. The association of the S100 proteins with CHIP provides a Ca2+-dependent regulatory mechanism for the ubiquitination and degradation of intracellular proteins by the CHIP-proteasome pathway.	SIGNOR-272918
P46531	Q9P2R6	binding	up-regulates activity	0.318	In mammalian cells, RERE co‐immunoprecipitates with CBF1 and Notch intracellular domain (NICD), and is recruited to nuclear foci formed by over‐expressed NICD1. RERE is also necessary for NICD to activate the expression of Notch target genes.	SIGNOR-264486
P49810	P55210	cleavage	up-regulates activity	0.318	In decreasing order of activity, caspase-8, -3, -1, -6 and -7 proteolysed PS2 at the recognition site D326SYD329.	SIGNOR-261751
O15534	P48729	phosphorylation	down-regulates quantity by destabilization	0.318	CKI\u03b1-Dependent Phosphorylation and Degradation of PER1.	SIGNOR-279700
P04637	P36873	dephosphorylation	down-regulates activity	0.318	Protein serine/threonine phosphatase-1 dephosphorylates p53 at Ser-15 and Ser-37 to modulate its transcriptional and apoptotic activities\|In addition, our results reveal that one of the molecular mechanisms by which PP-1 promotes cell survival is to dephosphorylate p53, and thus negatively regulate p53-dependent death pathway.	SIGNOR-248499
O60341	P68400	phosphorylation	up-regulates activity	0.318	We demonstrated here that phosphorylation and dephosphorylation of LSD1 at S131 and S137 was mediated by casein kinase 2 (CK2) and wild-type p53-induced phosphatase 1 (WIP1), respectively. LSD1, RNF168 and 53BP1 interacted with each other directly. CK2-mediated phosphorylation of LSD1 exhibited no impact on its interaction with 53BP1, but promoted its interaction with RNF168 and RNF168-dependent 53BP1 ubiquitination and subsequent recruitment to the DNA damage sites.	SIGNOR-276903
O14641	P60484	dephosphorylation	down-regulates activity	0.318	This showed that while both PTEN WT and the lipid phosphatase-inactive G129E mutant suppressed phosphorylation of DVL2 on serine 143 that accumulated upon PTEN knockdown, the C124S and Y138L mutants did not .\|Finally, it is important to point out that while our studies show that PTEN can directly dephosphorylate DVL2 in vitro, it is possible that regulation of serine 143 phosphorylation of DVL2 by PTEN in cells may require additional protein factors, or post-translational modifications.	SIGNOR-277035
Q16143	P53350	phosphorylation	down-regulates activity	0.318	Polo-like kinase (plk) family (plk1, plk2, and plk3) phosphorylate alpha-syn and beta-syn specifically at ser-129 and ser-118, respectively. Polo-like kinase 2 (plk2) phosphorylates alpha-synuclein at serine 129 in central nervous system. The membrane association of pd-linked mutant alpha -synuclein, but not wild-type -synuclein, was increased by serine 129 phosphorylation.	SIGNOR-176079
P48431	Q9HCK8	transcriptional regulation	down-regulates quantity	0.318	Many of the most significantly up-regulated genes in Chd8+/− and Chd8−/− NPCs are involved in later stages of neuronal development, including Ascl1 [a central driver of neural reprogramming (29)], Dcx, Map2, Nefm, Neurod4, and Neurog1 (Fig. 2 E and F). Additionally, we found that Sox3 is derepressed in both Chd8+/− and Chd8−/− NPCs, and several other Sox TF members (Sox2, Sox7, and Sox11) became derepressed in the Chd8−/− cells	SIGNOR-268921
P12931	Q01973	phosphorylation	up-regulates	0.318	Ror1 binds to and phosphorylates c-src / ror1 kinase-dependent c-src activation	SIGNOR-196751
Q96I25	P49759	phosphorylation	up-regulates activity	0.317	In this work, we show that Cdc2-like kinase 1 (Clk1) phosphorylates SPF45 on eight serine residues.	SIGNOR-262710
Q00975	Q9UQM7	phosphorylation	down-regulates	0.317	Here, we report a direct modulation of ca(v)2.2 channel inactivation properties by 14-3-3, a family of signaling proteins involved in a wide range of biological processes.Wild-type gst fusion proteins containing the putative 14-3-3-binding motif (aa 2076__?2140) werein vitro phosphorylated at s2126 by either camkii or pka, as detected by thesequence- and phosphorylation-specific antibody, anti-ps2126 (middle panel). Phosphorylation of s2126 significantly increases its binding to recombinant 14-3-3?	SIGNOR-149684
P12931	P43115	binding	up-regulates activity	0.317	These results clearly demonstrate that EP3 contributes to the activation of Src and its related cell growth in A549 cells treated with PGE2.	SIGNOR-278885
P41212	P28482	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-260086
Q14957	P62258	binding	up-regulates quantity by stabilization	0.317	Here, we demonstrate that PKB/Akt directly phosphorylates NR2C on serine 1096 (S1096). In addition, we identify 14-3-3epsilon as an NR2C interactor, whose binding is dependent on S1096 phosphorylation. These data are all consistent with a model in which NR1 and NR2C oligomerize, PKB phosphorylates S1096, and 14-3-3ε binds to phosphorylated NR2C thereby promoting NR2C-containing NMDA receptor surface expression in cerebellar granule cells.	SIGNOR-262622
Q8WUI4	P67775	dephosphorylation	up-regulates activity	0.317	Phosphorylation of conserved serine residues triggers association with 14-3-3 proteins and cytoplasmic relocalization of class IIa HDACs, which leads to the derepression of their target genes. \|Here we identify PP2A as a phosphatase responsible for dephosphorylating the 14-3-3 binding sites in class IIa HDACs.\|we demonstrate that PP2A constitutively dephosphorylates the class IIa member HDAC7 to control its biological functions as a regulator of T cell apoptosis and endothelial cell functions.	SIGNOR-248649
Q06187	Q03113	binding	up-regulates activity	0.317	Here we show that Ga12 binds directly to, and stimulates the activity of, Bruton’s tyrosine kinase (Btk) and a Ras GTPase-activating protein, Gap1m, in vitro and in vivo	SIGNOR-278082
Q9UM11	P11309	phosphorylation	down-regulates activity	0.317	Pim-1 phosphorylates Cdh1 and impairs binding of this protein to another APC/C complex member, CDC27. These modifications inhibit Skp2 from degradation.Pim-1 Impairs Cdh1 and CDC27 Interaction and Phosphorylates Cdh1.	SIGNOR-259820
P22415	P49715	binding	up-regulates activity	0.317	Our studies show that the human C/EBPa protein stimulates USF to bind to a USF consensus element within C/EBPa promoter and activates it by two- to threefold.The mechanism by which C/EBPa enhances USF binding and transactivation is currently under study.	SIGNOR-255701
O75460	Q15084	null	down-regulates activity	0.317	A resident ER protein disulfide isomerase, PDIA6, limits the duration of IRE1α activity by direct binding to cysteine148 in the luminal domain of the sensor,	SIGNOR-256536
Q06413	Q9UPW0	transcriptional regulation	up-regulates quantity by expression	0.317	Foxj3 transcriptionally activates Mef2c and regulates adult skeletal muscle fiber type identity.	SIGNOR-261606
P17861	O14818	binding	down-regulates quantity by destabilization	0.317	We saw preferential binding of XBP-1u to subunits _5, _6 and _7.2. We demonstrate that XBP-1u undergoes efficient degradation in vitro by 20S proteasomes in the absence of ubiquitination.	SIGNOR-239042
P41212	P27361	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
P67809	Q7Z6E9	ubiquitination	down-regulates quantity by destabilization	0.317	RBBP6 interacts with multifunctional protein YB-1 through its RING finger domain, leading to ubiquitination and proteosomal degradation of YB-1	SIGNOR-271773
Q15109	P05109	binding	up-regulates activity	0.317	RAGE and TLR4 are well-characterized S100A8 and S100A9 receptors and expressed in AML cells Once secreted, S100A8 and S100A9 induce immune and inflammatory responses9 through interaction with receptors such as Toll-like receptor 4 (TLR4), receptor for advanced glycation end-product (RAGE), and CD33	SIGNOR-261919
P08581	P23470	dephosphorylation	down-regulates activity	0.317	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-254712
Q9UQD0	P61328	binding	down-regulates activity	0.317	Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels.	SIGNOR-253412
P05771	Q8WV44	polyubiquitination	down-regulates quantity by destabilization	0.317	RINCK induces the ubiquitination of PKC both in vitro and in cells. Overexpression of RINCK reduces the levels of PKC in cells, whereas genetic knockdown of endogenous RINCK increases the levels of PKC. The RINCK-mediated ubiquitination is likely to be polyubiquitination, because the ubiquitinated PKCβII was detected as a high molecular weight smear.	SIGNOR-271667
P35580	Q02078	transcriptional regulation	up-regulates quantity by expression	0.317	Myocyte enhancer factor-2 and serum response factor binding elements regulate fast Myosin heavy chain transcription in vivo. We show that the upstream promoter region of the gene most abundantly expressed in mouse skeletal muscles, IIb MyHC, retains binding activity and transcriptional activation for three positive transcription factors, the serum response factor, Oct-1, and myocyte enhancer factor-2, whereas the other two genes (IIa and IId/x) have nucleotide substitutions in these sites that reduce binding and transcriptional activation	SIGNOR-238763
Q99250	Q96PU5	ubiquitination	down-regulates quantity by destabilization	0.317	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-253459
Q09472	Q15059	binding	up-regulates activity	0.317	Brd3 interacts with both IRF3 and p300, increases p300-mediated acetylation of IRF3, and enhances the association of IRF3 with p300 upon virus infection.\|Brd3 enhances p300-mediated acetylation of IRF3	SIGNOR-262044
Q9GZV5	P07947	phosphorylation	up-regulates activity	0.317	Yes directly phosphorylates YAP and TAZ, resulting in their increased nuclear localization and transcriptional activity.Analysis by mass spectrometry identified Tyr391 and Tyr407 as the two phosphorylation sites of YAP, whereas Tyr305 was the sole phosphorylated residue of TAZ (Fig. 5F and fig. S4, A to C).	SIGNOR-277654
P24928	P27361	phosphorylation	down-regulates	0.316	Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination.	SIGNOR-120176
P23528	O14965	phosphorylation	down-regulates activity	0.316	However, this study identified that CFL-1 also acts as a direct substrate of Aur-A, which phosphorylates CFL-1 at multiple sites, including S3, S8, and T25, resulting in its inactivation.\|In early cell mitotic phases, LIMK1 and Aur-A phosphorylate and inactivate CFL-1, while at the later stages, SSH-1 inactivates LIMK1 and dephosphorylates and activates CFL-1 [33] .	SIGNOR-279798
P24723	O15530	phosphorylation	up-regulates activity	0.316	Protein kinase C(eta) is phosphorylated by PDK1 in vitro, leading to kinase activation as similarly reported for protein kinase C(epsilon) activation by PDK1.	SIGNOR-280062
Q15208	P53350	phosphorylation	down-regulates activity	0.316	Here, we identified a conserved signaling axis in which NDR1 kinase activity is regulated by PLK1 in mitosis. PLK1 phosphorylates NDR1 at three putative threonine residues (T7, T183 and T407) at mitotic entry, which elicits PLK1-dependent suppression of NDR1 activity and ensures correct spindle orientation in mitosis.	SIGNOR-276914
P16949	P45983	phosphorylation	down-regulates	0.316	Involved in the regulation of the microtubule (mt) filament system by destabilizing microtubules. Prevents assembly and promotes disassembly of microtubules. Here we show that in response to hyperosmotic stress, jnk phosphorylates a key cytoplasmic microtubule regulatory protein, stathmin (stmn), on conserved ser-25 and ser-38 residues. In in vitro biochemical studies, we identified stmn ser-38 as the critical residue required for efficient phosphorylation by jnk and identified a novel kinase interaction domain in stmn required for recognition by jnk. We revealed that jnk was required for microtubule stabilization in response to hyperosmotic stress.	SIGNOR-166694

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

P62166

Q9NP60

0

binding

up-regulates activity

0.321

IL1 receptor accessory protein like, a protein involved in X-linked mental retardation, interacts with Neuronal Calcium Sensor-1 and regulates exocytosis. our data show that IL1RAPL interacts only with NCS-1 through its specific C-terminal domain. The functional relevance of IL1RAPL activity was further supported by the inhibitory effect on exocytosis in PC12 cells overexpressing IL1RAPL. Taken together, our data suggest that IL1RAPL may regulate calcium-dependent exocytosis and provide insight into the understanding of physiopathological mechanisms underlying cognitive impairment resulting from IL1RAPL dysfunction.

SIGNOR-264476

Q16666

P68400

0

phosphorylation

up-regulates activity

0.321

Here we examine the functionality of the interferon-induced factor 16 (IFI 16) CcN motif, demonstrating its ability to target a heterologous protein to the nucleus, and to be phosphorylated specifically by the CcN-motif-phosphorylating protein kinase CK2 (CK2). | Specific phosphorylation of IFI 16 Ser132 in HeLa cell extracts and by purified CK2 in vitro

SIGNOR-250902

Q99062

P09603

0

binding

up-regulates

0.321

A crystal structure of the signaling complex between human granulocyte colony-stimulating factor (gcsf) and a ligand binding region of gcsf receptor (gcsf-r), has been determined to 2.8 a resolution

SIGNOR-144737

P45983

Q92730

0

binding

up-regulates

0.321

In the non-canonical wnt pathway, frizzled uses galfaq or galfai and gbetagamma dimers to activate phospholipase c (plc), resulting in protein kinase c (pkc) activation and calcium mobilization that regulates the transcription factor nfat, and frizzled also signals through the small gtpases rho and rac to c-jun n-terminal kinase (jnk), which activates the ap1 transcription factor

SIGNOR-152811

O95319

P12931

0

phosphorylation

up-regulates activity

0.321

Site-directed mutagenesis of putative tyrosine phosphorylation sites in CUGBP2 identified tyrosine 39 as a c-Src target, and a CUGBP2 with a mutated tyrosine 39 displayed an attenuated ability to bind COX-2 mRNA.

SIGNOR-263195

P49810

P29466

0

cleavage

up-regulates activity

0.32

In decreasing order of activity, caspase-8, -3, -1, -6 and -7 proteolysed PS2 at the recognition site D326SYD329.

SIGNOR-261748

Q8NEG5

P51668

0

binding

up-regulates activity

0.32

MEX can act as an E3, Ub (ubiquitin) ligase, through the E2, Ub-conjugating enzymes UbcH5a, UbcH5c or UbcH6. A region of MEX that contains the RING fingers and the ZZ zinc finger was required for interaction with UbcH5a and MEX self-association, whereas the SWIM domain was critical for MEX ubiquitination. The expression of MEX promoted apoptosis that was induced through Fas, DR (death receptor) 3 and DR4 signalling, but not that mediated by the BH3 (Bcl-2 homology 3)-only protein BimEL or the chemotherapeutic drug adriamycin.

SIGNOR-271554

Q9NR30

Q92499

0

binding

up-regulates activity

0.32

We demonstrated here that DDX1-DDX21-DHX36 represents a dsRNA sensor that uses the adaptor molecule TRIF to activate the NF-ÎºB pathway and type I IFN responses in dendritic cells. Our study suggests that the DDX1-DDX21-DHX36 complex represents this missing poly I:C sensor, which uses DDX1 to bind poly I:C and uses DDX21 and DXH36 to bind TRIF. Poly I:C is a synthetic form of RNA that mimics double-stranded viral RNA.

SIGNOR-260191

Q92934

P41743

0

phosphorylation

down-regulates

0.32

In-vitro kinase activity assay showed that pkc-_ directly phosphorylated bad at phospho specific residues, ser-112, ser-136 and ser-155 which in turn induced inactivation of bad and disruption of bad/bcl-xl dimer

SIGNOR-172894

P51648

Q9NXK8

0

binding

down-regulates quantity by destabilization

0.32

We now show that SCFFBXL12 is an authentic E3 for the ALDH3 family of enzymes. We now show that the ubiquitin-dependent degradation of ALDH3 mediated by FBXL12 (F box and leucine-rich repeat protein 12) is essential for execution of the differentiation program of trophoblast stem cells (TSCs). FBXL12 is present only in eutherian mammals, and its expression is largely restricted to the placenta during mouse embryogenesis. FBXL12 was found to interact specifically with members of the ALDH3 family and to mediate their polyubiquitylation. Finally, coimmunoprecipitation analysis revealed that FBXL12 interacted efficiently only with members of the ALDH3 family (ALDH3A1, ALDH3A2, and ALDH3B1), showing little if any association with those of the ALDH1 family (ALDH1A1, ALDH1A2, and ALDH1A3) (Fig. 2H). Collectively, these results suggested that SCFFBXL12 is an authentic E3 specific for ALDH3 family members.

SIGNOR-272814

O95863

P52954

0

transcriptional regulation

up-regulates quantity by expression

0.32

Compared with the empty vector, LBX1 induced increased promoter activity of threefold to fourfold and fivefold to sixfold for ZEB1 and Snail1, respectively

SIGNOR-266053

Q16613

P17612

0

phosphorylation

up-regulates activity

0.32

AANAT1–207 was phosphorylated in vitro at both PKA sites, Thr-31 and Ser-205. regulation is achieved by binding to 14-3-3, which structurally modulates the substrate binding sites, leading to measurable effects on the affinity of AANAT for its substrates with an accompanying increase in activity at low substrate concentrations.

SIGNOR-250324

Q15468

P06493

0

phosphorylation

down-regulates activity

0.32

Importantly, we show that CDK1 and CyclinB phosphorylates the N-terminal domain of STIL, but not the region encompassing the CC or STAN motifs.

SIGNOR-279145

P51636

P68400

0

phosphorylation

up-regulates activity

0.32

We show that caveolin-2 is phosphorylated in vivo at two serine residues and that the phosphorylation of caveolin-2 is necessary for its actions as a positive regulator of caveolin-1 during organelle biogenesis in prostate cancer cells. Mutation of the primary phosphorylation sites on caveolin-2, serine 23 and 36, reduces the number of plasmalemma-attached caveolae

SIGNOR-101110

P10909

Q86TM6

0

polyubiquitination

down-regulates quantity by destabilization

0.32

We also report that the ER-associated ubiquitin ligase Hrd1/synoviolin can interact with, and ubiquitinate clusterin. The fact that cleaved endogenous clusterin appears, under certain conditions, to be subject to polyubiquitination (Figure 2C) and proteasomal degradation (1, 2) strongly suggests that it passed through the secretory pathway before reaching the cytosol.

SIGNOR-272629

Q7Z2E3

P05129

0

phosphorylation

up-regulates

0.32

We show the novel molecular consequences of increased kinase activities of mutants: aprataxin (aptx), a dna repair protein causative for autosomal recessive ataxia, was found to be a preferential substrate of mutant pkc gamma, and phosphorylation inhibited its nuclear entry. ollectively, phosphorylation occurred at thr111, reducing nuclear aptx.

SIGNOR-186409

P09086

P26583

0

binding

up-regulates activity

0.32

HMG2 and Oct2 interact via their HMG domains and POU homeodomains, respectively. This interaction is not restricted to Oct2, as other members of the octamer transcription factor family like Oct1 and Oct6 also interact with HMG2. The interaction with HMG2 results in a marked increase in the sequence-specific DNA binding activity of the Oct proteins

SIGNOR-240108

Q15797

P50750

0

phosphorylation

down-regulates

0.32

Phosphorylation of the linker region of smad1, a receptor-activated smad (r-smad), at serine 206 (s206) and s214 induced by bmp and mediated by cdk8/9 is critical for binding of the e3 ubiquitin ligase smurf1. Binding of smurf1 leads to polyubiquitination of smad1 and its degradation by the proteasome;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3.

SIGNOR-161569

Q04724

P68400

0

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

P30838

Q9NXK8

0

binding

down-regulates quantity by destabilization

0.32

We now show that SCFFBXL12 is an authentic E3 for the ALDH3 family of enzymes. We now show that the ubiquitin-dependent degradation of ALDH3 mediated by FBXL12 (F box and leucine-rich repeat protein 12) is essential for execution of the differentiation program of trophoblast stem cells (TSCs). FBXL12 is present only in eutherian mammals, and its expression is largely restricted to the placenta during mouse embryogenesis. FBXL12 was found to interact specifically with members of the ALDH3 family and to mediate their polyubiquitylation. Finally, coimmunoprecipitation analysis revealed that FBXL12 interacted efficiently only with members of the ALDH3 family (ALDH3A1, ALDH3A2, and ALDH3B1), showing little if any association with those of the ALDH1 family (ALDH1A1, ALDH1A2, and ALDH1A3) (Fig. 2H). Collectively, these results suggested that SCFFBXL12 is an authentic E3 specific for ALDH3 family members.

SIGNOR-272813

Q9BVN2

Q9Y4K3

0

polyubiquitination

down-regulates quantity by destabilization

0.32

We demonstrated that NESCA and NEMO interact by their N-terminal region. Beside to NEMO, we revealed that NESCA directly associates to the E3 ubiquitin ligase TRAF6, which in turn catalyzes NESCA polyubiquitination. Finally, we demonstrated that NESCA overexpression strongly inhibits TRAF6-mediated polyubiquitination of NEMO.

SIGNOR-272774

O60282

P53779

0

phosphorylation

down-regulates activity

0.32

Mass spectrometry identified a residue in the kinesin-1 motor domain that was phosphorylated by JNK3 and this modification reduced kinesin-1 binding to microtubules. JNK3 phosphorylates kinesin-1 at Ser176

SIGNOR-262950

Q9Y5Y9

Q96PU5

0

ubiquitination

down-regulates quantity by destabilization

0.32

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-253463

P14635

A6NLU0

0

ubiquitination

down-regulates quantity by destabilization

0.32

We conclude that, like many RING-finger containing proteins, RFPL4 is an E3 ubiquitin ligase. The specificity of its expression and these interactions suggest that RFPL4 targets cyclin B1 for proteasomal degradation, a key aspect of oocyte cell cycle control during meiosis and the crucial oocyte-to-embryo transition to mitosis.

SIGNOR-271476

P42680

P12931

0

phosphorylation

up-regulates activity

0.32

The proximal event following T cell-APC synapse formation is immediate activation of several signaling molecules: The Src kinase phosphorylates and activates Tec tyrosine kinases, which then activate PLC-\u03b3 that is required for IP 3 generation to sustain intracellular calcium flux.

SIGNOR-280135

P46531

Q00535

0

phosphorylation

up-regulates activity

0.32

An in vitro kinase reaction demonstrated that T2132, S2136, and S2141 were CDK5\u2010phosphorylated sites in the Notch1 peptide (Figure\u00a02B, C, and D).|In conclusion, CDK5 positively regulates Notch1 function via phosphorylation, which in turn promotes cell proliferation and migration.

SIGNOR-279401

P11362

P27361

0

phosphorylation

down-regulates

0.32

Erk-mediated phosphorylation of fibroblast growth factor receptor 1 on ser777 inhibits signaling

SIGNOR-200884

Q9P253

P62837

0

binding

up-regulates activity

0.32

VPS18 Ubiquitylates SNK in Vitro and in Vivo. The ubiquitylation of proteins by hVPS18 was selectively mediated by UbcH4.

SIGNOR-271549

O43521

Q16539

0

phosphorylation

down-regulates quantity by destabilization

0.32

Ser69 can also be phosphorylated by JNK and p38MAPK at least in vitro. Phosphorylation of BimEL on Ser69 promotes its ubiquitination.

SIGNOR-260442

P0DP23

O43303

0

binding

up-regulates activity

0.32

We report that CP110 interacts with two different Ca2+-binding proteins, calmodulin (CaM) and centrin, in vivo. our data demonstrate a functional role for CaM binding to CP110 and suggest that CP110 cooperates with CaM and centrin to regulate progression through cytokinesis.

SIGNOR-265965

P43353

Q9NXK8

0

binding

down-regulates quantity by destabilization

0.32

We now show that SCFFBXL12 is an authentic E3 for the ALDH3 family of enzymes. We now show that the ubiquitin-dependent degradation of ALDH3 mediated by FBXL12 (F box and leucine-rich repeat protein 12) is essential for execution of the differentiation program of trophoblast stem cells (TSCs). FBXL12 is present only in eutherian mammals, and its expression is largely restricted to the placenta during mouse embryogenesis. FBXL12 was found to interact specifically with members of the ALDH3 family and to mediate their polyubiquitylation. Finally, coimmunoprecipitation analysis revealed that FBXL12 interacted efficiently only with members of the ALDH3 family (ALDH3A1, ALDH3A2, and ALDH3B1), showing little if any association with those of the ALDH1 family (ALDH1A1, ALDH1A2, and ALDH1A3) (Fig. 2H). Collectively, these results suggested that SCFFBXL12 is an authentic E3 specific for ALDH3 family members.

SIGNOR-272815

O14939

Q05397

0

phosphorylation

up-regulates activity

0.32

The kinase domain of FAK interacts with PLD2-PH and induces tyrosine phosphorylation and activation of PLD2.

SIGNOR-279480

P46531

P49840

0

phosphorylation

down-regulates

0.319

Taken together, our results indicate that gsk-3alfa is a negative regulator of notch1/nicd.

SIGNOR-183969

P08581

P08047

0

transcriptional regulation

up-regulates quantity by expression

0.319

Furthermore, in transient cotransfection assays, overexpression of Sp1 and/or Sp3 stimulated HGF promoter activity independently and additively through binding to the Sp1 binding site in the HGF gene promoter region.

SIGNOR-241490

Q9UBK2

Q969K3

0

ubiquitination

down-regulates quantity by destabilization

0.319

Mechanistically, PGC1α was phosphorylated at serine (S) 636 by DNA-dependent protein kinase in response to irradiation. Phosphorylation at S636 promoted the degradation of PGC1α by facilitating its binding to the E3 ligase RNF34.

SIGNOR-277912

Q96FW1

P68400

0

phosphorylation

up-regulates activity

0.319

Casein kinase 2 (CK2)-dependent phosphorylation of OTUB1 at Ser16 played a critical role in ODN- and cathepsin K siRNA-mediated p53 stabilization. |Furthermore, although OTUB1 dramatically induced p53 deubiquitination, its mutant (S16A) and deletion mutant did not have this effec

SIGNOR-276527

Q9H6Z4

Q15418

0

phosphorylation

up-regulates quantity

0.319

RSK phosphorylates RanBP3 at Serine 58 residue in vitro and in vivo.RanBP3 phosphorylation increases its affinity towards Ran

SIGNOR-276149

Q9UKF7

P17252

0

phosphorylation

up-regulates activity

0.319

Only BIM-I caused a reduction in 14-3-3 binding (Figure 3B), suggesting that PKC could be responsible for one or both of the serine phosphorylations, pSer274 and pSer299.

SIGNOR-273801

P37840

Q9H4B4

0

phosphorylation

down-regulates activity

0.319

Polo-like kinase (plk) family (plk1, plk2, and plk3) phosphorylate alpha-syn and beta-syn specifically at ser-129 and ser-118, respectively. Polo-like kinase 2 (plk2) phosphorylates alpha-synuclein at serine 129 in central nervous system. The membrane association of pd-linked mutant alpha -synuclein, but not wild-type -synuclein, was increased by serine 129 phosphorylation.

SIGNOR-189053

P04637

Q9H0M0

0

ubiquitination

up-regulates activity

0.319

Unlike other E3 ligases, WWP1 increases p53 stability; inhibition of WWP1 expression or expression of a ligase-mutant form results in decreased p53 expression.|WWP1 associates with p53 and induces p53 ubiquitylation.

SIGNOR-278649

P41180

P05771

0

phosphorylation

down-regulates activity

0.319

Expression of a mutant CaR in which the major PKC phosphorylation site is altered by substitution of alanine for threonine (T888A) eliminated oscillatory behavior, producing [Ca(2+)](i) responses almost identical to those produced by the wild type CaR exposed to PKC inhibitors. These results support a model in which phosphorylation of the CaR at the inhibitory threonine 888 by PKC provides the negative feedback needed to cause [Ca(2+)](i) oscillations mediated by this receptor.

SIGNOR-249176

P10275

P17844

0

binding

up-regulates

0.319

P68 is a nuclear protein and interacts with ar / p68 co-occupies the active psa promoter at are regions and enhances ar transcriptional activity

SIGNOR-181456

P50148

P34969

0

binding

up-regulates activity

0.319

Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. | We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ≥ -1.0.

SIGNOR-257381

Q96J02

P31749

0

phosphorylation

up-regulates quantity

0.319

AKT1-mediated phosphorylation of ITCH at Ser257 drives its nuclear translocation

SIGNOR-272922

O60934

Q13428

0

relocalization

up-regulates activity

0.319

We further identify TCOF1 (also known as Treacle), a nucleolar factor implicated in ribosome biogenesis and mutated in Treacher Collins syndrome, as an interaction partner of NBS1, and demonstrate that NBS1 translocation and accumulation in the nucleoli is Treacle dependent.

SIGNOR-265085

P04179

Q9P275

0

deubiquitination

up-regulates quantity by stabilization

0.319

Protein stability of mitochondrial superoxide dismutase SOD2 is regulated by USP36|Finally, USP36 was shown to be a specific deubiquitinating enzyme that reduces the ubiquitination level of SOD2 and was involved in SOD2 protein stability by extending its half-life.

SIGNOR-272280

Q13547

Q9H4L7

0

binding

up-regulates activity

0.319

SMARCAD1 interacts with HDAC1 and KAP1 and is required for their binding to heterochromatin

SIGNOR-239835

P15976

Q03112

0

transcriptional regulation

up-regulates quantity by expression

0.319

We finally observed that the forced expression of Evi1 induced GATA-2 expression in a hematopoietic cell line, EML C1, along with GATA-1, Ang-1, Ang-2 and Tie2

SIGNOR-266061

P48736

Q15303

0

binding

up-regulates

0.319

Pi3k is the sole binding partner to six tyrosines of erbb3 and one in erbb4.

SIGNOR-146888

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

Q99683

Q5SGD2

0

dephosphorylation

down-regulates

0.318

Exogenous pp2cepsilon associated with exogenous ask1 in hek-293 cells under non-stressed conditions, inactivating ask1 by decreasing thr845 phosphorylation

SIGNOR-154554

P07550

Q9H6Z9

0

hydroxylation

up-regulates quantity by stabilization

0.318

We further show that the interaction of pVHL with beta(2)AR is dependent on proline hydroxylation (proline-382 and -395) and that the dioxygenase EGLN3 interacts directly with the beta(2)AR to serve as an endogenous beta(2)AR prolyl hydroxylase. Under hypoxic conditions, receptor hydroxylation and subsequent ubiquitylation decrease dramatically, thus attenuating receptor degradation and down-regulation.

SIGNOR-262007

P18084

O14713

0

binding

down-regulates activity

0.318

Integrins also bind to many PTBdomain-containing proteins (Calderwood et al., 2003) – including Dok1 and integrincytoplasmic-domain-associated protein 1 (ICAP1) – and these can compete with talin for binding to integrin and so can impair activation

SIGNOR-257660

Q15366

P28482

0

phosphorylation

up-regulates quantity by stabilization

0.318

We also identified 4 hnRNP-E2 MAPKERK1/2 phosphorylation sites and demonstrated that hnRNP-E2 is a bona fide MAPKERK1/2 substrate and that MAPKERK1/2-dependent phosphorylation of hnRNP-E2 at these amino acid residues is essential for increased hnRNP-E2 expression in BCR/ABL-expressing cells. Serine/threonine to alanine substitution abolishes hnRNP-E2 phosphorylation and markedly decreases its stability in BCR/ABL-expressing myeloid precursors. Consistent with the existence of a BCR/ABL-MAPK pathway that posttranslationally regulates hnRNP-E2 expression, sequence analysis of hnRNP-E2 revealed the presence of 4 consensus ERK phosphorylation sites (S/T-P)35,36 at amino acid residues 173, 189, 213, and 272 (Figure 2B).

SIGNOR-262912

Q9H4A6

P78527

0

phosphorylation

up-regulates activity

0.318

In response to DNA damage, DNA-PK phosphorylates GOLPH3, resulting in increased interaction with MYO18A, which applies a tensile force to the Golgi. Interference with the Golgi DNA damage response by depletion of DNA-PK, GOLPH3, or MYO18A reduces survival after DNA damage, whereas overexpression of GOLPH3, as is observed frequently in human cancers, confers resistance to killing by DNA-damaging agents

SIGNOR-253558

P38936

Q9H0Z9

0

post transcriptional regulation

up-regulates quantity by stabilization

0.318

Here, we found that RNPC1, an RNA-binding protein and a target of the p53 family, is required for maintaining the stability of the basal and stress-induced p21 transcript.

SIGNOR-275391

P04637

P51955

0

phosphorylation

down-regulates

0.318

NEK2 Phosphorylates p53 at Ser315 and Reduces Its Stability.|These results are consistent with NEK2 inhibiting p53 transcriptional activation functions.

SIGNOR-278488

Q13485

Q96JC1

0

relocalization

down-regulates activity

0.318

The data demonstrating binding of TLP to TGF-β and activin type II receptors and selective inhibition of Smad3/Smad4 complex formation by deregulated TLP suggest that TLP is involved in localizing these receptors and Smad4 to specific intracellular compartments, where it regulates formation of Smad3/Smad4 but not Smad2/Smad4 complexes.

SIGNOR-261377

P18846

P51812

0

phosphorylation

up-regulates activity

0.318

ATF1 and CREB can be phosphorylated by Rsk2 which is a protein kinase directly activated by Erk MAP kinase. These results suggest a signaling pathway in which Erk MAP kinase activates the c-fos enhancer by direct phosphorylation of p62TCF and by activation of Rsk related kinases that phosphorylate ATF1 and CREB.|ATF1 and CREB can be phosphorylated by Rsk2 which is a protein kinase directly activated by Erk MAP kinases.

SIGNOR-280117

P50222

O60315

0

transcriptional regulation

down-regulates quantity by repression

0.318

ZEB2 represses GAX transcription through multiple up- stream consensus binding sites.

SIGNOR-268951

P04004

P17252

0

phosphorylation

up-regulates quantity by stabilization

0.318

Phosphorylation of vitronectin on Ser362 by protein kinase C attenuates its cleavage by plasmin.

SIGNOR-248962

Q13224

O15409

0

transcriptional regulation

up-regulates quantity by expression

0.318

By interacting with CASK, TBR1 regulates several ASD candidate genes, such as GRIN2B, AUTS2 and RELN—all of which are recurrently mutated in ASD. In areas of the brain with overlapping expression patterns, such as in glutamatergic layer 6 neurons, the TBR1–FOXP2 interaction may result in co-ordinated regulation of common downstream targets.

SIGNOR-266834

P29034

Q9UNE7

0

polyubiquitination

down-regulates quantity by destabilization

0.318

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

SIGNOR-272918

P46531

Q9P2R6

0

binding

up-regulates activity

0.318

In mammalian cells, RERE co‐immunoprecipitates with CBF1 and Notch intracellular domain (NICD), and is recruited to nuclear foci formed by over‐expressed NICD1. RERE is also necessary for NICD to activate the expression of Notch target genes.

SIGNOR-264486

P49810

P55210

0

cleavage

up-regulates activity

0.318

In decreasing order of activity, caspase-8, -3, -1, -6 and -7 proteolysed PS2 at the recognition site D326SYD329.

SIGNOR-261751

O15534

P48729

0

phosphorylation

down-regulates quantity by destabilization

0.318

CKI\u03b1-Dependent Phosphorylation and Degradation of PER1.

SIGNOR-279700

P04637

P36873

0

dephosphorylation

down-regulates activity

0.318

Protein serine/threonine phosphatase-1 dephosphorylates p53 at Ser-15 and Ser-37 to modulate its transcriptional and apoptotic activities|In addition, our results reveal that one of the molecular mechanisms by which PP-1 promotes cell survival is to dephosphorylate p53, and thus negatively regulate p53-dependent death pathway.

SIGNOR-248499

O60341

P68400

0

phosphorylation

up-regulates activity

0.318

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

SIGNOR-276903

O14641

P60484

0

dephosphorylation

down-regulates activity

0.318

This showed that while both PTEN WT and the lipid phosphatase-inactive G129E mutant suppressed phosphorylation of DVL2 on serine 143 that accumulated upon PTEN knockdown, the C124S and Y138L mutants did not .|Finally, it is important to point out that while our studies show that PTEN can directly dephosphorylate DVL2 in vitro, it is possible that regulation of serine 143 phosphorylation of DVL2 by PTEN in cells may require additional protein factors, or post-translational modifications.

SIGNOR-277035

Q16143

P53350

0

phosphorylation

down-regulates activity

0.318

Polo-like kinase (plk) family (plk1, plk2, and plk3) phosphorylate alpha-syn and beta-syn specifically at ser-129 and ser-118, respectively. Polo-like kinase 2 (plk2) phosphorylates alpha-synuclein at serine 129 in central nervous system. The membrane association of pd-linked mutant alpha -synuclein, but not wild-type -synuclein, was increased by serine 129 phosphorylation.

SIGNOR-176079

P48431

Q9HCK8

0

transcriptional regulation

down-regulates quantity

0.318

Many of the most significantly up-regulated genes in Chd8+/− and Chd8−/− NPCs are involved in later stages of neuronal development, including Ascl1 [a central driver of neural reprogramming (29)], Dcx, Map2, Nefm, Neurod4, and Neurog1 (Fig. 2 E and F). Additionally, we found that Sox3 is derepressed in both Chd8+/− and Chd8−/− NPCs, and several other Sox TF members (Sox2, Sox7, and Sox11) became derepressed in the Chd8−/− cells

SIGNOR-268921

P12931

Q01973

0

phosphorylation

up-regulates

0.318

Ror1 binds to and phosphorylates c-src / ror1 kinase-dependent c-src activation

SIGNOR-196751

Q96I25

P49759

0

phosphorylation

up-regulates activity

0.317

In this work, we show that Cdc2-like kinase 1 (Clk1) phosphorylates SPF45 on eight serine residues.

SIGNOR-262710

Q00975

Q9UQM7

0

phosphorylation

down-regulates

0.317

Here, we report a direct modulation of ca(v)2.2 channel inactivation properties by 14-3-3, a family of signaling proteins involved in a wide range of biological processes.Wild-type gst fusion proteins containing the putative 14-3-3-binding motif (aa 2076__?2140) werein vitro phosphorylated at s2126 by either camkii or pka, as detected by thesequence- and phosphorylation-specific antibody, anti-ps2126 (middle panel). Phosphorylation of s2126 significantly increases its binding to recombinant 14-3-3?

SIGNOR-149684

P12931

P43115

0

binding

up-regulates activity

0.317

These results clearly demonstrate that EP3 contributes to the activation of Src and its related cell growth in A549 cells treated with PGE2.

SIGNOR-278885

P41212

P28482

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-260086

Q14957

P62258

0

binding

up-regulates quantity by stabilization

0.317

Here, we demonstrate that PKB/Akt directly phosphorylates NR2C on serine 1096 (S1096). In addition, we identify 14-3-3epsilon as an NR2C interactor, whose binding is dependent on S1096 phosphorylation. These data are all consistent with a model in which NR1 and NR2C oligomerize, PKB phosphorylates S1096, and 14-3-3ε binds to phosphorylated NR2C thereby promoting NR2C-containing NMDA receptor surface expression in cerebellar granule cells.

SIGNOR-262622

Q8WUI4

P67775

0

dephosphorylation

up-regulates activity

0.317

Phosphorylation of conserved serine residues triggers association with 14-3-3 proteins and cytoplasmic relocalization of class IIa HDACs, which leads to the derepression of their target genes. |Here we identify PP2A as a phosphatase responsible for dephosphorylating the 14-3-3 binding sites in class IIa HDACs.|we demonstrate that PP2A constitutively dephosphorylates the class IIa member HDAC7 to control its biological functions as a regulator of T cell apoptosis and endothelial cell functions.

SIGNOR-248649

Q06187

Q03113

0

binding

up-regulates activity

0.317

Here we show that Ga12 binds directly to, and stimulates the activity of, Bruton’s tyrosine kinase (Btk) and a Ras GTPase-activating protein, Gap1m, in vitro and in vivo

SIGNOR-278082

Q9UM11

P11309

0

phosphorylation

down-regulates activity

0.317

Pim-1 phosphorylates Cdh1 and impairs binding of this protein to another APC/C complex member, CDC27. These modifications inhibit Skp2 from degradation.Pim-1 Impairs Cdh1 and CDC27 Interaction and Phosphorylates Cdh1.

SIGNOR-259820

P22415

P49715

0

binding

up-regulates activity

0.317

Our studies show that the human C/EBPa protein stimulates USF to bind to a USF consensus element within C/EBPa promoter and activates it by two- to threefold.The mechanism by which C/EBPa enhances USF binding and transactivation is currently under study.

SIGNOR-255701

O75460

Q15084

0

null

down-regulates activity

0.317

A resident ER protein disulfide isomerase, PDIA6, limits the duration of IRE1α activity by direct binding to cysteine148 in the luminal domain of the sensor,

SIGNOR-256536

Q06413

Q9UPW0

0

transcriptional regulation

up-regulates quantity by expression

0.317

Foxj3 transcriptionally activates Mef2c and regulates adult skeletal muscle fiber type identity.

SIGNOR-261606

P17861

O14818

0

binding

down-regulates quantity by destabilization

0.317

We saw preferential binding of XBP-1u to subunits _5, _6 and _7.2. We demonstrate that XBP-1u undergoes efficient degradation in vitro by 20S proteasomes in the absence of ubiquitination.

SIGNOR-239042

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

P67809

Q7Z6E9

0

ubiquitination

down-regulates quantity by destabilization

0.317

RBBP6 interacts with multifunctional protein YB-1 through its RING finger domain, leading to ubiquitination and proteosomal degradation of YB-1

SIGNOR-271773

Q15109

P05109

0

binding

up-regulates activity

0.317

RAGE and TLR4 are well-characterized S100A8 and S100A9 receptors and expressed in AML cells Once secreted, S100A8 and S100A9 induce immune and inflammatory responses9 through interaction with receptors such as Toll-like receptor 4 (TLR4), receptor for advanced glycation end-product (RAGE), and CD33

SIGNOR-261919

P08581

P23470

0

dephosphorylation

down-regulates activity

0.317

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-254712

Q9UQD0

P61328

0

binding

down-regulates activity

0.317

Sodium channel fast inactivation is modulated by alpha subunit interaction with a family of cytoplasmic proteins termed fibroblast growth factor homologous factors (FHFs). In this paper, we report that all A-type FHFs exert rapid onset long-term inactivation on Nav1.6 and other sodium channels.

SIGNOR-253412

P05771

Q8WV44

0

polyubiquitination

down-regulates quantity by destabilization

0.317

RINCK induces the ubiquitination of PKC both in vitro and in cells. Overexpression of RINCK reduces the levels of PKC in cells, whereas genetic knockdown of endogenous RINCK increases the levels of PKC. The RINCK-mediated ubiquitination is likely to be polyubiquitination, because the ubiquitinated PKCβII was detected as a high molecular weight smear.

SIGNOR-271667

P35580

Q02078

0

transcriptional regulation

up-regulates quantity by expression

0.317

Myocyte enhancer factor-2 and serum response factor binding elements regulate fast Myosin heavy chain transcription in vivo. We show that the upstream promoter region of the gene most abundantly expressed in mouse skeletal muscles, IIb MyHC, retains binding activity and transcriptional activation for three positive transcription factors, the serum response factor, Oct-1, and myocyte enhancer factor-2, whereas the other two genes (IIa and IId/x) have nucleotide substitutions in these sites that reduce binding and transcriptional activation

SIGNOR-238763

Q99250

Q96PU5

0

ubiquitination

down-regulates quantity by destabilization

0.317

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-253459

Q09472

Q15059

0

binding

up-regulates activity

0.317

Brd3 interacts with both IRF3 and p300, increases p300-mediated acetylation of IRF3, and enhances the association of IRF3 with p300 upon virus infection.|Brd3 enhances p300-mediated acetylation of IRF3

SIGNOR-262044

Q9GZV5

P07947

0

phosphorylation

up-regulates activity

0.317

Yes directly phosphorylates YAP and TAZ, resulting in their increased nuclear localization and transcriptional activity.Analysis by mass spectrometry identified Tyr391 and Tyr407 as the two phosphorylation sites of YAP, whereas Tyr305 was the sole phosphorylated residue of TAZ (Fig. 5F and fig. S4, A to C).

SIGNOR-277654

P24928

P27361

0

phosphorylation

down-regulates

0.316

Erk1/2 are major ser-5 kinases after h2o2 treatment. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination.

SIGNOR-120176

P23528

O14965

0

phosphorylation

down-regulates activity

0.316

However, this study identified that CFL-1 also acts as a direct substrate of Aur-A, which phosphorylates CFL-1 at multiple sites, including S3, S8, and T25, resulting in its inactivation.|In early cell mitotic phases, LIMK1 and Aur-A phosphorylate and inactivate CFL-1, while at the later stages, SSH-1 inactivates LIMK1 and dephosphorylates and activates CFL-1 [33] .

SIGNOR-279798

P24723

O15530

0

phosphorylation

up-regulates activity

0.316

Protein kinase C(eta) is phosphorylated by PDK1 in vitro, leading to kinase activation as similarly reported for protein kinase C(epsilon) activation by PDK1.

SIGNOR-280062

Q15208

P53350

0

phosphorylation

down-regulates activity

0.316

Here, we identified a conserved signaling axis in which NDR1 kinase activity is regulated by PLK1 in mitosis. PLK1 phosphorylates NDR1 at three putative threonine residues (T7, T183 and T407) at mitotic entry, which elicits PLK1-dependent suppression of NDR1 activity and ensures correct spindle orientation in mitosis.

SIGNOR-276914

P16949

P45983

0

phosphorylation

down-regulates

0.316

Involved in the regulation of the microtubule (mt) filament system by destabilizing microtubules. Prevents assembly and promotes disassembly of microtubules. Here we show that in response to hyperosmotic stress, jnk phosphorylates a key cytoplasmic microtubule regulatory protein, stathmin (stmn), on conserved ser-25 and ser-38 residues. In in vitro biochemical studies, we identified stmn ser-38 as the critical residue required for efficient phosphorylation by jnk and identified a novel kinase interaction domain in stmn required for recognition by jnk. We revealed that jnk was required for microtubule stabilization in response to hyperosmotic stress.

SIGNOR-166694