GleghornLab/Signor_processed · Datasets at Hugging Face

IdA stringlengths 6 21	IdB stringlengths 6 21	labels float64 0 2	mechanism stringclasses 40 values	effect stringclasses 10 values	score float64 0.1 0.99 ⌀	sentence stringlengths 10 1.63k ⌀	signor_id stringlengths 12 14
P55211	P42574	2	cleavage	up-regulates activity	0.639	Active caspase-3 itself is able to process its upstream , caspase-8 and caspase-9, establishing a self-amplifying loop of caspase activation	SIGNOR-90397
P42574	P55211	2	cleavage	up-regulates activity	0.639	Following autoprocessing in the apoptosome, caspase-9 cleaves and activates caspase-3.	SIGNOR-133267
P12931	Q12913	2	phosphorylation	up-regulates activity	0.636	CK2-dependent phosphorylation of DEP-1 T1318 promotes Y1320 phosphorylation and Src activation upon VEGF stimulation.	SIGNOR-277877
Q13077	Q12933	2	binding	up-regulates	0.636	Our analysis indicates that traf1 and traf2 are associated with the cytoplasmic domain of tnf-r2 in a heterodimeric complex in which traf2 contacts the receptor directly. Traf1 interacts with tnf-r2 indirectly through heterodimer formation with traf2.	SIGNOR-35881
P08253	P01023	2	binding	down-regulates activity	0.636	Both PZP and a2M collagenase complexes incubated with gelatin demonstrated a significant inhibition of the catalytic activity\| MMP-2 and MMP-9 cause a significant degradation of these bands and the background, a degradation which is prevented by both a2M and PZP.	SIGNOR-261803
P01023	P08253	2	cleavage	down-regulates quantity by destabilization	0.636	The complex formation was confirmed by the use of 125I-labeled matrix metalloproteinase-2. The cleavage sites in the "bait" regions following formation of high-molecular-weight complexes of matrix metalloproteinases with the alpha-macroglobulins were determined by protein sequence analysis. Pregnancy zone protein was cleaved at Thr693-Tyr694 and alpha2-macroglobulin at Gly679-Leu680 and Arg696-Leu697 by matrix metalloproteinase-2. Matrix metalloproteinase-9 cleaved alpha2-macroglobulin at the same site as matrix metalloproteinase-2, but cleavage of pregnancy zone protein was at Leu753-Ser754.\|MMP-2 and MMP-9 cause a significant degradation of these bands and the background, a degradation which is prevented by both a2M and PZP.	SIGNOR-261739
P49840	P31749	2	phosphorylation	down-regulates	0.636	In response to insulin, gsk3a inhibited by phosphorylation at ser-21 by pkb/akt1;phosphorylation at this site causes a conformational change, preventing access of substrates to the active site.	SIGNOR-252589
Q12933	Q13077	2	binding	up-regulates	0.636	Traf1 and traf2 can form homo- and heterotypic dimers.	SIGNOR-34768
Q12913	P12931	2	phosphorylation	up-regulates activity	0.636	We demonstrate here that DEP-1 is phosphorylated in a Src- and Fyn-dependent manner on Y1311 and Y1320, which bind the Src SH2 domain. This allows DEP-1-catalyzed dephosphorylation of Src inhibitory Y529 and favors the VEGF-induced phosphorylation of Src substrates VE-cadherin and Cortactin.	SIGNOR-276373
Q07812	P10415	2	binding	down-regulates activity	0.636	Bcl-2 has the unique oncogenic role of extending cell survival by inhibiting a variety of apoptotic deaths. Bcl-2 exerts its action through heterodimerization with bax.	SIGNOR-36898
P31749	P49840	2	phosphorylation	down-regulates activity	0.636	GSK3_ negatively regulates AKT activation by phosphorylating AKT at T312 in the substrate binding site, which inhibited IL-1-induced AKT activation and function.	SIGNOR-252434
P10415	Q07812	2	binding	down-regulates activity	0.636	Bax shows extensive amino acid homology with Bcl-2 and forms homodimers and heterodimers with Bcl-2 in vivo. When Bax predominates, programed cell death is accelerated, and the death repressor activity of Bcl-2 is countered.	SIGNOR-249612
P36894	Q13873	2	phosphorylation	up-regulates	0.631	Bmp ligands bind to the bmp receptors bmpr1 and bmpr2, and bmpr2 then phosphorylates and activates bmpr1.	SIGNOR-180545
P23458	P14784	2	binding	up-regulates	0.631	In lymphocytes, binding of il-15 to the il-2/15rbg heterodimer induces jak1 activation that subsequently phosphorylates stat3 via the b-chain and jak3/stat5 activation via its g-chain	SIGNOR-204972
P14784	P23458	2	phosphorylation	up-regulates activity	0.631	In COS-7 cells, overexpression of Jak1 augmented phosphorylation of Y338 as well as Y392 and Y510. Y392 and Y510 were critical for IL-2-induced activation of signal transducers and activators of transcription (STAT proteins), Y338 was required for Shc-IL-2Rbeta association and for IL-2-induced tyrosine phosphorylation of Shc.	SIGNOR-251340
Q13873	P36894	2	binding	up-regulates	0.631	Using several complementary approaches, we investigated the formation of homomeric and heteromeric complexes between the two known bmp type i receptors	SIGNOR-75652
Q8IW41	P31152	2	phosphorylation	up-regulates activity	0.63	ERK3, ERK4 and p38 MAPK can all phosphorylate MK5 at Thr 182 , , , - ], but it is not known whether these enzymes also can phosphorylate Ser 115 and whether this modification contributes to ERK3-, ERK4-, or p38 MAPK -regulated subcellular localization of MK5.	SIGNOR-279072
P31152	Q8IW41	2	phosphorylation	up-regulates	0.63	This is due to mk5-dependent phosphorylation and only this retarded erk4 species is both phosphorylated on ser(186) and co-immunoprecipitates with wild-type mk5. We conclude that binding between erk4 and mk5 facilitates phosphorylation of ser(186) and stabilization of the erk4-mk5 complex.	SIGNOR-17069
P29992	Q9NQ66	2	binding	up-regulates	0.623	Plc-_1 stimulates hydrolysis of gq/11-bound gtp and acts as a gtpase-activating protein (gap) for its physiologic regulator, gq/11	SIGNOR-17239
Q9NQ66	P29992	2	binding	up-regulates activity	0.623	TRH-R1 receptor, which is coupled to Gq/11 protein, activates phospholipase C, mobilizes calcium and activates protein kinase C.	SIGNOR-267203
Q70Z35	P60484	2	binding	down-regulates activity	0.62	Here, we used cell biology, biochemistry, and genetic approaches to show that PTEN suppresses cell movement by blocking PREX2 GEF–catalyzed activation of the GTPase RAC1. PTEN binds PREX2 and directly inhibits GEF activity.	SIGNOR-259190
P17947	P15976	2	binding	down-regulates activity	0.62	GATA-1 represses PU.1 activity.We have in this report found that the GATA-1 transcription factor is capable of functionally interfering with the PU.1 protein and have provided evidence that this interference is mediated through interaction between the PU.1 ETS domain and the GATA-1 C-finger region.	SIGNOR-256050
P60484	Q70Z35	2	binding	down-regulates activity	0.62	Here, we report that P-REX2 interacts with PTEN via two interfaces. In summary, P-REX2 docks to the PDZ-BD of PTEN through its C-terminal domain, reads the phosphorylation state of the PTEN tail via the DH domain, and inhibits PTEN activity by unleashing the PH domain	SIGNOR-259189
P15976	P17947	2	binding	down-regulates activity	0.62	We find that PU.1 interacts directly with GATA-1, a zinc finger transcription factor required for erythroid differentiation. Interaction between PU.1 and GATA-1 requires intact DNA-binding domains in both proteins. PU.1 represses GATA-1-mediated transcriptional activation.	SIGNOR-256049
P10721	P22681	2	ubiquitination	down-regulates activity	0.618	KIT binds to and induces the phosphorylation of Cbl proteins, which in turn act as E3 ligases, mediating the ubiquitination and degradation of KIT and themselves. Tyrosine kinase binding and RING finger domains of Cbl are essential for Cbl-mediated ubiquitination and degradation of KIT.	SIGNOR-260104
P22681	P10721	2	phosphorylation	up-regulates activity	0.618	The activated KIT in turn induces phosphorylation and activation of Cbl proteins.	SIGNOR-279199
P42684	Q13671	2	phosphorylation	up-regulates	0.615	Rin1 binds to the abl sh3 and sh2 domains, and these inetractions stimulate abl2 catalytic activity. This leads to increased phosphorylation of crk and crkl	SIGNOR-136961
Q13671	P42684	2	phosphorylation	up-regulates activity	0.615	These findings suggested that RIN1 is phosphorylated by both ABL1 and ABL2.	SIGNOR-279676
P29350	P06239	2	phosphorylation	up-regulates activity	0.613	Two sites (Y-536 and Y-564) which are directly phosphorylated by Lck in vitro are also phosphorylated in vivo in LSTRA cells. .	SIGNOR-251387
P00533	P04626	2	binding	up-regulates	0.613	Although erbb-2 binds neither ligand, even in a heterodimeric receptor complex, it is the preferred heterodimer partner of the three other members, and it favors interaction with erbb-3.	SIGNOR-147838
P04626	P00533	2	phosphorylation	up-regulates activity	0.613	Induction of cancer cell migration by epidermal growth factor is initiated by specific phosphorylation of tyrosine 1248 of c-erbB-2 receptor via EGFR. \| In summary, c-erbB-2 up-regulation switches on the cell migration program by modulating the time course of PLC-gamma1 activation.	SIGNOR-251094
P06239	P29350	2	dephosphorylation	down-regulates activity	0.613	We demonstrate that shp-1 dephosphorylates the lymphoid-specific src family kinase lck at tyr-394. Because phosphorylation of tyr-394 activates lck, the fact that shp-1 specifically dephosphorylates this site suggests that shp-1 is a negative regulator of lck.	SIGNOR-106604
P03952	P00748	2	cleavage	up-regulates activity	0.606	FXIIa activates two serine proteinases, factor XI (FXI) and plasma prekallikrein (PK) that drive the coagulation and kallikrein–kinin systems, respectively	SIGNOR-263518
P00748	P03952	2	cleavage	up-regulates activity	0.606	FXIIa converts PK to the active protease PKa, which reciprocally activates more FXII\|In addition, PKa can initiate a further proteolysis of FXIIa into a ~30 kDa light chain fragment, termed β-FXIIa. The cleavage takes place at the peptide bond Arg353–Val354 and consequently, the active site released from the heavy chain and thus from surfaces.	SIGNOR-263520
Q05655	P12931	2	phosphorylation	up-regulates activity	0.602	Inhibition of Src decreased the cleavage of PKCdelta and modified the apoptotic responses of the cells to TRAIL and cisplatin, similar to effect of the PKCdeltaY332F mutant.\|These results demonstrate that the phosphorylation of tyrosine 332 by Src modulates the cleavage of PKCdelta and the sensitivity of glioma cells to TRAIL and cisplatin.	SIGNOR-278164
P12931	Q05655	2	phosphorylation	up-regulates activity	0.602	We conclude that treatment with either UV or PMA induces the phosphorylation of the PKC site Ser12 on c-SRC and that this specific phosphorylation event is significantly diminished in cells overexpressing PR55	SIGNOR-247974
P31749	Q15118	2	phosphorylation	up-regulates activity	0.601	Since both AKT-1, AKT-2, and SGK-1 are phosphorylated by PDK-1 and are themselves capable of phosphorylating DAF-16, their direct contact may reflect a temporary, regulatory interaction.\|This demonstrates that functional PDK-1 is required to activate AKT-1, AKT-2, and SGK-1 in vivo.	SIGNOR-278973
P46531	Q13573	2	binding	up-regulates	0.601	Contact with skip is required for biological activity of notchic. A mutation in the fourth ankyrin repeat that abolished notch signal transduction did not affect interaction with cbf1 but abolished interaction with skip.	SIGNOR-75788
Q13573	P46531	2	binding	up-regulates	0.601	Contact with skip is required for biological activity of notchic. A mutation in the fourth ankyrin repeat that abolished notch signal transduction did not affect interaction with cbf1 but abolished interaction with skip.	SIGNOR-86125
Q15118	P31749	2	phosphorylation	up-regulates activity	0.601	Using a phosphoproteomics screen, we now show that active Akt accumulates in the mitochondria during hypoxia and phosphorylates pyruvate dehydrogenase kinase 1 (PDK1) on Thr346 to inactivate the pyruvate dehydrogenase complex.	SIGNOR-277272
Q14469	Q06330	2	transcriptional regulation	up-regulates quantity	0.6	ligand-induced Notch signaling up-regulated HES1 mRNA expression within 1h and subsequently reduced expression of MyoD mRNA	SIGNOR-243178
Q06330	Q14469	2	binding	down-regulates	0.6	Here we show that hrt2 and hes1 interact with rbp-jkappa to negatively regulate notch-dependent activation of hrt and hes expression.	SIGNOR-146684
P19544	Q02962	2	transcriptional regulation	up-regulates quantity by expression	0.598	Cotransfection of Pax2 with the Wt1 reporter construct led to moderate activation of the Wt1 promoter.	SIGNOR-252290
Q02962	P19544	2	transcriptional regulation	down-regulates quantity by repression	0.598	A marked increase in WT1 protein levels coincided precisely with down-regulation of the Pax-2 gene in the individual precursor cells of the visceral glomerular epithelium, suggesting a direct effect of the WT1 repressor protein on Pax-2 regulatory elements. To examine whether WT1 could directly repress Pax-2 transcription, binding of WT1 to three high affinity sites in the 5' untranslated Pax-2 leader sequence was demonstrated by DNAseI footprinting analysis	SIGNOR-252298
Q07869	O00327	2	transcriptional regulation	up-regulates quantity by expression	0.596	We demonstrate that PPARalpha plays a specific role in the peripheral circadian control because it is required to maintain the circadian rhythm of the master clock gene brain and muscle Arnt-like protein 1 (bmal1) in vivo. This regulation occurs via a direct binding of PPARalpha on a potential PPARalpha response element located in the bmal1 promoter. Reversely, BMAL1 is an upstream regulator of PPARalpha gene expression.	SIGNOR-268025
O00327	Q07869	2	transcriptional regulation	up-regulates quantity by expression	0.596	We demonstrate that PPARalpha plays a specific role in the peripheral circadian control because it is required to maintain the circadian rhythm of the master clock gene brain and muscle Arnt-like protein 1 (bmal1) in vivo. This regulation occurs via a direct binding of PPARalpha on a potential PPARalpha response element located in the bmal1 promoter. Reversely, BMAL1 is an upstream regulator of PPARalpha gene expression.	SIGNOR-268024
P52735	P00533	2	phosphorylation	up-regulates	0.592	To understand the mechanism of egf-dependent vav2 activation, we examined first the egf-dependent phosphorylation sites on vav2 and the nature of interaction of vav2 with the activated egf receptor. Based on our in vitro and in vivo data all three tyrosine residues (142, 159, and 172) in the n-terminal domain of vav2 can be phosphorylated by the egf receptor.	SIGNOR-95980
P00533	P52735	2	binding	up-regulates	0.592	Oligomerization of receptor protein tyrosine kinases such as the epidermal growth factor receptor (egfr) by their cognate ligands leads to activation of the receptor.We Demonstrate that vav-2 is phosphorylated on tyrosine residues in response to egf and associates with the egfr in vivo.	SIGNOR-73874
Q13573	Q9Y618	2	binding	up-regulates	0.591	Protein-protein interaction assays demonstrated interaction between skip and the corepressor smrt.	SIGNOR-74227
Q9Y618	Q13573	2	binding	down-regulates	0.591	We present evidence that skip interacts with the cbf1 corepressor complex and that skip has a role in orchestrating the conversion of cbf1 from an smrt-hdac-tethered transcriptional repressor to a notchic-tethered activation complex.	SIGNOR-75785
P35236	Q16539	2	phosphorylation	down-regulates activity	0.59	The noncatalytic N terminus of HePTP binds Erk and p38 and is phosphorylated at Ser-72 and Thr-45 by these kinases. the N terminus of HePTP binds Erk and p38 but may release them upon phosphorylation.it is clear that phosphorylation of HePTP at Thr-45 and/or Ser-72 is not required for inhibition of MAP kinase. Rather, it seems that phosphorylation has the opposite effect, namely to lessen the inhibitory effect of HePTP.	SIGNOR-250109
Q16539	P35236	2	binding	down-regulates	0.59	Thus, beta(2)ar stimulation on a b cell phosphorylates and inactivates heptp in a gs/camp/pka-dependent manner to release bound p38 mapk, making more available for phosphorylation and subsequent ige regulation	SIGNOR-182525
P22681	Q96JA1	2	binding	up-regulates	0.589	We report upregulation of lrig1 transcript and protein upon egf stimulation, and physical association of the encoded protein with the four egfr orthologs of mammals. Upregulation of lrig1 is followed by enhanced ubiquitylation and degradation of egfr. The underlying mechanism involves recruitment of c-cbl, an e3 ubiquitin ligase that simultaneously ubiquitylates egfr and lrig1 and sorts them for degradation.	SIGNOR-127298
Q96JA1	P22681	2	ubiquitination	down-regulates	0.589	We report upregulation of lrig1 transcript and protein upon egf stimulation, and physical association of the encoded protein with the four egfr orthologs of mammals. Upregulation of lrig1 is followed by enhanced ubiquitylation and degradation of egfr. The underlying mechanism involves recruitment of c-cbl, an e3 ubiquitin ligase that simultaneously ubiquitylates egfr and lrig1 and sorts them for degradation.	SIGNOR-127289
P00533	P07948	2	phosphorylation	up-regulates activity	0.586	Taken together, our findings demonstrate that Yes and Lyn phosphorylate EGFR at Y1101 which influences EGFR nuclear translocation in this model of cetuximab resistance.	SIGNOR-279205
P07948	P00533	2	phosphorylation	up-regulates activity	0.586	EGFR phosphorylates p56 Lyn at Y32.\|In the presence of EGFR, p56 Lyn -mediated MCM7 phosphorylation was significantly augmented, suggesting that EGFR signaling potentiates p56 Lyn kinase activity for MCM7 phosphorylation.	SIGNOR-279369
Q15797	O43541	2	binding	down-regulates	0.579	Smad6 also inhibits bmp signaling by forming a complex with smad1 and by interfering with complex formation between smad1 and smad4	SIGNOR-103621
Q8N6T3	Q5S007	2	phosphorylation	down-regulates	0.579	Arfgap1 is an lrrk2 kinase substrate whose gap activity is inhibited by lrrk2. The phosphorylation of arfgap1 by lrrk2 was subjected to mass spectrometry to determine the sites of phosphorylation. There was 95.3% coverage and serines(s155, s246, s284) and threonine (t189, t216, t292) are phosphorylated by lrrk2. Mutational analysis of these serine and threonine amino acids to alanine reveals that no single amino acid is the predominant phospho-amino acid.	SIGNOR-196732
Q5S007	Q8N6T3	2	binding	up-regulates	0.579	The gtp hydrolysis activity of lrrk2 is markedly enhanced by arfgap1 supporting a role for arfgap1 as a gtpase-activating protein for lrrk2.Lrrk2 and arfgap1 interact in vitro in mammalian cells and in vivo in brain, and co-localize in the cytoplasm and at golgi membranes	SIGNOR-196264
O43541	Q15797	2	transcriptional regulation	up-regulates quantity	0.579	Chromatin immunoprecipitation (ChIP) revealed a subset of the BIG (BMP4 induced genes) signature, including Satb2, Smad6, Hand1, Gadd45γ and Gata3, that was bound by Smad1/5 in the developing mandible, revealing direct Smad-mediated regulation	SIGNOR-268935
P00747	P00750	2	binding	up-regulates activity	0.574	The conversion of plasminogen to plasmin can occur by several different mechanisms, but it appears that the most important in uiuo activator is tPA (2). tPA, M, = 70,000, is present in plasma as a single-chain serine protease, but proteolytic cleavage of the Agr275-Ile276 bond in tPA by plasmin yields a disulfide-linked two-chain enzyme	SIGNOR-263533
P12814	Q05397	2	phosphorylation	down-regulates activity	0.574	The cytoskeletal/non-muscle isoform of alpha-actinin is phosphorylated on its actin-binding domain by the focal adhesion kinase tyrosine 12 is the site of phosphorylation. The wild type recombinant protein was not phosphorylated in cells lacking the focal adhesion kinase (fak).Tyrosine phosphorylation reduced the amount of alpha-actinin that cosedimented with actin filaments.	SIGNOR-108329
P00750	P00747	2	cleavage	up-regulates activity	0.574	The conversion of plasminogen to plasmin can occur by several different mechanisms, but it appears that the most important in uiuo activator is tPA (2). tPA, M, = 70,000, is present in plasma as a single-chain serine protease, but proteolytic cleavage of the Agr275-Ile276 bond in tPA by plasmin yields a disulfide-linked two-chain enzyme	SIGNOR-263534
Q05397	P12814	2	binding	down-regulates activity	0.574	Consistent with the results obtained with COS-7 cells, coexpression of wild-type Œ±-actinin with PTP 1B in PTP 1B-null cells resulted in Src/Œ±-actinin binding and limited the interaction between FAK and Src	SIGNOR-261799
O75385	Q13131	2	phosphorylation	up-regulates activity	0.572	Ampk and ulk1 interact and that the latter is phosphorylated by ampk. This phosphorylation leads to the direct activation of ulk1 by ampk bypassing mtor-inhibition.	SIGNOR-173038
Q13131	O75385	2	phosphorylation	down-regulates activity	0.572	Ulk1/2 in turn phosphorylates all three subunits of ampk and thereby negatively regulates its activity.	SIGNOR-173047
P56178	P35548	2	binding	down-regulates activity	0.572	We demonstrate that dimerization by Msx and Dlx proteins is mediated through their homeodomains and that the residues required for this interaction correspond to those necessary for DNA binding. Unlike most other known examples of homeoprotein interactions, association of Msx and Dlx proteins does not promote cooperative DNA binding; instead, dimerization and DNA binding are mutually exclusive activities. Msx proteins act as transcriptional repressors and Dlx proteins act as activators, while in combination, Msx and Dlx proteins counteract each other's transcriptional activities.	SIGNOR-240990
P35548	P56178	2	binding	down-regulates activity	0.572	We demonstrate that dimerization by Msx and Dlx proteins is mediated through their homeodomains and that the residues required for this interaction correspond to those necessary for DNA binding. Unlike most other known examples of homeoprotein interactions, association of Msx and Dlx proteins does not promote cooperative DNA binding; instead, dimerization and DNA binding are mutually exclusive activities. Msx proteins act as transcriptional repressors and Dlx proteins act as activators, while in combination, Msx and Dlx proteins counteract each other's transcriptional activities.	SIGNOR-240925
P24941	P50613	2	phosphorylation	up-regulates activity	0.571	Phosphorylation of monomeric human CDK2 by CAK1 is more efficient than phosphorylation of the binary CDK2-cyclin A complex. Phosphorylated CDK2 exhibits histone H1 kinase activity corresponding to approximately 0.3% of that observed with the fully activated phosphorylated CDK2-cyclin A complex. Fluorescence measurements have shown that Thr160 phosphorylation increases the affinity of CDK2 for both histone substrate and ATP and decreases its affinity for ADP.	SIGNOR-250768
P50613	P24941	2	phosphorylation	up-regulates	0.571	Threonine-170 of cdk7 is phosphorylated in vitro by cdk2. Full activation of cdk7 requires phorylation of a conserved threonine residue at position 170 in its own t loop.	SIGNOR-85013
Q14511	O14965	2	phosphorylation	up-regulates activity	0.57	HEF1 interacts with AurA and is required for the activation of AurA kinase. Together, these data suggest a model in which an initial interaction of HEF1 with AurA prior to mitotic entry activates AurA, which then phosphorylates HEF1, promoting dissociation of the two proteins.	SIGNOR-262654
O14965	Q14511	2	binding	up-regulates activity	0.57	HEF1 interacts with AurA and is required for the activation of AurA kinase. Together, these data suggest a model in which an initial interaction of HEF1 with AurA prior to mitotic entry activates AurA, which then phosphorylates HEF1, promoting dissociation of the two proteins.	SIGNOR-262653
O15392	Q9NR28	2	binding	down-regulates	0.569	Diablo seem to function as a general iaps neutralizer by binding to these protein. Diablo promotes casp9 activation by binding to inhibitor of apoptosis proteins, iaps, and removing their inhibitory activity. mitochondrial survivin associated with smac/diablo, delaying its release.	SIGNOR-80212
Q9NR28	O15392	2	binding	down-regulates	0.569	Mitochondrial survivin associated with smac/diablo, delaying its release.	SIGNOR-155361
P27361	P06239	2	phosphorylation	up-regulates	0.566	The sh3 domain of lck modulates t-cell receptor-dependent activation of extracellular signal-regulated kinase through activation of raf-1.	SIGNOR-159168
P06239	P27361	2	phosphorylation	up-regulates activity	0.566	Phosphorylation at Ser-59 (or alternatively, its mutation to Glu) reverses the inhibition and allows interaction of the p56lck SH2 domain with p62.\|phosphotyrosine-independent binding of p62 to the p56lck SH2 domain appears to provide an alternative pathway for p56lck signaling that is regulated by Ser-59 phosphorylation.	SIGNOR-249469
P53355	P28482	2	phosphorylation	up-regulates	0.565	Dapk interacts with erk through a docking sequence within its death domain and is a substrate of erk. Phosphorylation of dapk at ser 735 by erk increases the catalytic activity of dapk both in vitro and in vivo	SIGNOR-132614
P28482	P53355	2	binding	down-regulates	0.565	Conversely, dapk promotes the cytoplasmic retention of erk, thereby inhibiting erk signaling in the nucleus.	SIGNOR-132610
O60885	P01106	2	null	down-regulates activity	0.562	Conversely, MYC inhibits BRD4's HAT activity, suggesting that MYC regulates its own transcription by limiting BRD4-mediated chromatin remodeling of its locus.	SIGNOR-262047
P01106	O60885	2	phosphorylation	down-regulates quantity by destabilization	0.562	We report that BRD4 phosphorylates MYC at Thr58, leading to MYC ubiquitination and degradation, thereby regulating MYC target genes.	SIGNOR-262046
O75151	Q14865	2	binding	up-regulates activity	0.56	We found that phosphorylated PHF2 then associates with ARID5B, a DNA-binding protein, and induce demethylation of methylated ARID5B. Assembly of the PHF2–ARID5B complex, its recruitment to target promoters, and its H3H9Me2 demethylase activity were dependent on PKA activity.	SIGNOR-264515
Q14865	O75151	2	binding	up-regulates activity	0.56	We found that phosphorylated PHF2 then associates with ARID5B, a DNA-binding protein, and induce demethylation of methylated ARID5B. Assembly of the PHF2–ARID5B complex, its recruitment to target promoters, and its H3H9Me2 demethylase activity were dependent on PKA activity.	SIGNOR-264514
P49841	O14965	2	phosphorylation	down-regulates activity	0.559	The recombinant human AURKA protein phosphorylated the GSK-3beta protein at Ser 9 in a concentration-dependent manner, in vitro.	SIGNOR-279357
O14965	P49841	2	phosphorylation	down-regulates activity	0.559	However, phosphorylation of AurA by GSK3B on S283/4 is known to promote autophosphorylation on S342 that is inhibitory to AurA activity, making it likely that GSK3B can govern AurA stability indirectly through conformational effects.\|In this study, GSK3B was proposed to promote FBXW7 targeting of AurA through priming a phospho-degron located in the kinase domain.	SIGNOR-279718
O15169	P48730	2	binding	up-regulates	0.556	We conclude that a major role of axin in the wnt is to provide the kinase activity that initiates the beta-catenin phosphorylation cascade at s45. This process is mediated by cki, the alfa, delta, or epsilon isoform, all detected in association with axin by lc/ms.	SIGNOR-87433
P17252	P19174	2	phosphorylation	up-regulates	0.556	Tnf-alfa binds to tnfr1 and activates pc-plc to induce pkcalfa and c-src activation, leading to tyrosine phosphorylation of ikkbeta at tyr188 and tyr199.	SIGNOR-99310
P19174	P17252	2	phosphorylation	down-regulates	0.556	The observation that pka also phosphorylates plc-yl on serine 1248 suggests that phosphorylation of this residue may be a common mechanism by which pkc and pka inhibit plc-yl.	SIGNOR-17905
O43379	P45983	2	phosphorylation	down-regulates quantity by destabilization	0.556	WDR62 is also negatively regulated by T1053 phosphorylation, leading to the recruitment of F-box and WD repeat domain-containing protein 7 (FBW7) and proteasomal degradation. \|JNK1 can induce the phosphorylation of WDR62 T1053	SIGNOR-271710
P48730	O15169	2	binding	up-regulates	0.556	Complex of axin and casein kinase i (cki) induces beta-catenin phosphorylation at a single site: serine 45 (s45).	SIGNOR-87401
P45983	O43379	2	relocalization	up-regulates activity	0.556	In the WT brain, the WDR62 scaffold organizes a protein complex including MEKK3, MKK4/7, and JNK1 to control NPC development during corticogenesis	SIGNOR-271718
P06748	Q8N726	2	binding	down-regulates quantity by destabilization	0.552	The Arf-NPM interaction seems to be critical in regulating the stability of both proteins. Arf, in fact, induces polyubiquitination and degradation of NPM and inhibits its effects on ribogenesis (18). NPM, instead, protects Arf from degradation and, surprisingly, antagonizes its ability to inhibit cell division	SIGNOR-245077
Q8N726	P06748	2	binding	up-regulates activity	0.552	The Arf-NPM interaction seems to be critical in regulating the stability of both proteins. Arf, in fact, induces polyubiquitination and degradation of NPM and inhibits its effects on ribogenesis (18). NPM, instead, protects Arf from degradation and, surprisingly, antagonizes its ability to inhibit cell division	SIGNOR-245073
Q99683	O95382	2	phosphorylation	up-regulates quantity by stabilization	0.551	ASK2 Activates ASK1 by Phosphorylation	SIGNOR-260832
O95382	Q99683	2	binding	up-regulates quantity by stabilization	0.551	C-terminal region of ASK1 binds to ASK2 and inhibits the degradation of ASK2	SIGNOR-260831
P08709	P00740	2	cleavage	up-regulates activity	0.55	The factor VII zymogen is cleaved at arginine 152 by a variety of proteases, including thrombin, factor IXa, factor Xa, and factor VIIa–tissue factor to produce the serine protease factor VIIa.	SIGNOR-263522
P00740	P08709	2	binding	up-regulates activity	0.55	TF has a high affinity for FVII and enables the trace levels (∼1% of the total FVII) of activated FVII (FVIIa) in the blood to cleave specific sites in the serine proteases FIX and FX, activating them into FIXa and FXa, respectively.	SIGNOR-263544
P04150	P10275	2	binding	down-regulates quantity by repression	0.547	Androgen and glucocorticoid receptor heterodimer formation. A possible mechanism for mutual inhibition of transcriptional activity	SIGNOR-48513
P10275	P04150	2	binding	down-regulates activity	0.547	Androgen and glucocorticoid receptor heterodimer formation. A possible mechanism for mutual inhibition of transcriptional activity.	SIGNOR-48516
P25490	P01106	2	binding	down-regulates activity	0.544	Inhibition of transcriptional regulator Yin-Yang-1 by association with c-Myc.Yin-Yang-1 (YY1) regulates the transcription of many genes, including the oncogenes c-fos and c-myc. Depending on the context, YY1 acts as a transcriptional repressor, a transcriptional activator, or a transcriptional initiator. In cotransfections, c-Myc inhibits both the repressor and the activator functions of YY1, which suggests that one way c-Myc acts is by modulating the activity of YY1.	SIGNOR-268795
P01106	P25490	2	transcriptional regulation	down-regulates quantity by repression	0.544	Inhibition of transcriptional regulator Yin-Yang-1 by association with c-Myc.Yin-Yang-1 (YY1) regulates the transcription of many genes, including the oncogenes c-fos and c-myc. Depending on the context, YY1 acts as a transcriptional repressor, a transcriptional activator, or a transcriptional initiator. In cotransfections, c-Myc inhibits both the repressor and the activator functions of YY1, which suggests that one way c-Myc acts is by modulating the activity of YY1.	SIGNOR-268794

P55211

P42574

2

cleavage

up-regulates activity

0.639

Active caspase-3 itself is able to process its upstream , caspase-8 and caspase-9, establishing a self-amplifying loop of caspase activation

SIGNOR-90397

P42574

P55211

2

cleavage

up-regulates activity

0.639

Following autoprocessing in the apoptosome, caspase-9 cleaves and activates caspase-3.

SIGNOR-133267

P12931

Q12913

2

phosphorylation

up-regulates activity

0.636

CK2-dependent phosphorylation of DEP-1 T1318 promotes Y1320 phosphorylation and Src activation upon VEGF stimulation.

SIGNOR-277877

Q13077

Q12933

2

binding

up-regulates

0.636

Our analysis indicates that traf1 and traf2 are associated with the cytoplasmic domain of tnf-r2 in a heterodimeric complex in which traf2 contacts the receptor directly. Traf1 interacts with tnf-r2 indirectly through heterodimer formation with traf2.

SIGNOR-35881

P08253

P01023

2

binding

down-regulates activity

0.636

Both PZP and a2M collagenase complexes incubated with gelatin demonstrated a significant inhibition of the catalytic activity| MMP-2 and MMP-9 cause a significant degradation of these bands and the background, a degradation which is prevented by both a2M and PZP.

SIGNOR-261803

P01023

P08253

2

cleavage

down-regulates quantity by destabilization

0.636

The complex formation was confirmed by the use of 125I-labeled matrix metalloproteinase-2. The cleavage sites in the "bait" regions following formation of high-molecular-weight complexes of matrix metalloproteinases with the alpha-macroglobulins were determined by protein sequence analysis. Pregnancy zone protein was cleaved at Thr693-Tyr694 and alpha2-macroglobulin at Gly679-Leu680 and Arg696-Leu697 by matrix metalloproteinase-2. Matrix metalloproteinase-9 cleaved alpha2-macroglobulin at the same site as matrix metalloproteinase-2, but cleavage of pregnancy zone protein was at Leu753-Ser754.|MMP-2 and MMP-9 cause a significant degradation of these bands and the background, a degradation which is prevented by both a2M and PZP.

SIGNOR-261739

P49840

P31749

2

phosphorylation

down-regulates

0.636

In response to insulin, gsk3a inhibited by phosphorylation at ser-21 by pkb/akt1;phosphorylation at this site causes a conformational change, preventing access of substrates to the active site.

SIGNOR-252589

Q12933

Q13077

2

binding

up-regulates

0.636

Traf1 and traf2 can form homo- and heterotypic dimers.

SIGNOR-34768

Q12913

P12931

2

phosphorylation

up-regulates activity

0.636

We demonstrate here that DEP-1 is phosphorylated in a Src- and Fyn-dependent manner on Y1311 and Y1320, which bind the Src SH2 domain. This allows DEP-1-catalyzed dephosphorylation of Src inhibitory Y529 and favors the VEGF-induced phosphorylation of Src substrates VE-cadherin and Cortactin.

SIGNOR-276373

Q07812

P10415

2

binding

down-regulates activity

0.636

Bcl-2 has the unique oncogenic role of extending cell survival by inhibiting a variety of apoptotic deaths. Bcl-2 exerts its action through heterodimerization with bax.

SIGNOR-36898

P31749

P49840

2

phosphorylation

down-regulates activity

0.636

GSK3_ negatively regulates AKT activation by phosphorylating AKT at T312 in the substrate binding site, which inhibited IL-1-induced AKT activation and function.

SIGNOR-252434

P10415

Q07812

2

binding

down-regulates activity

0.636

Bax shows extensive amino acid homology with Bcl-2 and forms homodimers and heterodimers with Bcl-2 in vivo. When Bax predominates, programed cell death is accelerated, and the death repressor activity of Bcl-2 is countered.

SIGNOR-249612

P36894

Q13873

2

phosphorylation

up-regulates

0.631

Bmp ligands bind to the bmp receptors bmpr1 and bmpr2, and bmpr2 then phosphorylates and activates bmpr1.

SIGNOR-180545

P23458

P14784

2

binding

up-regulates

0.631

In lymphocytes, binding of il-15 to the il-2/15rbg heterodimer induces jak1 activation that subsequently phosphorylates stat3 via the b-chain and jak3/stat5 activation via its g-chain

SIGNOR-204972

P14784

P23458

2

phosphorylation

up-regulates activity

0.631

In COS-7 cells, overexpression of Jak1 augmented phosphorylation of Y338 as well as Y392 and Y510. Y392 and Y510 were critical for IL-2-induced activation of signal transducers and activators of transcription (STAT proteins), Y338 was required for Shc-IL-2Rbeta association and for IL-2-induced tyrosine phosphorylation of Shc.

SIGNOR-251340

Q13873

P36894

2

binding

up-regulates

0.631

Using several complementary approaches, we investigated the formation of homomeric and heteromeric complexes between the two known bmp type i receptors

SIGNOR-75652

Q8IW41

P31152

2

phosphorylation

up-regulates activity

0.63

ERK3, ERK4 and p38 MAPK can all phosphorylate MK5 at Thr 182 , , , - ], but it is not known whether these enzymes also can phosphorylate Ser 115 and whether this modification contributes to ERK3-, ERK4-, or p38 MAPK -regulated subcellular localization of MK5.

SIGNOR-279072

P31152

Q8IW41

2

phosphorylation

up-regulates

0.63

This is due to mk5-dependent phosphorylation and only this retarded erk4 species is both phosphorylated on ser(186) and co-immunoprecipitates with wild-type mk5. We conclude that binding between erk4 and mk5 facilitates phosphorylation of ser(186) and stabilization of the erk4-mk5 complex.

SIGNOR-17069

P29992

Q9NQ66

2

binding

up-regulates

0.623

Plc-_1 stimulates hydrolysis of gq/11-bound gtp and acts as a gtpase-activating protein (gap) for its physiologic regulator, gq/11

SIGNOR-17239

Q9NQ66

P29992

2

binding

up-regulates activity

0.623

TRH-R1 receptor, which is coupled to Gq/11 protein, activates phospholipase C, mobilizes calcium and activates protein kinase C.

SIGNOR-267203

Q70Z35

P60484

2

binding

down-regulates activity

0.62

Here, we used cell biology, biochemistry, and genetic approaches to show that PTEN suppresses cell movement by blocking PREX2 GEF–catalyzed activation of the GTPase RAC1. PTEN binds PREX2 and directly inhibits GEF activity.

SIGNOR-259190

P17947

P15976

2

binding

down-regulates activity

0.62

GATA-1 represses PU.1 activity.We have in this report found that the GATA-1 transcription factor is capable of functionally interfering with the PU.1 protein and have provided evidence that this interference is mediated through interaction between the PU.1 ETS domain and the GATA-1 C-finger region.

SIGNOR-256050

P60484

Q70Z35

2

binding

down-regulates activity

0.62

Here, we report that P-REX2 interacts with PTEN via two interfaces. In summary, P-REX2 docks to the PDZ-BD of PTEN through its C-terminal domain, reads the phosphorylation state of the PTEN tail via the DH domain, and inhibits PTEN activity by unleashing the PH domain

SIGNOR-259189

P15976

P17947

2

binding

down-regulates activity

0.62

We find that PU.1 interacts directly with GATA-1, a zinc finger transcription factor required for erythroid differentiation. Interaction between PU.1 and GATA-1 requires intact DNA-binding domains in both proteins. PU.1 represses GATA-1-mediated transcriptional activation.

SIGNOR-256049

P10721

P22681

2

ubiquitination

down-regulates activity

0.618

KIT binds to and induces the phosphorylation of Cbl proteins, which in turn act as E3 ligases, mediating the ubiquitination and degradation of KIT and themselves. Tyrosine kinase binding and RING finger domains of Cbl are essential for Cbl-mediated ubiquitination and degradation of KIT.

SIGNOR-260104

P22681

P10721

2

phosphorylation

up-regulates activity

0.618

The activated KIT in turn induces phosphorylation and activation of Cbl proteins.

SIGNOR-279199

P42684

Q13671

2

phosphorylation

up-regulates

0.615

Rin1 binds to the abl sh3 and sh2 domains, and these inetractions stimulate abl2 catalytic activity. This leads to increased phosphorylation of crk and crkl

SIGNOR-136961

Q13671

P42684

2

phosphorylation

up-regulates activity

0.615

These findings suggested that RIN1 is phosphorylated by both ABL1 and ABL2.

SIGNOR-279676

P29350

P06239

2

phosphorylation

up-regulates activity

0.613

Two sites (Y-536 and Y-564) which are directly phosphorylated by Lck in vitro are also phosphorylated in vivo in LSTRA cells. .

SIGNOR-251387

P00533

P04626

2

binding

up-regulates

0.613

Although erbb-2 binds neither ligand, even in a heterodimeric receptor complex, it is the preferred heterodimer partner of the three other members, and it favors interaction with erbb-3.

SIGNOR-147838

P04626

P00533

2

phosphorylation

up-regulates activity

0.613

Induction of cancer cell migration by epidermal growth factor is initiated by specific phosphorylation of tyrosine 1248 of c-erbB-2 receptor via EGFR. | In summary, c-erbB-2 up-regulation switches on the cell migration program by modulating the time course of PLC-gamma1 activation.

SIGNOR-251094

P06239

P29350

2

dephosphorylation

down-regulates activity

0.613

We demonstrate that shp-1 dephosphorylates the lymphoid-specific src family kinase lck at tyr-394. Because phosphorylation of tyr-394 activates lck, the fact that shp-1 specifically dephosphorylates this site suggests that shp-1 is a negative regulator of lck.

SIGNOR-106604

P03952

P00748

2

cleavage

up-regulates activity

0.606

FXIIa activates two serine proteinases, factor XI (FXI) and plasma prekallikrein (PK) that drive the coagulation and kallikrein–kinin systems, respectively

SIGNOR-263518

P00748

P03952

2

cleavage

up-regulates activity

0.606

FXIIa converts PK to the active protease PKa, which reciprocally activates more FXII|In addition, PKa can initiate a further proteolysis of FXIIa into a ~30 kDa light chain fragment, termed β-FXIIa. The cleavage takes place at the peptide bond Arg353–Val354 and consequently, the active site released from the heavy chain and thus from surfaces.

SIGNOR-263520

Q05655

P12931

2

phosphorylation

up-regulates activity

0.602

Inhibition of Src decreased the cleavage of PKCdelta and modified the apoptotic responses of the cells to TRAIL and cisplatin, similar to effect of the PKCdeltaY332F mutant.|These results demonstrate that the phosphorylation of tyrosine 332 by Src modulates the cleavage of PKCdelta and the sensitivity of glioma cells to TRAIL and cisplatin.

SIGNOR-278164

P12931

Q05655

2

phosphorylation

up-regulates activity

0.602

We conclude that treatment with either UV or PMA induces the phosphorylation of the PKC site Ser12 on c-SRC and that this specific phosphorylation event is significantly diminished in cells overexpressing PR55

SIGNOR-247974

P31749

Q15118

2

phosphorylation

up-regulates activity

0.601

Since both AKT-1, AKT-2, and SGK-1 are phosphorylated by PDK-1 and are themselves capable of phosphorylating DAF-16, their direct contact may reflect a temporary, regulatory interaction.|This demonstrates that functional PDK-1 is required to activate AKT-1, AKT-2, and SGK-1 in vivo.

SIGNOR-278973

P46531

Q13573

2

binding

up-regulates

0.601

Contact with skip is required for biological activity of notchic. A mutation in the fourth ankyrin repeat that abolished notch signal transduction did not affect interaction with cbf1 but abolished interaction with skip.

SIGNOR-75788

Q13573

P46531

2

binding

up-regulates

0.601

Contact with skip is required for biological activity of notchic. A mutation in the fourth ankyrin repeat that abolished notch signal transduction did not affect interaction with cbf1 but abolished interaction with skip.

SIGNOR-86125

Q15118

P31749

2

phosphorylation

up-regulates activity

0.601

Using a phosphoproteomics screen, we now show that active Akt accumulates in the mitochondria during hypoxia and phosphorylates pyruvate dehydrogenase kinase 1 (PDK1) on Thr346 to inactivate the pyruvate dehydrogenase complex.

SIGNOR-277272

Q14469

Q06330

2

transcriptional regulation

up-regulates quantity

0.6

ligand-induced Notch signaling up-regulated HES1 mRNA expression within 1h and subsequently reduced expression of MyoD mRNA

SIGNOR-243178

Q06330

Q14469

2

binding

down-regulates

0.6

Here we show that hrt2 and hes1 interact with rbp-jkappa to negatively regulate notch-dependent activation of hrt and hes expression.

SIGNOR-146684

P19544

Q02962

2

transcriptional regulation

up-regulates quantity by expression

0.598

Cotransfection of Pax2 with the Wt1 reporter construct led to moderate activation of the Wt1 promoter.

SIGNOR-252290

Q02962

P19544

2

transcriptional regulation

down-regulates quantity by repression

0.598

A marked increase in WT1 protein levels coincided precisely with down-regulation of the Pax-2 gene in the individual precursor cells of the visceral glomerular epithelium, suggesting a direct effect of the WT1 repressor protein on Pax-2 regulatory elements. To examine whether WT1 could directly repress Pax-2 transcription, binding of WT1 to three high affinity sites in the 5' untranslated Pax-2 leader sequence was demonstrated by DNAseI footprinting analysis

SIGNOR-252298

Q07869

O00327

2

transcriptional regulation

up-regulates quantity by expression

0.596

We demonstrate that PPARalpha plays a specific role in the peripheral circadian control because it is required to maintain the circadian rhythm of the master clock gene brain and muscle Arnt-like protein 1 (bmal1) in vivo. This regulation occurs via a direct binding of PPARalpha on a potential PPARalpha response element located in the bmal1 promoter. Reversely, BMAL1 is an upstream regulator of PPARalpha gene expression.

SIGNOR-268025

O00327

Q07869

2

transcriptional regulation

up-regulates quantity by expression

0.596

We demonstrate that PPARalpha plays a specific role in the peripheral circadian control because it is required to maintain the circadian rhythm of the master clock gene brain and muscle Arnt-like protein 1 (bmal1) in vivo. This regulation occurs via a direct binding of PPARalpha on a potential PPARalpha response element located in the bmal1 promoter. Reversely, BMAL1 is an upstream regulator of PPARalpha gene expression.

SIGNOR-268024

P52735

P00533

2

phosphorylation

up-regulates

0.592

To understand the mechanism of egf-dependent vav2 activation, we examined first the egf-dependent phosphorylation sites on vav2 and the nature of interaction of vav2 with the activated egf receptor. Based on our in vitro and in vivo data all three tyrosine residues (142, 159, and 172) in the n-terminal domain of vav2 can be phosphorylated by the egf receptor.

SIGNOR-95980

P00533

P52735

2

binding

up-regulates

0.592

Oligomerization of receptor protein tyrosine kinases such as the epidermal growth factor receptor (egfr) by their cognate ligands leads to activation of the receptor.We Demonstrate that vav-2 is phosphorylated on tyrosine residues in response to egf and associates with the egfr in vivo.

SIGNOR-73874

Q13573

Q9Y618

2

binding

up-regulates

0.591

Protein-protein interaction assays demonstrated interaction between skip and the corepressor smrt.

SIGNOR-74227

Q9Y618

Q13573

2

binding

down-regulates

0.591

We present evidence that skip interacts with the cbf1 corepressor complex and that skip has a role in orchestrating the conversion of cbf1 from an smrt-hdac-tethered transcriptional repressor to a notchic-tethered activation complex.

SIGNOR-75785

P35236

Q16539

2

phosphorylation

down-regulates activity

0.59

The noncatalytic N terminus of HePTP binds Erk and p38 and is phosphorylated at Ser-72 and Thr-45 by these kinases. the N terminus of HePTP binds Erk and p38 but may release them upon phosphorylation.it is clear that phosphorylation of HePTP at Thr-45 and/or Ser-72 is not required for inhibition of MAP kinase. Rather, it seems that phosphorylation has the opposite effect, namely to lessen the inhibitory effect of HePTP.

SIGNOR-250109

Q16539

P35236

2

binding

down-regulates

0.59

Thus, beta(2)ar stimulation on a b cell phosphorylates and inactivates heptp in a gs/camp/pka-dependent manner to release bound p38 mapk, making more available for phosphorylation and subsequent ige regulation

SIGNOR-182525

P22681

Q96JA1

2

binding

up-regulates

0.589

We report upregulation of lrig1 transcript and protein upon egf stimulation, and physical association of the encoded protein with the four egfr orthologs of mammals. Upregulation of lrig1 is followed by enhanced ubiquitylation and degradation of egfr. The underlying mechanism involves recruitment of c-cbl, an e3 ubiquitin ligase that simultaneously ubiquitylates egfr and lrig1 and sorts them for degradation.

SIGNOR-127298

Q96JA1

P22681

2

ubiquitination

down-regulates

0.589

We report upregulation of lrig1 transcript and protein upon egf stimulation, and physical association of the encoded protein with the four egfr orthologs of mammals. Upregulation of lrig1 is followed by enhanced ubiquitylation and degradation of egfr. The underlying mechanism involves recruitment of c-cbl, an e3 ubiquitin ligase that simultaneously ubiquitylates egfr and lrig1 and sorts them for degradation.

SIGNOR-127289

P00533

P07948

2

phosphorylation

up-regulates activity

0.586

Taken together, our findings demonstrate that Yes and Lyn phosphorylate EGFR at Y1101 which influences EGFR nuclear translocation in this model of cetuximab resistance.

SIGNOR-279205

P07948

P00533

2

phosphorylation

up-regulates activity

0.586

EGFR phosphorylates p56 Lyn at Y32.|In the presence of EGFR, p56 Lyn -mediated MCM7 phosphorylation was significantly augmented, suggesting that EGFR signaling potentiates p56 Lyn kinase activity for MCM7 phosphorylation.

SIGNOR-279369

Q15797

O43541

2

binding

down-regulates

0.579

Smad6 also inhibits bmp signaling by forming a complex with smad1 and by interfering with complex formation between smad1 and smad4

SIGNOR-103621

Q8N6T3

Q5S007

2

phosphorylation

down-regulates

0.579

Arfgap1 is an lrrk2 kinase substrate whose gap activity is inhibited by lrrk2. The phosphorylation of arfgap1 by lrrk2 was subjected to mass spectrometry to determine the sites of phosphorylation. There was 95.3% coverage and serines(s155, s246, s284) and threonine (t189, t216, t292) are phosphorylated by lrrk2. Mutational analysis of these serine and threonine amino acids to alanine reveals that no single amino acid is the predominant phospho-amino acid.

SIGNOR-196732

Q5S007

Q8N6T3

2

binding

up-regulates

0.579

The gtp hydrolysis activity of lrrk2 is markedly enhanced by arfgap1 supporting a role for arfgap1 as a gtpase-activating protein for lrrk2.Lrrk2 and arfgap1 interact in vitro in mammalian cells and in vivo in brain, and co-localize in the cytoplasm and at golgi membranes

SIGNOR-196264

O43541

Q15797

2

transcriptional regulation

up-regulates quantity

0.579

Chromatin immunoprecipitation (ChIP) revealed a subset of the BIG (BMP4 induced genes) signature, including Satb2, Smad6, Hand1, Gadd45γ and Gata3, that was bound by Smad1/5 in the developing mandible, revealing direct Smad-mediated regulation

SIGNOR-268935

P00747

P00750

2

binding

up-regulates activity

0.574

The conversion of plasminogen to plasmin can occur by several different mechanisms, but it appears that the most important in uiuo activator is tPA (2). tPA, M, = 70,000, is present in plasma as a single-chain serine protease, but proteolytic cleavage of the Agr275-Ile276 bond in tPA by plasmin yields a disulfide-linked two-chain enzyme

SIGNOR-263533

P12814

Q05397

2

phosphorylation

down-regulates activity

0.574

The cytoskeletal/non-muscle isoform of alpha-actinin is phosphorylated on its actin-binding domain by the focal adhesion kinase tyrosine 12 is the site of phosphorylation. The wild type recombinant protein was not phosphorylated in cells lacking the focal adhesion kinase (fak).Tyrosine phosphorylation reduced the amount of alpha-actinin that cosedimented with actin filaments.

SIGNOR-108329

P00750

P00747

2

cleavage

up-regulates activity

0.574

The conversion of plasminogen to plasmin can occur by several different mechanisms, but it appears that the most important in uiuo activator is tPA (2). tPA, M, = 70,000, is present in plasma as a single-chain serine protease, but proteolytic cleavage of the Agr275-Ile276 bond in tPA by plasmin yields a disulfide-linked two-chain enzyme

SIGNOR-263534

Q05397

P12814

2

binding

down-regulates activity

0.574

Consistent with the results obtained with COS-7 cells, coexpression of wild-type Œ±-actinin with PTP 1B in PTP 1B-null cells resulted in Src/Œ±-actinin binding and limited the interaction between FAK and Src

SIGNOR-261799

O75385

Q13131

2

phosphorylation

up-regulates activity

0.572

Ampk and ulk1 interact and that the latter is phosphorylated by ampk. This phosphorylation leads to the direct activation of ulk1 by ampk bypassing mtor-inhibition.

SIGNOR-173038

Q13131

O75385

2

phosphorylation

down-regulates activity

0.572

Ulk1/2 in turn phosphorylates all three subunits of ampk and thereby negatively regulates its activity.

SIGNOR-173047

P56178

P35548

2

binding

down-regulates activity

0.572

We demonstrate that dimerization by Msx and Dlx proteins is mediated through their homeodomains and that the residues required for this interaction correspond to those necessary for DNA binding. Unlike most other known examples of homeoprotein interactions, association of Msx and Dlx proteins does not promote cooperative DNA binding; instead, dimerization and DNA binding are mutually exclusive activities. Msx proteins act as transcriptional repressors and Dlx proteins act as activators, while in combination, Msx and Dlx proteins counteract each other's transcriptional activities.

SIGNOR-240990

P35548

P56178

2

binding

down-regulates activity

0.572

We demonstrate that dimerization by Msx and Dlx proteins is mediated through their homeodomains and that the residues required for this interaction correspond to those necessary for DNA binding. Unlike most other known examples of homeoprotein interactions, association of Msx and Dlx proteins does not promote cooperative DNA binding; instead, dimerization and DNA binding are mutually exclusive activities. Msx proteins act as transcriptional repressors and Dlx proteins act as activators, while in combination, Msx and Dlx proteins counteract each other's transcriptional activities.

SIGNOR-240925

P24941

P50613

2

phosphorylation

up-regulates activity

0.571

Phosphorylation of monomeric human CDK2 by CAK1 is more efficient than phosphorylation of the binary CDK2-cyclin A complex. Phosphorylated CDK2 exhibits histone H1 kinase activity corresponding to approximately 0.3% of that observed with the fully activated phosphorylated CDK2-cyclin A complex. Fluorescence measurements have shown that Thr160 phosphorylation increases the affinity of CDK2 for both histone substrate and ATP and decreases its affinity for ADP.

SIGNOR-250768

P50613

P24941

2

phosphorylation

up-regulates

0.571

Threonine-170 of cdk7 is phosphorylated in vitro by cdk2. Full activation of cdk7 requires phorylation of a conserved threonine residue at position 170 in its own t loop.

SIGNOR-85013

Q14511

O14965

2

phosphorylation

up-regulates activity

0.57

HEF1 interacts with AurA and is required for the activation of AurA kinase. Together, these data suggest a model in which an initial interaction of HEF1 with AurA prior to mitotic entry activates AurA, which then phosphorylates HEF1, promoting dissociation of the two proteins.

SIGNOR-262654

O14965

Q14511

2

binding

up-regulates activity

0.57

HEF1 interacts with AurA and is required for the activation of AurA kinase. Together, these data suggest a model in which an initial interaction of HEF1 with AurA prior to mitotic entry activates AurA, which then phosphorylates HEF1, promoting dissociation of the two proteins.

SIGNOR-262653

O15392

Q9NR28

2

binding

down-regulates

0.569

Diablo seem to function as a general iaps neutralizer by binding to these protein. Diablo promotes casp9 activation by binding to inhibitor of apoptosis proteins, iaps, and removing their inhibitory activity. mitochondrial survivin associated with smac/diablo, delaying its release.

SIGNOR-80212

Q9NR28

O15392

2

binding

down-regulates

0.569

Mitochondrial survivin associated with smac/diablo, delaying its release.

SIGNOR-155361

P27361

P06239

2

phosphorylation

up-regulates

0.566

The sh3 domain of lck modulates t-cell receptor-dependent activation of extracellular signal-regulated kinase through activation of raf-1.

SIGNOR-159168

P06239

P27361

2

phosphorylation

up-regulates activity

0.566

Phosphorylation at Ser-59 (or alternatively, its mutation to Glu) reverses the inhibition and allows interaction of the p56lck SH2 domain with p62.|phosphotyrosine-independent binding of p62 to the p56lck SH2 domain appears to provide an alternative pathway for p56lck signaling that is regulated by Ser-59 phosphorylation.

SIGNOR-249469

P53355

P28482

2

phosphorylation

up-regulates

0.565

Dapk interacts with erk through a docking sequence within its death domain and is a substrate of erk. Phosphorylation of dapk at ser 735 by erk increases the catalytic activity of dapk both in vitro and in vivo

SIGNOR-132614

P28482

P53355

2

binding

down-regulates

0.565

Conversely, dapk promotes the cytoplasmic retention of erk, thereby inhibiting erk signaling in the nucleus.

SIGNOR-132610

O60885

P01106

2

null

down-regulates activity

0.562

Conversely, MYC inhibits BRD4's HAT activity, suggesting that MYC regulates its own transcription by limiting BRD4-mediated chromatin remodeling of its locus.

SIGNOR-262047

P01106

O60885

2

phosphorylation

down-regulates quantity by destabilization

0.562

We report that BRD4 phosphorylates MYC at Thr58, leading to MYC ubiquitination and degradation, thereby regulating MYC target genes.

SIGNOR-262046

O75151

Q14865

2

binding

up-regulates activity

0.56

We found that phosphorylated PHF2 then associates with ARID5B, a DNA-binding protein, and induce demethylation of methylated ARID5B. Assembly of the PHF2–ARID5B complex, its recruitment to target promoters, and its H3H9Me2 demethylase activity were dependent on PKA activity.

SIGNOR-264515

Q14865

O75151

2

binding

up-regulates activity

0.56

We found that phosphorylated PHF2 then associates with ARID5B, a DNA-binding protein, and induce demethylation of methylated ARID5B. Assembly of the PHF2–ARID5B complex, its recruitment to target promoters, and its H3H9Me2 demethylase activity were dependent on PKA activity.

SIGNOR-264514

P49841

O14965

2

phosphorylation

down-regulates activity

0.559

The recombinant human AURKA protein phosphorylated the GSK-3beta protein at Ser 9 in a concentration-dependent manner, in vitro.

SIGNOR-279357

O14965

P49841

2

phosphorylation

down-regulates activity

0.559

However, phosphorylation of AurA by GSK3B on S283/4 is known to promote autophosphorylation on S342 that is inhibitory to AurA activity, making it likely that GSK3B can govern AurA stability indirectly through conformational effects.|In this study, GSK3B was proposed to promote FBXW7 targeting of AurA through priming a phospho-degron located in the kinase domain.

SIGNOR-279718

O15169

P48730

2

binding

up-regulates

0.556

We conclude that a major role of axin in the wnt is to provide the kinase activity that initiates the beta-catenin phosphorylation cascade at s45. This process is mediated by cki, the alfa, delta, or epsilon isoform, all detected in association with axin by lc/ms.

SIGNOR-87433

P17252

P19174

2

phosphorylation

up-regulates

0.556

Tnf-alfa binds to tnfr1 and activates pc-plc to induce pkcalfa and c-src activation, leading to tyrosine phosphorylation of ikkbeta at tyr188 and tyr199.

SIGNOR-99310

P19174

P17252

2

phosphorylation

down-regulates

0.556

The observation that pka also phosphorylates plc-yl on serine 1248 suggests that phosphorylation of this residue may be a common mechanism by which pkc and pka inhibit plc-yl.

SIGNOR-17905

O43379

P45983

2

phosphorylation

down-regulates quantity by destabilization

0.556

WDR62 is also negatively regulated by T1053 phosphorylation, leading to the recruitment of F-box and WD repeat domain-containing protein 7 (FBW7) and proteasomal degradation. |JNK1 can induce the phosphorylation of WDR62 T1053

SIGNOR-271710

P48730

O15169

2

binding

up-regulates

0.556

Complex of axin and casein kinase i (cki) induces beta-catenin phosphorylation at a single site: serine 45 (s45).

SIGNOR-87401

P45983

O43379

2

relocalization

up-regulates activity

0.556

In the WT brain, the WDR62 scaffold organizes a protein complex including MEKK3, MKK4/7, and JNK1 to control NPC development during corticogenesis

SIGNOR-271718

P06748

Q8N726

2

binding

down-regulates quantity by destabilization

0.552

The Arf-NPM interaction seems to be critical in regulating the stability of both proteins. Arf, in fact, induces polyubiquitination and degradation of NPM and inhibits its effects on ribogenesis (18). NPM, instead, protects Arf from degradation and, surprisingly, antagonizes its ability to inhibit cell division

SIGNOR-245077

Q8N726

P06748

2

binding

up-regulates activity

0.552

The Arf-NPM interaction seems to be critical in regulating the stability of both proteins. Arf, in fact, induces polyubiquitination and degradation of NPM and inhibits its effects on ribogenesis (18). NPM, instead, protects Arf from degradation and, surprisingly, antagonizes its ability to inhibit cell division

SIGNOR-245073

Q99683

O95382

2

phosphorylation

up-regulates quantity by stabilization

0.551

ASK2 Activates ASK1 by Phosphorylation

SIGNOR-260832

O95382

Q99683

2

binding

up-regulates quantity by stabilization

0.551

C-terminal region of ASK1 binds to ASK2 and inhibits the degradation of ASK2

SIGNOR-260831

P08709

P00740

2

cleavage

up-regulates activity

0.55

The factor VII zymogen is cleaved at arginine 152 by a variety of proteases, including thrombin, factor IXa, factor Xa, and factor VIIa–tissue factor to produce the serine protease factor VIIa.

SIGNOR-263522

P00740

P08709

2

binding

up-regulates activity

0.55

TF has a high affinity for FVII and enables the trace levels (∼1% of the total FVII) of activated FVII (FVIIa) in the blood to cleave specific sites in the serine proteases FIX and FX, activating them into FIXa and FXa, respectively.

SIGNOR-263544

P04150

P10275

2

binding

down-regulates quantity by repression

0.547

Androgen and glucocorticoid receptor heterodimer formation. A possible mechanism for mutual inhibition of transcriptional activity

SIGNOR-48513

P10275

P04150

2

binding

down-regulates activity

0.547

Androgen and glucocorticoid receptor heterodimer formation. A possible mechanism for mutual inhibition of transcriptional activity.

SIGNOR-48516

P25490

P01106

2

binding

down-regulates activity

0.544

Inhibition of transcriptional regulator Yin-Yang-1 by association with c-Myc.Yin-Yang-1 (YY1) regulates the transcription of many genes, including the oncogenes c-fos and c-myc. Depending on the context, YY1 acts as a transcriptional repressor, a transcriptional activator, or a transcriptional initiator. In cotransfections, c-Myc inhibits both the repressor and the activator functions of YY1, which suggests that one way c-Myc acts is by modulating the activity of YY1.

SIGNOR-268795

P01106

P25490

2

transcriptional regulation

down-regulates quantity by repression

0.544

Inhibition of transcriptional regulator Yin-Yang-1 by association with c-Myc.Yin-Yang-1 (YY1) regulates the transcription of many genes, including the oncogenes c-fos and c-myc. Depending on the context, YY1 acts as a transcriptional repressor, a transcriptional activator, or a transcriptional initiator. In cotransfections, c-Myc inhibits both the repressor and the activator functions of YY1, which suggests that one way c-Myc acts is by modulating the activity of YY1.

SIGNOR-268794