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
P31749	P53804	2	ubiquitination	down-regulates quantity by destabilization	0.395	TTC3 is an Akt-specific E3 ligase that binds to phosphorylated Akt and facilitates its ubiquitination and degradation within the nucleus	SIGNOR-252436
Q99576	O43524	2	transcriptional regulation	up-regulates quantity by expression	0.395	We have analyzed the promoter of human gilz (glucocorticoid-induced leucine zipper), a dexamethasone-inducible gene that is involved in regulating apoptosis, and identified six glucocorticoid (GC)-responsive elements and three Forkhead responsive elements (FHREs).	SIGNOR-255950
P53804	P31749	2	phosphorylation	up-regulates	0.395	Phosphorylation of ttc3 at ser378 is required for efficient biological function together, these observations support that ttc3 is a phosphorylation target of akt both in an in vitro and in a cellular context	SIGNOR-252508
O43524	Q99576	2	relocalization	down-regulates activity	0.395	GILZ inhibits FOXO1, FOXO3, and FOXO4 transcriptional activities measured with natural or synthetic FOXO-responsive promoters in HL-60 cells.	SIGNOR-256147
P15172	P06400	2	binding	up-regulates	0.394	Cycline/cdk2 blocks myod-induced gene expression through the phosphorylation of rb, preventing rb from binding and transactivating myod, and triggering s phase entry instead of differentiation.	SIGNOR-176563
P06400	P15172	2	transcriptional regulation	up-regulates quantity by expression	0.394	Here we report that, at the onset of differentiation, activation by MyoD of the Rb, p21, and cyclin D3 genes occurs in the absence of new protein synthesis and with the requirement of the p300 transcriptional coactivator.	SIGNOR-238532
P42680	Q9ULZ2	2	binding	up-regulates activity	0.392	In 293 cells expressing recombinant BRDG1 and various PTKs, Tec and Pyk2, but not Btk, Bmx, Lyn, Syk, or c-Abl, induced marked phosphorylation of BRDG1 on tyrosine residues. BRDG1 was also phosphorylated by Tec directly in vitro. Furthermore, BRDG1 was shown to participate in a positive feedback loop by increasing the activity of Tec. BRDG1 thus appears to function as a docking protein acting downstream of Tec in BCR signaling. BRDG1 may activate Tec by disrupting an intramolecular interaction.	SIGNOR-261819
P35548	Q07687	2	binding	down-regulates activity	0.392	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-240911
Q9ULZ2	P42680	2	phosphorylation	up-regulates activity	0.392	In 293 cells expressing recombinant BRDG1 and various PTKs, Tec and Pyk2, but not Btk, Bmx, Lyn, Syk, or c-Abl, induced marked phosphorylation of BRDG1 on tyrosine residues. BRDG1 was also phosphorylated by Tec directly in vitro. Efficient phosphorylation of BRDG1 by Tec required the PH and SH2 domains as well as the kinase domain of the latter. Furthermore, BRDG1 was shown to participate in a positive feedback loop by increasing the activity of Tec. BRDG1 transcripts are abundant in the human B cell line Ramos, and the endogenous protein underwent tyrosine phosphorylation in response to BCR stimulation. BRDG1 thus appears to function as a docking protein acting downstream of Tec in BCR signaling.	SIGNOR-261817
Q07687	P35548	2	binding	down-regulates activity	0.392	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-240932
P28360	P56178	2	binding	down-regulates activity	0.389	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-240921
P56178	P28360	2	binding	down-regulates activity	0.389	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-240987
Q13315	Q9NQS1	2	binding	up-regulates activity	0.381	These data suggest that Aven overexpression can activate ATM and that Aven phosphorylation in a positive feedback loop enforces Aven activity, making it a more potent ATM activator.	SIGNOR-262638
Q9NQS1	Q13315	2	phosphorylation	up-regulates activity	0.381	Aven is also a substrate of the ATM kinase. Mutation of ATM-mediated phosphorylation sites on Aven reduced its ability to activate ATM, suggesting that Aven activation of ATM after DNA damage is enhanced by ATM-mediated Aven phosphorylation. We found that mutating S135 and S308 sites to Alanine largely dampened Aven’s phosphorylation by ATM (though some phosphorylation remained, due to either a contaminating kinase or an unidentified ATM phosphorylation site).	SIGNOR-262636
O95551	Q9Y4K3	2	ubiquitination	up-regulates activity	0.378	TTRAP is ubiquitylated by TRAF6 and promotes TRAF6 dependent ubiquitylation of TAK1.\|In addition, we noted that the presence of TRAF6 strengthened the interaction between TTRAP and the TGF-\u03b2 receptor complex (see also later).	SIGNOR-278717
Q9Y4K3	O95551	2	binding	up-regulates activity	0.378	TTRAP associates with TRAF6.The TAK1-TTRAP-TRAF6 complex is stabilized by ubiquitylation and recruited to TβRI.	SIGNOR-277189
P04637	P49915	2	binding	up-regulates	0.378	In response to genotoxic stress or nucleotide deprivation, gmps becomes nuclear and facilitates p53 stabilization by promoting its transfer from mdm2 to a gmps-usp7 deubiquitylation complex.	SIGNOR-204409
P49915	P04637	2	transcriptional regulation	down-regulates quantity by repression	0.378	Herein, we identified GMP synthetase (GMPS), a key enzyme of de novo purine biosynthesis, as an important p53 repression target using a large-scale proteomics approach. This p53-mediated repression of GMPS could be validated by immunoblotting in Sk-Hep1, HepG2, and HuH6 cells.	SIGNOR-267342
Q15118	P31751	2	phosphorylation	up-regulates activity	0.375	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-277271
P31751	Q15118	2	phosphorylation	up-regulates activity	0.375	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-279248
Q13546	Q9UHD2	2	phosphorylation	down-regulates activity	0.373	Our data clearly indicate that TBK1 can directly phosphorylate RIPK1 at T189.\|TBK1 inhibits RIPK1 by direct phosphorylation.	SIGNOR-279388
Q9UHD2	Q13546	2	phosphorylation	up-regulates activity	0.373	Additionally, RIPK1-dependent hyper-phosphorylation of TBK1 in Casp8 Ripk3 cells occurred during MNV-1 infection (Figure 4F).\|RIPK1 and its kinase activity were required to promote increased TBK1 phosphorylation in the absence of caspase-8 (Figure 3E), suggesting that RIPK1 may promote TBK1 activation.	SIGNOR-279278
P49841	Q9UKA4	2	binding	down-regulates activity	0.372	A-kinase anchoring protein 220 (AKAP220) is a multivalent anchoring protein that can sequester a variety of signal transduction enzymes. These include protein kinase A (PKA) and glycogen synthase kinase 3beta (GSK3beta). Using a combination of molecular and cellular approaches we show that GSK3beta phosphorylation of Thr-1132 on AKAP220 initiates recruitment of this kinase into the enzyme scaffold. We also find that AKAP220 anchors GSK3beta and its substrate beta-catenin in membrane ruffles.	SIGNOR-264817
Q9UKA4	P49841	2	phosphorylation	down-regulates activity	0.372	A-kinase anchoring protein 220 (AKAP220) is a multivalent anchoring protein that can sequester a variety of signal transduction enzymes. These include protein kinase A (PKA) and glycogen synthase kinase 3beta (GSK3beta). Using a combination of molecular and cellular approaches we show that GSK3beta phosphorylation of Thr-1132 on AKAP220 initiates recruitment of this kinase into the enzyme scaffold. We also find that AKAP220 anchors GSK3beta and its substrate beta-catenin in membrane ruffles.	SIGNOR-264816
Q13351	Q01543	2	binding	down-regulates activity	0.371	FLI-1 represses the transcriptional activity of EKLF.Our data indicate that the ETS domain of FLI-1 is absolutely required to inhibit EKLF activity. Since the FLI-1 ETS domain interacts with the DNA binding domain of EKLF, one possibility could be that FLI-1 inhibits the binding of EKLF to its DNA targets	SIGNOR-256044
Q01543	Q13351	2	binding	down-regulates activity	0.371	The present study also shows that EKLF itself inhibits FLI-1 activity. As suggested above for the inhibition of EKLF activity, the inhibition of FLI-1 activity most probably involves the indirect recruitment of EKLF to FLI-1 target promoters by protein-protein interaction.	SIGNOR-256046
P12931	Q96AC1	2	binding	up-regulates activity	0.37	Here we report that Src binds to and phosphorylates Kindlin-2 at Y193. Reciprocally, Kindlin-2-Y193 phosphorylation activates and maintains Src kinase activity. Kindlin-2-Y193 phosphorylation is also involved in its binding capacity with Migfilin and the recruitment of Migfilin to the focal adhesions. Functionally, we demonstrate that Kindlin-2-Y193 phosphorylation regulates Kindlin-2-mediated cell spreading and migration.	SIGNOR-266101
Q96AC1	P12931	2	phosphorylation	up-regulates activity	0.37	Here we report that Src binds to and phosphorylates Kindlin-2 at Y193. Reciprocally, Kindlin-2-Y193 phosphorylation activates and maintains Src kinase activity. Kindlin-2-Y193 phosphorylation is also involved in its binding capacity with Migfilin and the recruitment of Migfilin to the focal adhesions. Functionally, we demonstrate that Kindlin-2-Y193 phosphorylation regulates Kindlin-2-mediated cell spreading and migration.	SIGNOR-266100
P06213	P29350	2	dephosphorylation	down-regulates	0.359	Finally, we have tested the set of ptps for their ability to dephosphorylate a phosphopeptide corresponding to the irk autophosphorylation site. tc-ptp, sap-1, and ptp-1b all tested positive, but ptp-? Showed no activity, although the same gst-ptp preparation could efficiently convert pnpp (tablei). Interestingly, many other ptps showed activity, namely dep-1, glepp-1, lar, ptp-?, -?, -?, And shp-1.	SIGNOR-75938
P29350	P06213	2	phosphorylation	up-regulates	0.359	Insulin stimulates the phosphorylation of tyr538 and the catalytic activity of ptp1c, a protein tyrosine phosphatase with src homology-2 domains. these results suggest that ptp1c is a target protein for the insulin receptor tyrosine kinase	SIGNOR-26870
P68400	P06493	2	phosphorylation	up-regulates	0.355	Four residues within this domain, thr-344, thr-360, ser-362, and ser-370, conform to the minimal consensus sequence for p34cdc2 phosphorylationthe high stoichiometry of phosphorylation suggests that phosphorylation could regulate functional properties of ckii and that it could in some way participate in the burst of phosphorylation that accompanies the activation of p34graphic at the ggraphic-m transition	SIGNOR-29525
P06493	P68400	2	phosphorylation	up-regulates	0.355	Additionally, transfection of cdc2 with a mutation at ser(39) to ala, which is the ck2 phosphorylation site, partially inhibits cell cycle progression in g(1) to g(2) phase following 6-tg treatment.	SIGNOR-134846
Q05923	P31152	2	phosphorylation	up-regulates activity	0.353	However, co-expression of ERK4 significantly increased the half-life of DUSP2 (XREF_FIG).\|In support of the latter notion we have shown that wild-type ERK4 can phosphorylate DUSP2 in vitro and future studies will be aimed at identifying the relevant site (s) of modification and determining their influence on DUSP2 stability.	SIGNOR-278959
P31152	Q05923	2	dephosphorylation	down-regulates activity	0.353	DUSP2 can dephosphorylate both ERK3 and ERK4 when expressed in mammalian cells.\|Finally, we demonstrate that DUSP2 inhibits ERK3 and ERK4 mediated activation of MK5.	SIGNOR-277068
Q13191	Q06418	2	phosphorylation	up-regulates activity	0.35	To test whether phosphorylation of Cbl-b at Tyr133 and/or Tyr363 by Tyro3 is important for its ubiquitin ligase function, we examined the ubiquitination of the Cbl-b mutants and Tyro3.	SIGNOR-279577
Q06418	Q13191	2	ubiquitination	up-regulates activity	0.35	Consistent with these data, we also found that Tyro3 is ubiquitinated by Cbl-b.\|These data suggest that not only was Tyro3 a ubiquitination target of Cbl-b, but also that Cbl-b was a phosphorylation target of Tyro3.	SIGNOR-278807
P14780	P20742	2	binding	down-regulates activity	0.349	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-261802
P20742	P14780	2	cleavage	down-regulates quantity by destabilization	0.349	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-261785
Q12986	P11940	2	binding	up-regulates activity	0.344	We identifiednew protein partners of NFX1-123, including several cytoplasmic poly(A) binding proteins (PABPCs) thatinteracted with NFX1-123 through its N-terminal PAM2 motif. Central to our findings were our observations that PABPCs copurify with NFX1-123, that a PAM2 motif is present in NFX1, and this motif and the PABPCs are important in the enhancement of hTERT activity by NFX1-123.	SIGNOR-261052
P11940	Q12986	2	binding	up-regulates activity	0.344	NFX1-123 augments the activation of hTERT expression through interactions with PABPCs	SIGNOR-226011
P00519	Q13043	2	phosphorylation	down-regulates	0.343	Here, we identify clk1, clk4, mst1, mst2 and ttk (also known as mps1) as novel thr735 kinases in vitro / phosphorylation of thr735 in c-abl is critical for binding to 14-3-3	SIGNOR-181060
Q13043	P00519	2	phosphorylation	up-regulates activity	0.343	In the present study, we demonstrate that the protein kinase c-Abl phosphorylates MST1 at Y433, which triggers the stabilization and activation of MST1.	SIGNOR-260927
Q10571	Q09472	2	binding	up-regulates	0.342	Our results indicate that mn1 is a transcription coactivator rather than a sequence-specific transcription factor, and that it may stimulate rar/rxr-mediated transcription through interaction with p160 and p300.	SIGNOR-97899
Q09472	Q10571	2	binding	up-regulates activity	0.342	Taken together, our results indicate that MN1 is a transcription coactivator rather than a sequence-specific transcription factor, and that it may stimulate RAR/RXR-mediated transcription through interaction with p160 and p300.	SIGNOR-256020
P35790	P12931	2	phosphorylation	up-regulates activity	0.336	We find that CHKA forms a complex with EGFR in a c-Src-dependent manner. Endogenous CHKA and EGFR co-immunoprecipitated from a variety of breast cancer cell lines and immortalized mammary epithelial cells. CHKA interacted with the EGFR kinase domain upon c-Src co-overexpression and was phosphorylated in a c-Src-dependent manner on Y197 and Y333.	SIGNOR-266350
P12931	P35790	2	phosphorylation	down-regulates activity	0.336	Figure XREF_FIG shows that even though Chk phosphorylated Tyr 527 of Src to a level much lower than that of Csk, it was a much more efficient inhibitor of Src kinase activity.\|These results suggest that Chk inhibited Src with a mechanism independent of Tyr-527 phosphorylation.	SIGNOR-279731
Q96KG7	O95477	2	binding	up-regulates activity	0.332	ABCA1 and MEGF10 interact during engulfment. MEGF10 function can be modulated by the ATP binding cassette transporter ABCA1, ortholog to CED-7. by the combined use of cellular and biochemical approaches we provide evidence that ABCA1 and MEGF10 interact at the molecular level.	SIGNOR-265164
O95477	Q96KG7	2	binding	up-regulates activity	0.332	ABCA1 and MEGF10 interact during engulfment. MEGF10 function can be modulated by the ATP binding cassette transporter ABCA1, ortholog to CED-7. by the combined use of cellular and biochemical approaches we provide evidence that ABCA1 and MEGF10 interact at the molecular level.	SIGNOR-265165
P20742	P08253	2	cleavage	down-regulates quantity by destabilization	0.329	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-261796
P08253	P20742	2	binding	down-regulates activity	0.329	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-261804
P04637	Q6UB99	2	binding	up-regulates activity	0.308	Ankyrin repeat domain 11, ANKRD11 (also known as ANR11 or ANCO1), was found to be a novel p53-interacting protein that enhanced the transcriptional activity of p53. In addition, ANKRD11 itself was found to be a novel p53 target gene. These findings demonstrate a role for ANKRD11 as a p53 coactivator and suggest the involvement of ANKRD11 in a regulatory feedback loop with p53.	SIGNOR-266734
Q6UB99	P04637	2	transcriptional regulation	up-regulates quantity by expression	0.308	Ankyrin repeat domain 11, ANKRD11 (also known as ANR11 or ANCO1), was found to be a novel p53-interacting protein that enhanced the transcriptional activity of p53. In addition, ANKRD11 itself was found to be a novel p53 target gene. These findings demonstrate a role for ANKRD11 as a p53 coactivator and suggest the involvement of ANKRD11 in a regulatory feedback loop with p53.	SIGNOR-266735
P42684	P09619	2	phosphorylation	up-regulates activity	0.303	PDGFRβ directly phosphorylates multiple novel sites on the N-terminal half of Abl2, including Y116, Y139, and Y161 within the Src homology 3 domain, and Y299, Y303, and Y310 on the kinase domain.We also found that PDGFRβ-mediated phosphorylation of Abl2 in vitro activates Abl2 kinase activity, but mutation of these four tyrosines (Y116, Y161, Y272, and Y310) to phenylalanine abrogated PDGFRβ-mediated activation of Abl2.	SIGNOR-277303
O15355	Q13315	2	phosphorylation	up-regulates activity	0.303	ATM indeed mediated PPM1G phosphorylation at S183, and mutation of this residue (S183A) abrogated detection with the phospho-specific antibody	SIGNOR-255591
P09619	P42684	2	phosphorylation	up-regulates activity	0.303	C-Abl phosphorylates three tyrosine residues on PDGFR-beta (Y686, Y934, Y970), while Arg only phosphorylatesY686. Y686 and Y934 reside in PDGFR-beta catalytic domains, while Y970 is in the C-terminal tail. Using site-directed mutagenesis, we show that Abl-dependent phosphorylation of PDGFR-beta activates PDGFR-beta activity, in vitro, but serves to downregulate PDGFR-mediated chemotaxis.	SIGNOR-276140
Q13315	O15355	2	dephosphorylation	down-regulates activity	0.303	After ionizing radiation, dephosphorylation of USP7S by the ATM-dependent protein phosphatase PPM1G leads to USP7S downregulation, followed by Mdm2 downregulation and accumulation of p53. \|ATM Dependent Downregulation of USP7 and HAUSP by PPM1G Activates p53 Response to DNA Damage.\|DNA Damage Leads to ATM Dependent USP7S Dephosphorylation by PPM1G.	SIGNOR-277158
P33981	O96017	2	phosphorylation	up-regulates	0.292	Phosphorylation at ttk/hmps1 thr288 is enhanced by chk2 in vitro and in vivo after ir	SIGNOR-242665
O96017	P33981	2	phosphorylation	up-regulates	0.292	Ttk/hmps1 directly phosphorylates chk2 on thr-68 in vitro.ablation of ttk expression using small interfering rna results not only in reduced chk2 thr-68 phosphorylation, but also in impaired growth arrest. Our results are consistent with a model in which ttk functions upstream from chk2 in response to dna damage	SIGNOR-132665
P49841	Q16539	2	phosphorylation	down-regulates	0.29	However p38alfa also inactivates gsk3b by direct phosphorilation of the c-terminal residue ser389. this non-canonicl p38 mapk-dependent phosphorilation of gsk3b seems to occur primarily in the brain and thymocytes.	SIGNOR-157548
Q16539	P49841	2	binding	down-regulates	0.29	Here we show that similar to the interaction with traf4 and axin, the kinase domain of mekk4 interacts with the multifunctional serine/threonine kinase gsk3beta. Gsk3beta binding to mekk4 blocks mekk4 dimerization that is required for mekk4 activation, effectively inhibiting mekk4 stimulation of the jnk and p38 mapk pathways	SIGNOR-157544
Q96KB5	P28482	2	phosphorylation	up-regulates activity	0.283	In the present study, Ser32 was revealed to be a novel phosphorylated site on TOPK that could be activated by ERK2.\|TOPK/PBK is phosphorylated by ERK2 at serine 32, promotes tumorigenesis and is involved in sorafenib resistance in RCC.	SIGNOR-279744
Q15788	Q8IXJ9	2	binding	up-regulates activity	0.283	We also show that ASXL1 associates specifically with SRC-1 and cooperates synergistically in the transcriptional activation. Further data indicated that the transactivation domain (AD; amino acids 300–655) of ASXL1, newly defined in this study, interacts with the C-terminal AD2 (amino acids 1217–1441) of SRC-1, suggesting that one AD cooperates with the other AD in transcriptional activation by RAR.	SIGNOR-255931
P28482	Q96KB5	2	phosphorylation	up-regulates activity	0.283	Phosphorylation of ELK1 or ERK2 increased dramatically compared with controls and suggested that TOPK or ERK2 could enhance ERK2 or TOPK kinase activity by respective and mutual phosphorylation of each other.\|The results indicated that active TOPK could strongly phosphorylate ERK2 and very weakly phosphorylate ERK1.	SIGNOR-278417
Q8IXJ9	Q15788	2	binding	up-regulates activity	0.283	We also show that ASXL1 associates specifically with SRC-1 and cooperates synergistically in the transcriptional activation.Therefore, both the ability to bind SRC-1 and the autonomous activation of ASXL1 are required for its coactivator function. Further data indicated that the transactivation domain (AD; amino acids 300–655) of ASXL1, newly defined in this study, interacts with the C-terminal AD2 (amino acids 1217–1441) of SRC-1, suggesting that one AD cooperates with the other AD in transcriptional activation by RAR.	SIGNOR-255924
Q02156	P49841	2	phosphorylation	up-regulates	0.268	Specifically, we have identified three phosphorylation sites within pkcepsilon that control its association with 14-3-3.kinase (ser 350), gsk3 (ser 346) and pkc itself (ser 368)	SIGNOR-179412
P49841	Q02156	2	phosphorylation	down-regulates activity	0.268	However, PKCepsilon and Akt can also phosphorylate GSK3beta directly.	SIGNOR-279101
Q9Y4E8	Q7Z569	2	ubiquitination	down-regulates quantity by destabilization	0.267	Here we report on a novel interaction between the E3 ligase BRAP (also referred to as IMP), a negative regulator of the MAPK scaffold protein KSR, and two closely related deubiquitylases, USP15 and USP4. USP15 as well as USP4 oppose the autoubiquitylation of BRAP, whereas BRAP promotes the ubiquitylation of USP15.	SIGNOR-272029
Q7Z569	Q9Y4E8	2	deubiquitination	up-regulates quantity by stabilization	0.267	Here we report on a novel interaction between the E3 ligase BRAP (also referred to as IMP), a negative regulator of the MAPK scaffold protein KSR, and two closely related deubiquitylases, USP15 and USP4. USP15 as well as USP4 oppose the autoubiquitylation of BRAP, whereas BRAP promotes the ubiquitylation of USP15.	SIGNOR-272030
P53667	O14965	2	phosphorylation	up-regulates activity	0.262	Because Aur-A phosphorylates and activates LIMK1 , we examined the activation status of LIMK1 during mitosis in cells treated with MLN8237.\|Because Aur-A phosphorylates and activates LIMK1 [ xref ], we examined the activation status of LIMK1 during mitosis in cells treated with MLN8237.	SIGNOR-279799
O14965	P53667	2	phosphorylation	up-regulates activity	0.262	Here, we report a novel functional cooperativity between Aur-A and LIMK1 through mutual phosphorylation. LIMK1 is recruited to the centrosomes during early prophase and then to the spindle poles, where it colocalizes with Aur-A. Aur-A physically associates with LIMK1 and activates it through phosphorylation, which is important for its centrosomal and spindle pole localization. Aur-A also acts as a substrate of LIMK1, and the function of LIMK1 is important for its specific localization and regulation of spindle morphology.	SIGNOR-276400
P10600	P10600	2	binding	up-regulates	0.2	The active form of tgf-b is a dimer stabilized by hydrophobic interactions and usually further strengthened by an intersubunit disulfide bridge	SIGNOR-148611
P61812	P61812	2	binding	up-regulates	0.2	The active form of tgf-b is a dimer stabilized by hydrophobic interactions and usually further strengthened by an intersubunit disulfide bridge	SIGNOR-148608
P51955	P51955	2	phosphorylation	up-regulates	0.2	Enzymatic activity, induced;	SIGNOR-151763
Q02763	Q02763	2	phosphorylation	down-regulates activity	0.2	The Tie2 nucleotide binding loop is in an inhibitory conformation, which is not seen in other kinase structures, while its activation loop adopts an activated-like conformation in the absence of phosphorylation. Tyr-897, located in the N-terminal domain, may negatively regulate the activity of Tie2 by preventing dimerization of the kinase domains or by recruiting phosphatases when it is phosphorylated.	SIGNOR-246662
P09619	P09619	2	phosphorylation	up-regulates activity	0.2	We used two platelet-derived growth factor beta-receptor (beta-PDGFR) mutants to identify events that are required for full engagement (autophosphorylation and activation of the kinase activity) of the beta-PDGFR kinase. The F79/81 receptor (Tyr to Phe substitution at 579 and 581 in the juxtamembrane domain of the receptor) was capable of only very modest ligand-dependent autophosphorylation and also failed to associate with numerous SH2 domain-containing proteins.	SIGNOR-250254
Q13177	Q13177	2	phosphorylation	up-regulates activity	0.2	Eight autophosphorylation sites were identified in Cdc42-activated gamma-PAK, six of which are in common with those previously reported in alpha-PAK, while Ser-19 and Ser-165 appear to be uniquely phosphorylated in the gamma-form. Further, the phosphorylation of Ser-141, Ser-165, and Thr-402 was found to correlate with gamma-PAK activation. Autophosphorylation of γ-PAK with MgATP alone takes place at Ser-19, Ser-20, Ser-55, Ser-192, and Ser-197.	SIGNOR-250227
P54753	P54753	2	phosphorylation	up-regulates activity	0.2	Tyrosine-614, the major autophosphorylation site of the receptor tyrosine kinase HEK2, functions as multi-docking site for SH2-domain mediated interactions. a single amino acid substitution (Y614F) clearly reduces the phosphotyrosine content of HEK2 and abrogates its ability to bind rasGAP, Crk and Fyn indicating that this residue functions as major phosphorylation and multi-docking site.	SIGNOR-251126
O15530	O15530	2	phosphorylation	down-regulates quantity by destabilization	0.2	PDK1 kinase activity is negatively regulated by binding to 14-3-3 through the PDK1 autophosphorylation site Ser-241. PDK1 binds to 14-3-3 in vivo and in vitro through the residues surrounding the autophosphorylation site Ser-241 and that the association is achieved only when Ser-241 has been phosphorylated	SIGNOR-250077
Q02156	Q02156	2	phosphorylation	down-regulates	0.2	Protein kinase-inactive mutants of pkcepsilon were not phosphorylated at ser(729) in cells, and phosphorylation of this site leads to dephosphorylation of the activation-loop thr(566)	SIGNOR-117324
O14920	O14920	2	phosphorylation	down-regulates activity	0.2	Once activated, IKKbeta autophosphorylated at a carboxyl-terminal serine cluster. Such phosphorylation decreased IKK activity and may prevent prolonged activation of the inflammatory response.	SIGNOR-251278
Q01974	Q01974	2	binding	up-regulates	0.2	Wnt5a induces homodimerization and activation of ror2 receptor tyrosine kinase	SIGNOR-199588
P29597	P29597	2	phosphorylation	up-regulates activity	0.2	These results indicate that tyk2 is activated by phosphorylation on tyr-1054 and/or tyr-1055The K930R mutant, bearing a mutation in the ATP binding site, is catalytically inactive (Fig. 3B, lanes 5 and 6). This protein is not basally phosphorylated, while the wt and the Y1054F/Y1055F proteins are (Fig. 3A), suggesting that autophosphorylation is responsible for the basal level of phosphorylation.	SIGNOR-43092
Q92918	Q92918	2	phosphorylation	up-regulates	0.2	Activation of hematopoietic progenitor kinase 1 involves relocation, autophosphorylation, and transphosphorylation by protein kinase d1.	SIGNOR-134490
P07333	P07333	2	phosphorylation	down-regulates	0.2	Csf-1-mediated wild-type (wt)-csf-1r phosphorylation was not markedly affected by sfk inhibition, indicating that lack of sfk binding is not responsible for diminished y559f phosphorylation. Unexpectedly, cells expressing y559f were hyperproliferative in response to csf-1. Hyperproliferation correlated with prolonged activation of akt, erk, and stat5 in the y559f mutant. Consistent with a defect in receptor negative regulation, c-cbl tyrosine phosphorylation and csf-1r/c-cbl co-association were almost undetectable in the y559f mutant. Furthermore, y559f underwent reduced multiubiquitination and delayed receptor internalization and degradation. In conclusion, we propose that tyr559 is a switch residue that functions in kinase regulation, signal transduction and, indirectly, receptor down-regulation.	SIGNOR-127622
P04626	P04626	2	phosphorylation	up-regulates	0.2	Stimulation of these molecules, however, failed to induce efficient cell migration in the absence of neu/erbb2 phosphorylation at tyr 1201 or tyr 1227	SIGNOR-124860
Q13188	P00519	2	phosphorylation	up-regulates	0.2	We demonstrate that c-abl kinase phosphorylates mst2 at an evolutionarily conserved site, y81, within the kinase domain. We further show that the phosphorylation of mst2 by c-abl leads to the disruption of the interaction with raf-1 proteins and the enhancement of homodimerization of mst2 proteins. It thereby enhances the mst2 activation and induces neuronal cell death.	SIGNOR-197538
P33981	P33981	2	phosphorylation	down-regulates	0.2	We have identified 16 sites of mps1 autophosphorylation in vitro, several of which are required for catalytic activity / mutation of thr675 to alanine increased mps1 catalytic domain activity, and this was reduced to wt levels by mutation to aspartate	SIGNOR-179904
P07949	P07949	2	phosphorylation	up-regulates	0.2	Mass spectrometric analysis revealed that ret tyr(900) was autophosphorylation site. Tyr900 can partially replace the function of tyr905 as a local switch for kinase activation	SIGNOR-148992
P10721	P10721	2	phosphorylation	up-regulates	0.2	Identification of tyr-703 and tyr-936 as autophosphorylation sites in c-kit/scfr	SIGNOR-68643
P30304	Q92630	2	phosphorylation	down-regulates quantity by destabilization	0.2	Here we describe a novel ubiquitin/proteasome-mediated pathway negatively regulating CDC25A stability, dependent on its phosphorylation by the serine/threonine kinase DYRK2. DYRK2 phosphorylates CDC25A on at least 7 residues, resulting in its degradation independent of the known CDC25A E3 ubiquitin ligases.	SIGNOR-276737
Q16620	Q16620	2	phosphorylation	up-regulates activity	0.2	TrkB autophosphorylation occurs on five cytoplasmic tyrosines: Y484, Y670, Y674, Y675, and Y785. Mutagenesis of Y484 inhibits the interaction between Shc and TrkB, and also block the E3DNF-inducible tyrosine phoslphorylation of Shc	SIGNOR-250204
Q14680	Q14680	2	phosphorylation	up-regulates	0.2	We have mapped no less than 16 autophosphorylation sites including serines, threonines, and a tyrosine residue and show that the phosphorylation of thr167 and ser171 is required for the activation of melk.We have not yet explored the role of autophosphorylation of nine residues in the c-terminal, autoinhibitory domain (fig. 4c). An enticing hypothesis is that these autophosphorylations decrease the inhibitory potency of this domain and thereby contribute to the activation of the kinase.	SIGNOR-141030
Q12866	Q12866	2	phosphorylation	up-regulates	0.2	By using a vaccinia virus expression system to express a constitutively activated form of nyk, we identified the major sites of nyk autophosphorylation in tryptic peptide iy749sgdy753y754r. Tyr-749, tyr-753, and tyr-754 in this peptide lie in the activation loop of the kinase domain.	SIGNOR-42914
P78527	P78527	2	phosphorylation	up-regulates activity	0.2	We have identified seven in vitro autophosphorylation sites in DNA-PKcs. Six of these sites (Thr2609, Ser2612, Thr2620, Ser2624, Thr2638 and Thr2647) are clustered in a region of 38 amino acids in the central region of the protein. Five of these sites (Thr2609, Ser2612, Thr2638, Thr2647 and Ser3205) are conserved between six vertebrate species. Moreover, we show that DNA-PKcs is phosphorylated in vivo at Thr2609, Ser2612, Thr2638 and Thr2647 in okadaic acid-treated human cells. \| Thus phosphorylation of DNA-PKcs at one or more of the autophosphorylation sites identified in this study is likely to be required for DNA-PKcs function.	SIGNOR-249157
O00444	O00444	2	phosphorylation	up-regulates	0.2	Autophosphorylation probably plays a role in the process of centriole duplication, because mimicking s305 phosphorylation enhances the ability of overexpressed plk4 to induce centriole amplification. Importantly, we show that s305-phosphorylated plk4 is specifically sequestered at the centrosome contrary to the nonphosphorylated form.	SIGNOR-162559
Q5S007	Q5S007	2	phosphorylation	up-regulates	0.2	Three putative autophosphorylation sites (thr-2031, ser-2032, and thr-2035) have been identified within the activation segment of the lrrk2 kinase domain based on sequence homology to mixed-lineage kinases. Phosphorylation at one or more of these sites is critical for the kinase activity of lrrk2.	SIGNOR-166470
P52333	P52333	2	phosphorylation	up-regulates	0.2	The phosphorylation of wt jak3 and y980f/y981f/y785f mutant jak3 is presumably mediated through autophosphorylation at distinct jak3 sites within this model systemhosphorylation of jak3 on y785 has been reported to create a binding site for the adaptor protein sh2b-beta	SIGNOR-160660
Q07812	Q07812	2	binding	up-regulates activity	0.2	Following bid-induced conformational change, bax oligomerizes and inserts tightly within the outer mitochondrial membrane. The integration of bax in the outer mitochondrial membrane is followed by cytochrome crelease	SIGNOR-73895
P05771	P05771	2	phosphorylation	up-regulates	0.2	The catalytic or kinase domain requires phosphorylation at three sites for full activation (24, 25): ? Phosphorylation of threonine 500 (thr-500) in the activation loop by the upstream kinase pdk-1 is a prerequisite for the maturation of the enzyme (26), which subsequently leads to autophosphorylation at threonine 641 (thr-641) in the turn motif and serine 660 (ser-660) in the hydrophobic motif	SIGNOR-150865
P06213	P06213	2	phosphorylation	up-regulates activity	0.2	We identified the major autophosphorylation sites in the insulin receptor and correlated their phosphorylation with the phosphotransferase activity of the receptor on synthetic peptides. We conclude that 1) autophosphorylation of the insulin receptor begins by phosphorylation of Tyr-1146 and either Tyr-1150 or Tyr-1151;	SIGNOR-106510

P31749

P53804

2

ubiquitination

down-regulates quantity by destabilization

0.395

TTC3 is an Akt-specific E3 ligase that binds to phosphorylated Akt and facilitates its ubiquitination and degradation within the nucleus

SIGNOR-252436

Q99576

O43524

2

transcriptional regulation

up-regulates quantity by expression

0.395

We have analyzed the promoter of human gilz (glucocorticoid-induced leucine zipper), a dexamethasone-inducible gene that is involved in regulating apoptosis, and identified six glucocorticoid (GC)-responsive elements and three Forkhead responsive elements (FHREs).

SIGNOR-255950

P53804

P31749

2

phosphorylation

up-regulates

0.395

Phosphorylation of ttc3 at ser378 is required for efficient biological function together, these observations support that ttc3 is a phosphorylation target of akt both in an in vitro and in a cellular context

SIGNOR-252508

O43524

Q99576

2

relocalization

down-regulates activity

0.395

GILZ inhibits FOXO1, FOXO3, and FOXO4 transcriptional activities measured with natural or synthetic FOXO-responsive promoters in HL-60 cells.

SIGNOR-256147

P15172

P06400

2

binding

up-regulates

0.394

Cycline/cdk2 blocks myod-induced gene expression through the phosphorylation of rb, preventing rb from binding and transactivating myod, and triggering s phase entry instead of differentiation.

SIGNOR-176563

P06400

P15172

2

transcriptional regulation

up-regulates quantity by expression

0.394

Here we report that, at the onset of differentiation, activation by MyoD of the Rb, p21, and cyclin D3 genes occurs in the absence of new protein synthesis and with the requirement of the p300 transcriptional coactivator.

SIGNOR-238532

P42680

Q9ULZ2

2

binding

up-regulates activity

0.392

In 293 cells expressing recombinant BRDG1 and various PTKs, Tec and Pyk2, but not Btk, Bmx, Lyn, Syk, or c-Abl, induced marked phosphorylation of BRDG1 on tyrosine residues. BRDG1 was also phosphorylated by Tec directly in vitro. Furthermore, BRDG1 was shown to participate in a positive feedback loop by increasing the activity of Tec. BRDG1 thus appears to function as a docking protein acting downstream of Tec in BCR signaling. BRDG1 may activate Tec by disrupting an intramolecular interaction.

SIGNOR-261819

P35548

Q07687

2

binding

down-regulates activity

0.392

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-240911

Q9ULZ2

P42680

2

phosphorylation

up-regulates activity

0.392

In 293 cells expressing recombinant BRDG1 and various PTKs, Tec and Pyk2, but not Btk, Bmx, Lyn, Syk, or c-Abl, induced marked phosphorylation of BRDG1 on tyrosine residues. BRDG1 was also phosphorylated by Tec directly in vitro. Efficient phosphorylation of BRDG1 by Tec required the PH and SH2 domains as well as the kinase domain of the latter. Furthermore, BRDG1 was shown to participate in a positive feedback loop by increasing the activity of Tec. BRDG1 transcripts are abundant in the human B cell line Ramos, and the endogenous protein underwent tyrosine phosphorylation in response to BCR stimulation. BRDG1 thus appears to function as a docking protein acting downstream of Tec in BCR signaling.

SIGNOR-261817

Q07687

P35548

2

binding

down-regulates activity

0.392

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-240932

P28360

P56178

2

binding

down-regulates activity

0.389

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-240921

P56178

P28360

2

binding

down-regulates activity

0.389

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-240987

Q13315

Q9NQS1

2

binding

up-regulates activity

0.381

These data suggest that Aven overexpression can activate ATM and that Aven phosphorylation in a positive feedback loop enforces Aven activity, making it a more potent ATM activator.

SIGNOR-262638

Q9NQS1

Q13315

2

phosphorylation

up-regulates activity

0.381

Aven is also a substrate of the ATM kinase. Mutation of ATM-mediated phosphorylation sites on Aven reduced its ability to activate ATM, suggesting that Aven activation of ATM after DNA damage is enhanced by ATM-mediated Aven phosphorylation. We found that mutating S135 and S308 sites to Alanine largely dampened Aven’s phosphorylation by ATM (though some phosphorylation remained, due to either a contaminating kinase or an unidentified ATM phosphorylation site).

SIGNOR-262636

O95551

Q9Y4K3

2

ubiquitination

up-regulates activity

0.378

TTRAP is ubiquitylated by TRAF6 and promotes TRAF6 dependent ubiquitylation of TAK1.|In addition, we noted that the presence of TRAF6 strengthened the interaction between TTRAP and the TGF-\u03b2 receptor complex (see also later).

SIGNOR-278717

Q9Y4K3

O95551

2

binding

up-regulates activity

0.378

TTRAP associates with TRAF6.The TAK1-TTRAP-TRAF6 complex is stabilized by ubiquitylation and recruited to TβRI.

SIGNOR-277189

P04637

P49915

2

binding

up-regulates

0.378

In response to genotoxic stress or nucleotide deprivation, gmps becomes nuclear and facilitates p53 stabilization by promoting its transfer from mdm2 to a gmps-usp7 deubiquitylation complex.

SIGNOR-204409

P49915

P04637

2

transcriptional regulation

down-regulates quantity by repression

0.378

Herein, we identified GMP synthetase (GMPS), a key enzyme of de novo purine biosynthesis, as an important p53 repression target using a large-scale proteomics approach. This p53-mediated repression of GMPS could be validated by immunoblotting in Sk-Hep1, HepG2, and HuH6 cells.

SIGNOR-267342

Q15118

P31751

2

phosphorylation

up-regulates activity

0.375

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-277271

P31751

Q15118

2

phosphorylation

up-regulates activity

0.375

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-279248

Q13546

Q9UHD2

2

phosphorylation

down-regulates activity

0.373

Our data clearly indicate that TBK1 can directly phosphorylate RIPK1 at T189.|TBK1 inhibits RIPK1 by direct phosphorylation.

SIGNOR-279388

Q9UHD2

Q13546

2

phosphorylation

up-regulates activity

0.373

Additionally, RIPK1-dependent hyper-phosphorylation of TBK1 in Casp8 Ripk3 cells occurred during MNV-1 infection (Figure 4F).|RIPK1 and its kinase activity were required to promote increased TBK1 phosphorylation in the absence of caspase-8 (Figure 3E), suggesting that RIPK1 may promote TBK1 activation.

SIGNOR-279278

P49841

Q9UKA4

2

binding

down-regulates activity

0.372

A-kinase anchoring protein 220 (AKAP220) is a multivalent anchoring protein that can sequester a variety of signal transduction enzymes. These include protein kinase A (PKA) and glycogen synthase kinase 3beta (GSK3beta). Using a combination of molecular and cellular approaches we show that GSK3beta phosphorylation of Thr-1132 on AKAP220 initiates recruitment of this kinase into the enzyme scaffold. We also find that AKAP220 anchors GSK3beta and its substrate beta-catenin in membrane ruffles.

SIGNOR-264817

Q9UKA4

P49841

2

phosphorylation

down-regulates activity

0.372

A-kinase anchoring protein 220 (AKAP220) is a multivalent anchoring protein that can sequester a variety of signal transduction enzymes. These include protein kinase A (PKA) and glycogen synthase kinase 3beta (GSK3beta). Using a combination of molecular and cellular approaches we show that GSK3beta phosphorylation of Thr-1132 on AKAP220 initiates recruitment of this kinase into the enzyme scaffold. We also find that AKAP220 anchors GSK3beta and its substrate beta-catenin in membrane ruffles.

SIGNOR-264816

Q13351

Q01543

2

binding

down-regulates activity

0.371

FLI-1 represses the transcriptional activity of EKLF.Our data indicate that the ETS domain of FLI-1 is absolutely required to inhibit EKLF activity. Since the FLI-1 ETS domain interacts with the DNA binding domain of EKLF, one possibility could be that FLI-1 inhibits the binding of EKLF to its DNA targets

SIGNOR-256044

Q01543

Q13351

2

binding

down-regulates activity

0.371

The present study also shows that EKLF itself inhibits FLI-1 activity. As suggested above for the inhibition of EKLF activity, the inhibition of FLI-1 activity most probably involves the indirect recruitment of EKLF to FLI-1 target promoters by protein-protein interaction.

SIGNOR-256046

P12931

Q96AC1

2

binding

up-regulates activity

0.37

Here we report that Src binds to and phosphorylates Kindlin-2 at Y193. Reciprocally, Kindlin-2-Y193 phosphorylation activates and maintains Src kinase activity. Kindlin-2-Y193 phosphorylation is also involved in its binding capacity with Migfilin and the recruitment of Migfilin to the focal adhesions. Functionally, we demonstrate that Kindlin-2-Y193 phosphorylation regulates Kindlin-2-mediated cell spreading and migration.

SIGNOR-266101

Q96AC1

P12931

2

phosphorylation

up-regulates activity

0.37

Here we report that Src binds to and phosphorylates Kindlin-2 at Y193. Reciprocally, Kindlin-2-Y193 phosphorylation activates and maintains Src kinase activity. Kindlin-2-Y193 phosphorylation is also involved in its binding capacity with Migfilin and the recruitment of Migfilin to the focal adhesions. Functionally, we demonstrate that Kindlin-2-Y193 phosphorylation regulates Kindlin-2-mediated cell spreading and migration.

SIGNOR-266100

P06213

P29350

2

dephosphorylation

down-regulates

0.359

Finally, we have tested the set of ptps for their ability to dephosphorylate a phosphopeptide corresponding to the irk autophosphorylation site. tc-ptp, sap-1, and ptp-1b all tested positive, but ptp-? Showed no activity, although the same gst-ptp preparation could efficiently convert pnpp (tablei). Interestingly, many other ptps showed activity, namely dep-1, glepp-1, lar, ptp-?, -?, -?, And shp-1.

SIGNOR-75938

P29350

P06213

2

phosphorylation

up-regulates

0.359

Insulin stimulates the phosphorylation of tyr538 and the catalytic activity of ptp1c, a protein tyrosine phosphatase with src homology-2 domains. these results suggest that ptp1c is a target protein for the insulin receptor tyrosine kinase

SIGNOR-26870

P68400

P06493

2

phosphorylation

up-regulates

0.355

Four residues within this domain, thr-344, thr-360, ser-362, and ser-370, conform to the minimal consensus sequence for p34cdc2 phosphorylationthe high stoichiometry of phosphorylation suggests that phosphorylation could regulate functional properties of ckii and that it could in some way participate in the burst of phosphorylation that accompanies the activation of p34graphic at the ggraphic-m transition

SIGNOR-29525

P06493

P68400

2

phosphorylation

up-regulates

0.355

Additionally, transfection of cdc2 with a mutation at ser(39) to ala, which is the ck2 phosphorylation site, partially inhibits cell cycle progression in g(1) to g(2) phase following 6-tg treatment.

SIGNOR-134846

Q05923

P31152

2

phosphorylation

up-regulates activity

0.353

However, co-expression of ERK4 significantly increased the half-life of DUSP2 (XREF_FIG).|In support of the latter notion we have shown that wild-type ERK4 can phosphorylate DUSP2 in vitro and future studies will be aimed at identifying the relevant site (s) of modification and determining their influence on DUSP2 stability.

SIGNOR-278959

P31152

Q05923

2

dephosphorylation

down-regulates activity

0.353

DUSP2 can dephosphorylate both ERK3 and ERK4 when expressed in mammalian cells.|Finally, we demonstrate that DUSP2 inhibits ERK3 and ERK4 mediated activation of MK5.

SIGNOR-277068

Q13191

Q06418

2

phosphorylation

up-regulates activity

0.35

To test whether phosphorylation of Cbl-b at Tyr133 and/or Tyr363 by Tyro3 is important for its ubiquitin ligase function, we examined the ubiquitination of the Cbl-b mutants and Tyro3.

SIGNOR-279577

Q06418

Q13191

2

ubiquitination

up-regulates activity

0.35

Consistent with these data, we also found that Tyro3 is ubiquitinated by Cbl-b.|These data suggest that not only was Tyro3 a ubiquitination target of Cbl-b, but also that Cbl-b was a phosphorylation target of Tyro3.

SIGNOR-278807

P14780

P20742

2

binding

down-regulates activity

0.349

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-261802

P20742

P14780

2

cleavage

down-regulates quantity by destabilization

0.349

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-261785

Q12986

P11940

2

binding

up-regulates activity

0.344

We identifiednew protein partners of NFX1-123, including several cytoplasmic poly(A) binding proteins (PABPCs) thatinteracted with NFX1-123 through its N-terminal PAM2 motif. Central to our findings were our observations that PABPCs copurify with NFX1-123, that a PAM2 motif is present in NFX1, and this motif and the PABPCs are important in the enhancement of hTERT activity by NFX1-123.

SIGNOR-261052

P11940

Q12986

2

binding

up-regulates activity

0.344

NFX1-123 augments the activation of hTERT expression through interactions with PABPCs

SIGNOR-226011

P00519

Q13043

2

phosphorylation

down-regulates

0.343

Here, we identify clk1, clk4, mst1, mst2 and ttk (also known as mps1) as novel thr735 kinases in vitro / phosphorylation of thr735 in c-abl is critical for binding to 14-3-3

SIGNOR-181060

Q13043

P00519

2

phosphorylation

up-regulates activity

0.343

In the present study, we demonstrate that the protein kinase c-Abl phosphorylates MST1 at Y433, which triggers the stabilization and activation of MST1.

SIGNOR-260927

Q10571

Q09472

2

binding

up-regulates

0.342

Our results indicate that mn1 is a transcription coactivator rather than a sequence-specific transcription factor, and that it may stimulate rar/rxr-mediated transcription through interaction with p160 and p300.

SIGNOR-97899

Q09472

Q10571

2

binding

up-regulates activity

0.342

Taken together, our results indicate that MN1 is a transcription coactivator rather than a sequence-specific transcription factor, and that it may stimulate RAR/RXR-mediated transcription through interaction with p160 and p300.

SIGNOR-256020

P35790

P12931

2

phosphorylation

up-regulates activity

0.336

We find that CHKA forms a complex with EGFR in a c-Src-dependent manner. Endogenous CHKA and EGFR co-immunoprecipitated from a variety of breast cancer cell lines and immortalized mammary epithelial cells. CHKA interacted with the EGFR kinase domain upon c-Src co-overexpression and was phosphorylated in a c-Src-dependent manner on Y197 and Y333.

SIGNOR-266350

P12931

P35790

2

phosphorylation

down-regulates activity

0.336

Figure XREF_FIG shows that even though Chk phosphorylated Tyr 527 of Src to a level much lower than that of Csk, it was a much more efficient inhibitor of Src kinase activity.|These results suggest that Chk inhibited Src with a mechanism independent of Tyr-527 phosphorylation.

SIGNOR-279731

Q96KG7

O95477

2

binding

up-regulates activity

0.332

ABCA1 and MEGF10 interact during engulfment. MEGF10 function can be modulated by the ATP binding cassette transporter ABCA1, ortholog to CED-7. by the combined use of cellular and biochemical approaches we provide evidence that ABCA1 and MEGF10 interact at the molecular level.

SIGNOR-265164

O95477

Q96KG7

2

binding

up-regulates activity

0.332

ABCA1 and MEGF10 interact during engulfment. MEGF10 function can be modulated by the ATP binding cassette transporter ABCA1, ortholog to CED-7. by the combined use of cellular and biochemical approaches we provide evidence that ABCA1 and MEGF10 interact at the molecular level.

SIGNOR-265165

P20742

P08253

2

cleavage

down-regulates quantity by destabilization

0.329

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-261796

P08253

P20742

2

binding

down-regulates activity

0.329

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-261804

P04637

Q6UB99

2

binding

up-regulates activity

0.308

Ankyrin repeat domain 11, ANKRD11 (also known as ANR11 or ANCO1), was found to be a novel p53-interacting protein that enhanced the transcriptional activity of p53. In addition, ANKRD11 itself was found to be a novel p53 target gene. These findings demonstrate a role for ANKRD11 as a p53 coactivator and suggest the involvement of ANKRD11 in a regulatory feedback loop with p53.

SIGNOR-266734

Q6UB99

P04637

2

transcriptional regulation

up-regulates quantity by expression

0.308

Ankyrin repeat domain 11, ANKRD11 (also known as ANR11 or ANCO1), was found to be a novel p53-interacting protein that enhanced the transcriptional activity of p53. In addition, ANKRD11 itself was found to be a novel p53 target gene. These findings demonstrate a role for ANKRD11 as a p53 coactivator and suggest the involvement of ANKRD11 in a regulatory feedback loop with p53.

SIGNOR-266735

P42684

P09619

2

phosphorylation

up-regulates activity

0.303

PDGFRβ directly phosphorylates multiple novel sites on the N-terminal half of Abl2, including Y116, Y139, and Y161 within the Src homology 3 domain, and Y299, Y303, and Y310 on the kinase domain.We also found that PDGFRβ-mediated phosphorylation of Abl2 in vitro activates Abl2 kinase activity, but mutation of these four tyrosines (Y116, Y161, Y272, and Y310) to phenylalanine abrogated PDGFRβ-mediated activation of Abl2.

SIGNOR-277303

O15355

Q13315

2

phosphorylation

up-regulates activity

0.303

ATM indeed mediated PPM1G phosphorylation at S183, and mutation of this residue (S183A) abrogated detection with the phospho-specific antibody

SIGNOR-255591

P09619

P42684

2

phosphorylation

up-regulates activity

0.303

C-Abl phosphorylates three tyrosine residues on PDGFR-beta (Y686, Y934, Y970), while Arg only phosphorylatesY686. Y686 and Y934 reside in PDGFR-beta catalytic domains, while Y970 is in the C-terminal tail. Using site-directed mutagenesis, we show that Abl-dependent phosphorylation of PDGFR-beta activates PDGFR-beta activity, in vitro, but serves to downregulate PDGFR-mediated chemotaxis.

SIGNOR-276140

Q13315

O15355

2

dephosphorylation

down-regulates activity

0.303

After ionizing radiation, dephosphorylation of USP7S by the ATM-dependent protein phosphatase PPM1G leads to USP7S downregulation, followed by Mdm2 downregulation and accumulation of p53. |ATM Dependent Downregulation of USP7 and HAUSP by PPM1G Activates p53 Response to DNA Damage.|DNA Damage Leads to ATM Dependent USP7S Dephosphorylation by PPM1G.

SIGNOR-277158

P33981

O96017

2

phosphorylation

up-regulates

0.292

Phosphorylation at ttk/hmps1 thr288 is enhanced by chk2 in vitro and in vivo after ir

SIGNOR-242665

O96017

P33981

2

phosphorylation

up-regulates

0.292

Ttk/hmps1 directly phosphorylates chk2 on thr-68 in vitro.ablation of ttk expression using small interfering rna results not only in reduced chk2 thr-68 phosphorylation, but also in impaired growth arrest. Our results are consistent with a model in which ttk functions upstream from chk2 in response to dna damage

SIGNOR-132665

P49841

Q16539

2

phosphorylation

down-regulates

0.29

However p38alfa also inactivates gsk3b by direct phosphorilation of the c-terminal residue ser389. this non-canonicl p38 mapk-dependent phosphorilation of gsk3b seems to occur primarily in the brain and thymocytes.

SIGNOR-157548

Q16539

P49841

2

binding

down-regulates

0.29

Here we show that similar to the interaction with traf4 and axin, the kinase domain of mekk4 interacts with the multifunctional serine/threonine kinase gsk3beta. Gsk3beta binding to mekk4 blocks mekk4 dimerization that is required for mekk4 activation, effectively inhibiting mekk4 stimulation of the jnk and p38 mapk pathways

SIGNOR-157544

Q96KB5

P28482

2

phosphorylation

up-regulates activity

0.283

In the present study, Ser32 was revealed to be a novel phosphorylated site on TOPK that could be activated by ERK2.|TOPK/PBK is phosphorylated by ERK2 at serine 32, promotes tumorigenesis and is involved in sorafenib resistance in RCC.

SIGNOR-279744

Q15788

Q8IXJ9

2

binding

up-regulates activity

0.283

We also show that ASXL1 associates specifically with SRC-1 and cooperates synergistically in the transcriptional activation. Further data indicated that the transactivation domain (AD; amino acids 300–655) of ASXL1, newly defined in this study, interacts with the C-terminal AD2 (amino acids 1217–1441) of SRC-1, suggesting that one AD cooperates with the other AD in transcriptional activation by RAR.

SIGNOR-255931

P28482

Q96KB5

2

phosphorylation

up-regulates activity

0.283

Phosphorylation of ELK1 or ERK2 increased dramatically compared with controls and suggested that TOPK or ERK2 could enhance ERK2 or TOPK kinase activity by respective and mutual phosphorylation of each other.|The results indicated that active TOPK could strongly phosphorylate ERK2 and very weakly phosphorylate ERK1.

SIGNOR-278417

Q8IXJ9

Q15788

2

binding

up-regulates activity

0.283

We also show that ASXL1 associates specifically with SRC-1 and cooperates synergistically in the transcriptional activation.Therefore, both the ability to bind SRC-1 and the autonomous activation of ASXL1 are required for its coactivator function. Further data indicated that the transactivation domain (AD; amino acids 300–655) of ASXL1, newly defined in this study, interacts with the C-terminal AD2 (amino acids 1217–1441) of SRC-1, suggesting that one AD cooperates with the other AD in transcriptional activation by RAR.

SIGNOR-255924

Q02156

P49841

2

phosphorylation

up-regulates

0.268

Specifically, we have identified three phosphorylation sites within pkcepsilon that control its association with 14-3-3.kinase (ser 350), gsk3 (ser 346) and pkc itself (ser 368)

SIGNOR-179412

P49841

Q02156

2

phosphorylation

down-regulates activity

0.268

However, PKCepsilon and Akt can also phosphorylate GSK3beta directly.

SIGNOR-279101

Q9Y4E8

Q7Z569

2

ubiquitination

down-regulates quantity by destabilization

0.267

Here we report on a novel interaction between the E3 ligase BRAP (also referred to as IMP), a negative regulator of the MAPK scaffold protein KSR, and two closely related deubiquitylases, USP15 and USP4. USP15 as well as USP4 oppose the autoubiquitylation of BRAP, whereas BRAP promotes the ubiquitylation of USP15.

SIGNOR-272029

Q7Z569

Q9Y4E8

2

deubiquitination

up-regulates quantity by stabilization

0.267

Here we report on a novel interaction between the E3 ligase BRAP (also referred to as IMP), a negative regulator of the MAPK scaffold protein KSR, and two closely related deubiquitylases, USP15 and USP4. USP15 as well as USP4 oppose the autoubiquitylation of BRAP, whereas BRAP promotes the ubiquitylation of USP15.

SIGNOR-272030

P53667

O14965

2

phosphorylation

up-regulates activity

0.262

Because Aur-A phosphorylates and activates LIMK1 , we examined the activation status of LIMK1 during mitosis in cells treated with MLN8237.|Because Aur-A phosphorylates and activates LIMK1 [ xref ], we examined the activation status of LIMK1 during mitosis in cells treated with MLN8237.

SIGNOR-279799

O14965

P53667

2

phosphorylation

up-regulates activity

0.262

Here, we report a novel functional cooperativity between Aur-A and LIMK1 through mutual phosphorylation. LIMK1 is recruited to the centrosomes during early prophase and then to the spindle poles, where it colocalizes with Aur-A. Aur-A physically associates with LIMK1 and activates it through phosphorylation, which is important for its centrosomal and spindle pole localization. Aur-A also acts as a substrate of LIMK1, and the function of LIMK1 is important for its specific localization and regulation of spindle morphology.

SIGNOR-276400

P10600

2

binding

up-regulates

0.2

The active form of tgf-b is a dimer stabilized by hydrophobic interactions and usually further strengthened by an intersubunit disulfide bridge

SIGNOR-148611

P61812

2

binding

up-regulates

0.2

The active form of tgf-b is a dimer stabilized by hydrophobic interactions and usually further strengthened by an intersubunit disulfide bridge

SIGNOR-148608

P51955

2

phosphorylation

up-regulates

0.2

Enzymatic activity, induced;

SIGNOR-151763

Q02763

2

phosphorylation

down-regulates activity

0.2

The Tie2 nucleotide binding loop is in an inhibitory conformation, which is not seen in other kinase structures, while its activation loop adopts an activated-like conformation in the absence of phosphorylation. Tyr-897, located in the N-terminal domain, may negatively regulate the activity of Tie2 by preventing dimerization of the kinase domains or by recruiting phosphatases when it is phosphorylated.

SIGNOR-246662

P09619

2

phosphorylation

up-regulates activity

0.2

We used two platelet-derived growth factor beta-receptor (beta-PDGFR) mutants to identify events that are required for full engagement (autophosphorylation and activation of the kinase activity) of the beta-PDGFR kinase. The F79/81 receptor (Tyr to Phe substitution at 579 and 581 in the juxtamembrane domain of the receptor) was capable of only very modest ligand-dependent autophosphorylation and also failed to associate with numerous SH2 domain-containing proteins.

SIGNOR-250254

Q13177

2

phosphorylation

up-regulates activity

0.2

Eight autophosphorylation sites were identified in Cdc42-activated gamma-PAK, six of which are in common with those previously reported in alpha-PAK, while Ser-19 and Ser-165 appear to be uniquely phosphorylated in the gamma-form. Further, the phosphorylation of Ser-141, Ser-165, and Thr-402 was found to correlate with gamma-PAK activation. Autophosphorylation of γ-PAK with MgATP alone takes place at Ser-19, Ser-20, Ser-55, Ser-192, and Ser-197.

SIGNOR-250227

P54753

2

phosphorylation

up-regulates activity

0.2

Tyrosine-614, the major autophosphorylation site of the receptor tyrosine kinase HEK2, functions as multi-docking site for SH2-domain mediated interactions. a single amino acid substitution (Y614F) clearly reduces the phosphotyrosine content of HEK2 and abrogates its ability to bind rasGAP, Crk and Fyn indicating that this residue functions as major phosphorylation and multi-docking site.

SIGNOR-251126

O15530

2

phosphorylation

down-regulates quantity by destabilization

0.2

PDK1 kinase activity is negatively regulated by binding to 14-3-3 through the PDK1 autophosphorylation site Ser-241. PDK1 binds to 14-3-3 in vivo and in vitro through the residues surrounding the autophosphorylation site Ser-241 and that the association is achieved only when Ser-241 has been phosphorylated

SIGNOR-250077

Q02156

2

phosphorylation

down-regulates

0.2

Protein kinase-inactive mutants of pkcepsilon were not phosphorylated at ser(729) in cells, and phosphorylation of this site leads to dephosphorylation of the activation-loop thr(566)

SIGNOR-117324

O14920

2

phosphorylation

down-regulates activity

0.2

Once activated, IKKbeta autophosphorylated at a carboxyl-terminal serine cluster. Such phosphorylation decreased IKK activity and may prevent prolonged activation of the inflammatory response.

SIGNOR-251278

Q01974

2

binding

up-regulates

0.2

Wnt5a induces homodimerization and activation of ror2 receptor tyrosine kinase

SIGNOR-199588

P29597

2

phosphorylation

up-regulates activity

0.2

These results indicate that tyk2 is activated by phosphorylation on tyr-1054 and/or tyr-1055The K930R mutant, bearing a mutation in the ATP binding site, is catalytically inactive (Fig. 3B, lanes 5 and 6). This protein is not basally phosphorylated, while the wt and the Y1054F/Y1055F proteins are (Fig. 3A), suggesting that autophosphorylation is responsible for the basal level of phosphorylation.

SIGNOR-43092

Q92918

2

phosphorylation

up-regulates

0.2

Activation of hematopoietic progenitor kinase 1 involves relocation, autophosphorylation, and transphosphorylation by protein kinase d1.

SIGNOR-134490

P07333

2

phosphorylation

down-regulates

0.2

Csf-1-mediated wild-type (wt)-csf-1r phosphorylation was not markedly affected by sfk inhibition, indicating that lack of sfk binding is not responsible for diminished y559f phosphorylation. Unexpectedly, cells expressing y559f were hyperproliferative in response to csf-1. Hyperproliferation correlated with prolonged activation of akt, erk, and stat5 in the y559f mutant. Consistent with a defect in receptor negative regulation, c-cbl tyrosine phosphorylation and csf-1r/c-cbl co-association were almost undetectable in the y559f mutant. Furthermore, y559f underwent reduced multiubiquitination and delayed receptor internalization and degradation. In conclusion, we propose that tyr559 is a switch residue that functions in kinase regulation, signal transduction and, indirectly, receptor down-regulation.

SIGNOR-127622

P04626

2

phosphorylation

up-regulates

0.2

Stimulation of these molecules, however, failed to induce efficient cell migration in the absence of neu/erbb2 phosphorylation at tyr 1201 or tyr 1227

SIGNOR-124860

Q13188

P00519

2

phosphorylation

up-regulates

0.2

We demonstrate that c-abl kinase phosphorylates mst2 at an evolutionarily conserved site, y81, within the kinase domain. We further show that the phosphorylation of mst2 by c-abl leads to the disruption of the interaction with raf-1 proteins and the enhancement of homodimerization of mst2 proteins. It thereby enhances the mst2 activation and induces neuronal cell death.

SIGNOR-197538

P33981

2

phosphorylation

down-regulates

0.2

We have identified 16 sites of mps1 autophosphorylation in vitro, several of which are required for catalytic activity / mutation of thr675 to alanine increased mps1 catalytic domain activity, and this was reduced to wt levels by mutation to aspartate

SIGNOR-179904

P07949

2

phosphorylation

up-regulates

0.2

Mass spectrometric analysis revealed that ret tyr(900) was autophosphorylation site. Tyr900 can partially replace the function of tyr905 as a local switch for kinase activation

SIGNOR-148992

P10721

2

phosphorylation

up-regulates

0.2

Identification of tyr-703 and tyr-936 as autophosphorylation sites in c-kit/scfr

SIGNOR-68643

P30304

Q92630

2

phosphorylation

down-regulates quantity by destabilization

0.2

Here we describe a novel ubiquitin/proteasome-mediated pathway negatively regulating CDC25A stability, dependent on its phosphorylation by the serine/threonine kinase DYRK2. DYRK2 phosphorylates CDC25A on at least 7 residues, resulting in its degradation independent of the known CDC25A E3 ubiquitin ligases.

SIGNOR-276737

Q16620

2

phosphorylation

up-regulates activity

0.2

TrkB autophosphorylation occurs on five cytoplasmic tyrosines: Y484, Y670, Y674, Y675, and Y785. Mutagenesis of Y484 inhibits the interaction between Shc and TrkB, and also block the E3DNF-inducible tyrosine phoslphorylation of Shc

SIGNOR-250204

Q14680

2

phosphorylation

up-regulates

0.2

We have mapped no less than 16 autophosphorylation sites including serines, threonines, and a tyrosine residue and show that the phosphorylation of thr167 and ser171 is required for the activation of melk.We have not yet explored the role of autophosphorylation of nine residues in the c-terminal, autoinhibitory domain (fig. 4c). An enticing hypothesis is that these autophosphorylations decrease the inhibitory potency of this domain and thereby contribute to the activation of the kinase.

SIGNOR-141030

Q12866

2

phosphorylation

up-regulates

0.2

By using a vaccinia virus expression system to express a constitutively activated form of nyk, we identified the major sites of nyk autophosphorylation in tryptic peptide iy749sgdy753y754r. Tyr-749, tyr-753, and tyr-754 in this peptide lie in the activation loop of the kinase domain.

SIGNOR-42914

P78527

2

phosphorylation

up-regulates activity

0.2

We have identified seven in vitro autophosphorylation sites in DNA-PKcs. Six of these sites (Thr2609, Ser2612, Thr2620, Ser2624, Thr2638 and Thr2647) are clustered in a region of 38 amino acids in the central region of the protein. Five of these sites (Thr2609, Ser2612, Thr2638, Thr2647 and Ser3205) are conserved between six vertebrate species. Moreover, we show that DNA-PKcs is phosphorylated in vivo at Thr2609, Ser2612, Thr2638 and Thr2647 in okadaic acid-treated human cells. | Thus phosphorylation of DNA-PKcs at one or more of the autophosphorylation sites identified in this study is likely to be required for DNA-PKcs function.

SIGNOR-249157

O00444

2

phosphorylation

up-regulates

0.2

Autophosphorylation probably plays a role in the process of centriole duplication, because mimicking s305 phosphorylation enhances the ability of overexpressed plk4 to induce centriole amplification. Importantly, we show that s305-phosphorylated plk4 is specifically sequestered at the centrosome contrary to the nonphosphorylated form.

SIGNOR-162559

Q5S007

2

phosphorylation

up-regulates

0.2

Three putative autophosphorylation sites (thr-2031, ser-2032, and thr-2035) have been identified within the activation segment of the lrrk2 kinase domain based on sequence homology to mixed-lineage kinases. Phosphorylation at one or more of these sites is critical for the kinase activity of lrrk2.

SIGNOR-166470

P52333

2

phosphorylation

up-regulates

0.2

The phosphorylation of wt jak3 and y980f/y981f/y785f mutant jak3 is presumably mediated through autophosphorylation at distinct jak3 sites within this model systemhosphorylation of jak3 on y785 has been reported to create a binding site for the adaptor protein sh2b-beta

SIGNOR-160660

Q07812

2

binding

up-regulates activity

0.2

Following bid-induced conformational change, bax oligomerizes and inserts tightly within the outer mitochondrial membrane. The integration of bax in the outer mitochondrial membrane is followed by cytochrome crelease

SIGNOR-73895

P05771

2

phosphorylation

up-regulates

0.2

The catalytic or kinase domain requires phosphorylation at three sites for full activation (24, 25): ? Phosphorylation of threonine 500 (thr-500) in the activation loop by the upstream kinase pdk-1 is a prerequisite for the maturation of the enzyme (26), which subsequently leads to autophosphorylation at threonine 641 (thr-641) in the turn motif and serine 660 (ser-660) in the hydrophobic motif

SIGNOR-150865

P06213

2

phosphorylation

up-regulates activity

0.2

We identified the major autophosphorylation sites in the insulin receptor and correlated their phosphorylation with the phosphotransferase activity of the receptor on synthetic peptides. We conclude that 1) autophosphorylation of the insulin receptor begins by phosphorylation of Tyr-1146 and either Tyr-1150 or Tyr-1151;

SIGNOR-106510