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
Q9ULB5	P35222	1	binding	up-regulates activity	0.568	At its C-terminus, cadherin interacts with Î²-catenin, which dynamically associates with Î±-catenin, a direct binding partner of filamentous actin	SIGNOR-265869
Q05655	P29474	1	phosphorylation	down-regulates activity	0.568	The phosphorylation of both S617 and S635 have also been shown to promote increased eNOS-derived NO release (Michell et al., 2002). The phosphorylaiton of S617 can be induced by PKA or Akt activity, and may serve to sensitize eNOS to calmodulin binding and modulate the phosphorylation of other eNOS sites	SIGNOR-251631
P28335	P50148	1	binding	up-regulates activity	0.568	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. \| We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. \| The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257221
Q9Y3A6	P49755	1	binding	up-regulates activity	0.568	P28 forms hetero-oligomeric complexes with p23. p23 is a major determinant for efficient targeting of p28 to the ERGIC	SIGNOR-261298
P12931	Q12879	1	phosphorylation	up-regulates activity	0.567	To gain further insight into the roles of Src and Fyn in the phosphorylation and regulation of the NMDA receptor, we have characterized the tyrosine phosphorylation of NR2A and NR2B by exogenous Src and FynIn the case of NR2A, three potential tyrosine phosphorylation sites have been proposed: Tyr1105, Tyr1267 and Tyr1387 (Zheng et al. 1998; Bi et al. 2000), all of which are similarly located in the C-terminal, cytoplasmic domain.	SIGNOR-247167
P12931	P33151	1	phosphorylation	down-regulates activity	0.567	cadherins also act to prevent epithelial cell motilityCadherin-cytoskeletal interactions occur through a number of adaptor proteins that interact with the C-terminal portion of the cadherin cytoplasmic tail, including the _-, _-, and _-catenin (6, 10). Additionally, VE-cadherin stability at the plasma membrane may be regulated by the binding of p120-catenin to the juxtamembrane region of the cytoplasmic tailWe show here that tyrosine phosphorylation of the adherens junction protein VE-cadherin at two critical tyrosines, Tyr-658 and Tyr-731, via tyrosine kinase activation or phosphatase inactivation was sufficient to prevent the binding of p120- and beta-catenin, respectively, to the cytoplasmic tail of VE-cadherinVE-cadherin becomes phosphorylated on Tyr-658 and/or Tyr-731 in response to Src kinase activity.	SIGNOR-246462
P31749	O43521	1	phosphorylation	down-regulates activity	0.567	Recombinant Akt could directly phosphorylate a GST-Bim(EL) fusion protein and identified the Akt phosphorylation site in the Bim(EL) domain as Ser(87). Further, we demonstrated that cytokine stimulation promotes Bim(EL) binding to 14-3-3 proteins. Finally, we show that mutation of Ser(87) dramatically increases the apoptotic potency of Bim(EL).	SIGNOR-252487
P42345	P30622	1	phosphorylation	up-regulates activity	0.567	By contrast to the phosphorylation of p150 Glued by PKA, inhibition of mTOR by rapamycin inhibited the ability of CLIP-170 to bind to microtubules, suggesting that phosphorylation by mTOR promotes CLIP-170 microtubule binding.\|The new study confirms this physical interaction in animal cells and suggests that mTOR phosphorylates CLIP-170 on some, but not all, of the sites that are phosphorylated in vivo.	SIGNOR-279231
O15530	Q16512	1	phosphorylation	up-regulates	0.567	It is shown that activation in vitro and in vivo involves the activation loop phosphorylation of prk1/2 by 3-phosphoinositide-dependent protein kinase-1 (pdk1) /pdk1 phosphorylates the prks at their conserved activation loop threonines (thr-774 and thr-816 for prk1 and prk2, respectively)	SIGNOR-76640
P25116	P30679	1	binding	up-regulates activity	0.567	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. \| We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. \| The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257353
Q969H0	P24864	1	binding	down-regulates quantity by destabilization	0.567	Cdk2 (S384) and GSK3 (T380) prime cyclin E for destruction. The hyper-phosphorylated T380/S384 degron has high affinity for monomeric Fbw7α, which engages the remainder of the SCF to initiate cyclin E's ubiquitination by an E2 enzyme	SIGNOR-271643
Q12923	Q9BUL8	1	dephosphorylation	down-regulates activity	0.567	In addition, our yeast two-hybrid analysis revealed that CCM3 also binds to the 270-kDa nonreceptor protein tyrosine phos- phatase FAP-1 in a region predicted to contain the C- terminal phosphatase domain [23]. We have shown that this catalytic domain is capable to dephosphorylate CCM3. By dephosphorylation, FAP-1 might therefore negatively reg- ulate CCM3 activity and downstream signaling.	SIGNOR-248714
O75385	Q13501	1	phosphorylation	down-regulates quantity by destabilization	0.567	ULK1 phosphorylates p62 at the Ser403 site.	SIGNOR-278349
Q9UI47	P12830	1	relocalization	up-regulates quantity	0.567	Overexpression of CTNNA3 in a CTNNA1 negative colon carcinoma cell line resulted in the reassembly of the adherens and tight junctions through the recruitment of CTNNA3 interacting partners such as E-cadherin, β-catenin, plakoglobin, and ZO-14	SIGNOR-265492
Q04759	P35568	1	phosphorylation	down-regulates activity	0.567	Protein kinase C Theta inhibits insulin signaling by phosphorylating IRS1 at Ser(1101).	SIGNOR-260906
P02649	P10636	1	binding	up-regulates activity	0.567	Isoform specific interactions of ApoE have been shown with the microtubule-associated protein tau, which forms the neurofibrillary tangle in this disease.\|Phosphorylation of serine262 in domain I of tau decreases tau binding to microtubules and also abolishes binding by ApoE3.	SIGNOR-262588
Q8IVT5	P10398	1	binding	up-regulates activity	0.567	In mammals, RAF family kinases include three catalytically competent enzymes (ARAF, BRAF and CRAF) and two pseudokinases (KSR1 and KSR2) that have been described as scaffolds owing to their apparent ability to bridge RAF isoforms and their substrate, mitogen-activated protein kinase kinase (MEK).Kinase suppressor of Ras (KSR) pseudokinases were also shown to dimerize with kinase-competent RAFs to stimulate catalysis allosterically.	SIGNOR-273876
P45983	P40763	1	phosphorylation	up-regulates activity	0.567	Transfection of the cells with sirna specific for jnk1 revealed that jnk silencing reduced serine727 phosphorylation of stat3,	SIGNOR-235704
Q9H0K1	P35568	1	phosphorylation	down-regulates quantity	0.567	SIK2 is known to attenuate insulin signaling by phosphorylating IRS-1/Ser789	SIGNOR-265745
Q13191	P62993	1	binding	up-regulates activity	0.567	Here we show that in unstimulated Jurkat cells Cbl is co-immunoprecipitated with monoclonal antibody against Grb2.	SIGNOR-236051
P29323	P12931	1	binding	up-regulates	0.566	We propose src kinase as a downstream effector that mediates the neuron's response to eph receptor activation	SIGNOR-58142
P17706	P35968	1	dephosphorylation	down-regulates activity	0.566	We show that a TCPTP substrate-trapping mutant interacts with VEGFR2. Moreover, TCPTP dephosphorylates VEGFR2 in a phosphosite-specific manner, inhibits its kinase activity and prevents its internalization from the cell surface. \|The autophosphorylation sites Tyr1054/1059 and Tyr1214 were dephosphorylated by TCPTP (Fig. 4B). Tyr996, the functional significance of which is currently uncertain (Olsson et al., 2006), was a TCPTP target as well.	SIGNOR-248399
O14672	P01133	1	cleavage	up-regulates activity	0.566	Like ADAM17, ADAM10 has also been implicated in the activation of specific EGFR ligands, especially EGF and betacellulin	SIGNOR-259840
P49336	P84022	1	phosphorylation	down-regulates	0.566	Similarly, tgf-?-Induced and cdk8/9-mediated phosphorylation of smad3 at threonine 179 (t179) is important for binding of the nedd4l e3 ubiquitin ligase, which accelerates smad3 turnover;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3.	SIGNOR-161557
O43295	P63000	1	gtpase-activating protein	down-regulates activity	0.566	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)\|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs\| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260518
Q68EM7	P63000	1	guanine nucleotide exchange factor	up-regulates activity	0.566	ARHGAP17 is a Rho GTPase-activating protein of Rac1	SIGNOR-272166
Q16611	P99999	1	relocalization	up-regulates	0.566	Allosteric activation of bak induces its intramembranous oligomerization into a proposed pore for cytochrome c efflux	SIGNOR-105206
P17612	P63104	1	phosphorylation	down-regulates activity	0.566	Phosphorylation by pka leads to modulation of 14-3-3zeta dimerization and affect its interaction with partner proteins. Substitution of ser58 to ala completely abolished phosphorylation of 14-3-3zeta by pka.	SIGNOR-143373
P06239	P27361	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
P51610	O43889	1	binding	up-regulates activity	0.566	We also show that while interaction with HCF is not required for the ability of Luman to activate transcription when tethered to the GAL4 promoter, it appears to be essential for Luman to activate transcription through CRE sites.	SIGNOR-241372
Q9NVW2	Q86U70	1	polyubiquitination	down-regulates quantity by destabilization	0.566	Here we identify RLIM as a ubiquitin protein ligase that is able to target CLIM cofactors for degradation through the 26S proteasome pathway.	SIGNOR-272617
P28482	P10636	1	phosphorylation	down-regulates activity	0.566	Using nanoelectrospray mass spectrometry, we have undertaken an extensive comparison of phosphorylation in vitro by several candidate tau kinases, namely, JNK, p38, ERK2, and glycogen synthase kinase 3beta (GSK3beta). Between 10 and 15 sites were identified for each kinase. The three MAP kinases phosphorylated Ser202 and Thr205 but not detectably Ser199, whereas conversely GSK3beta phosphorylated Ser199 but not detectably Ser202 or Thr205. Phosphorylated Ser404 was found with all of these kinases except JNK. The MAP kinases may not be strictly proline specific: p38 phosphorylated the nonproline sites Ser185, Thr245, Ser305, and Ser356, whereas ERK2 was the most strict. All of the sites detected except Thr245 and Ser305 are known or suspected phosphorylation sites in paired helical filament-tau extracted from Alzheimer brains. Thus, the three MAP kinases and GSK3beta are importantly all strong candidates as tau kinases that may be involved in the pathogenic hyperphosphorylation of tau in Alzheimer's disease.	SIGNOR-249416
Q2M1Z3	P63000	1	gtpase-activating protein	down-regulates activity	0.566	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)\|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs\| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260489
Q07817	P21796	1	binding	down-regulates activity	0.566	The anti-apoptotic protein Bcl-x(L) closes VDAC by binding to it directly	SIGNOR-249614
P27361	P06239	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
Q13315	P15336	1	phosphorylation	up-regulates	0.566	Here, we demonstrate that the protein kinase atm phosphorylates atf2 on serines 490 and 498 following ionizing radiation (ir). dose- and time-dependent phosphorylation of atf2 by atm that results in its rapid colocalization with gamma-h2ax and mrn components into ir-induced foci (irif)	SIGNOR-137619
Q96J02	O15350	1	ubiquitination	down-regulates quantity by destabilization	0.566	Collectively, our present findings suggest that MDM2 promotes Itch-mediated degradation of p73 through the interaction with Itch in HeLa cells	SIGNOR-278699
Q08209	Q14934	1	dephosphorylation	up-regulates	0.566	Calcineurin directly dephosphorylates nfat resulting in the nuclear import of nfat.	SIGNOR-176379
P53350	Q99741	1	phosphorylation	up-regulates	0.566	Binding between cdc6 and plk1 occurs through the polo-box domain of plk1, and cdc6 is phosphorylated by plk1 on t37. These results suggest that plk1-mediated phosphorylation of cdc6 promotes the interaction of cdc6 and cdk1, leading to the attenuation of cdk1 activity, release of separase, and subsequent anaphase progression.	SIGNOR-169184
P06748	P49450	1	binding	up-regulates activity	0.566	Here we demonstrate that prenucleosomal CENP-A is complexed with histone H4, nucleophosmin 1, and HJURPA minority of NPM1 cofractionated with prenucleosomal CENP-A, consistent with only a small proportion of total NPM1 stably associated with CENP-A. The partial overlap of NPM1 and HJURP with each other supports their formation of distinct prenucleosomal complexes with CENP-A. it is also possible that NPM1 plays a non essential role in the assembly of CENP-A nucleosomes or the nucleophosmin paralogues NPM2 and NPM3 may compensate for the absence of NPM1.	SIGNOR-263708
P78552	P29597	1	binding	up-regulates	0.566	IL-4R, ?c, and IL-13R1 All contain proline-rich box-1 regions that bind jak1, jak3, and tyk2, respectivelyil-4 uses the type ii receptor, and IL-13R1 Binds tyk2. Il-13 results in activation of jak1 and tyk2 in hematopoietic and nonhematopoietic cells.	SIGNOR-100756
P24394	P35568	1	phosphorylation	up-regulates	0.566	Irs-1 and a homologous protein, irs-2 (also known as 4-phosphotyrosine substrate), are recruited to phosphorylated y497 of IL-4R After ligand binding, leading to phosphorylation and activation of irs-1 and irs-2.	SIGNOR-100768
O96017	Q9UQ84	1	phosphorylation	down-regulates activity	0.565	Inhibition of Exo1 activity by the DDR kinase Rad53.\|Unlike Sae2/CtIP activation by CDK, Exo1 phosphorylation by Rad53 limits extended resection of ssDNA at uncapped telomeres and consequently minimizes further activation of the DDR.	SIGNOR-279028
P28482	P53355	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
Q06413	P23409	1	transcriptional regulation	up-regulates quantity by expression	0.565	Myogenin and MEF2 function synergistically to activate the MRF4 promoter during myogenesis.	SIGNOR-238652
P12931	Q9Y4K3	1	phosphorylation	up-regulates activity	0.565	To gain further insights into the molecular mechanisms, we employed mass spectrometry to identify the specific tyrosine residues of Traf6 that are phosphorylated by c-Src.By mutating these phosphorylation sites to phenylalanine, we disrupted Traf6-mediated polyubiquitination and subsequently observed the inactivation of AEP. This finding suggests that the phosphorylation of Traf6 by c-Src is crucial for AEP activation.	SIGNOR-277866
P12931	O43597	1	phosphorylation	up-regulates	0.565	Activation of signalling by fibroblast growth factor receptor leads to phosphorylation of the signalling attenuator human sprouty 2 (hspry2) on residue y55. we show that hspry2 is a direct substrate for src family kinases, including src itself.Phosphorylation of hspry2 is required for hspry2 to inhibit activation of the extracellular signal-regulated kinase pathway.	SIGNOR-131189
P0DP25	P29474	1	binding	up-regulates activity	0.565	Electrons flow from the C-terminal reductase domain of one NOS monomer to the N-terminal oxygenase domain of the other NOS monomer (Siddhanta et al., 1998). The primary mode of enzyme activation is the binding of calcium-bound calmodulin to the N-terminal CaM-binding domain. This facilitates a structure change and the flow of electrons from NADPH through the flavins to the oxygenase domain of the other eNOS monomer	SIGNOR-266339
Q9ULT6	Q9ULV1	1	ubiquitination	down-regulates quantity	0.565	Here we show that the cell-surface transmembrane E3 ubiquitin ligase zinc and ring finger 3 (ZNRF3) and its homologue ring finger 43 (RNF43) are negative feedback regulators of Wnt signalling. ZNRF3 is associated with the Wnt receptor complex, and inhibits Wnt signalling by promoting the turnover of frizzled and LRP6.	SIGNOR-260115
P05771	P14598	1	phosphorylation	up-regulates	0.565	Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation.	SIGNOR-89197
Q12851	Q13233	1	binding	up-regulates	0.565	The mekk1 associated with the gck carboxyl terminus is catalytically active.	SIGNOR-59682
P17655	Q15078	1	cleavage	up-regulates activity	0.565	Calpains also modulate the activity of CDK5. Physiologically, CDK 5 is activated by p35 and its cleaved product p25. The latter has a longer half life than p35 and therefore it is a more potent activator of CDK5. The cleavage of p35 to p25 is mediated by calpain	SIGNOR-251610
P53355	P28482	2	binding	down-regulates	0.565	Conversely, dapk promotes the cytoplasmic retention of erk, thereby inhibiting erk signaling in the nucleus.	SIGNOR-132610
P27361	Q13950	1	phosphorylation	up-regulates	0.565	In this study, we identified two phosphorylation sites in runx2 at ser301 and ser319 that are required for mapk-dependent activation of runx2 transcriptional activity and osteoblast differentiation.	SIGNOR-188347
O43586	Q99952	1	binding	up-regulates activity	0.565	These data confirm the importance of these residues to the binding interaction, and they suggest that much of the COOH-terminal region of PTP HSCF may be required for highest affinity binding to PST PIP.\|Because this protein-protein interaction appears to be required for the dephosphorylation of PST PIP phosphotyrosines (20), it may be a potentially important new mechanism for the regulation of the cytoskeleton.	SIGNOR-262594
P27361	P17655	1	phosphorylation	up-regulates	0.565	Epidermal growth factor activates m-calpain (calpain ii), at least in part, by extracellular signal-regulated kinase-mediated phosphorylation.We now show that erk directly phosphorylates and activates m-calpain both in vitro and in vivo. We identified serine 50 as required for epidermal growth factor (egf)-induced calpain activation in vitro and in vivo.	SIGNOR-123083
P25116	Q03113	1	binding	up-regulates activity	0.565	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. \| We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. \| The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257403
Q96FW1	P04637	1	deubiquitination	up-regulates quantity by stabilization	0.565	Furthermore, although OTUB1 dramatically induced p53 deubiquitination, its mutant (S16A) and deletion mutant did not have this effec	SIGNOR-276528
P23443	Q9BPZ7	1	phosphorylation	down-regulates activity	0.565	Consistently, we detected in vivo Sin1 phosphorylation triggered by S6K1 and to a lesser extent, Akt1, but not other characterized AGC kinases (XREF_FIG and XREF_SUPPLEMENTARY).\|Here we report that phosphorylation of Sin1 at Thr 86 and Thr 398 suppresses mTORC2 kinase activity by dissociating Sin1 from mTORC2.	SIGNOR-279568
B2RTY4	P61586	1	gtpase-activating protein	down-regulates activity	0.565	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)\|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs\| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260508
P78536	O14944	1	cleavage	up-regulates activity	0.565	ADAM17 is involved in the release and activation of several growth factors and cytokine receptor ligands. Among the growth factors activated by ADAM17 are TGF-alpha, amphiregulin, epiregulin and HB-EGF	SIGNOR-259843
Q9C004	Q15569	1	binding	down-regulates activity	0.565	Spry4 negatively regulates the kinase activity of TESK1 by associating with it through the C-terminal cysteine-rich region of Spry4	SIGNOR-253032
P63279	O75030	1	ubiquitination	down-regulates	0.565	Furthermore, we identified lysine 201 as a potential ubiquitination site. A lysine to arginine mutation abolished mitf (k201r) degradation by hubc9 in vivo.	SIGNOR-75117
Q14318	P42345	1	binding	down-regulates	0.565	Fkbp38 binds to mtor and inhibits its activity in a manner similar to that of the fkbp12-rapamycin complex.	SIGNOR-159013
P12931	P78352	1	phosphorylation	up-regulates	0.565	These results indicate that psd-95 phosphorylation by src facilitates the integration of pyk2 to psd-95 signal complex, the activation of pyk2/src, as well as the subsequent tyrosine phosphorylation of nr2a, which ultimately results in the upregulation of nmda receptor function and synaptic transmission.	SIGNOR-205120
O95644	P60568	1	transcriptional regulation	up-regulates quantity by expression	0.565	Together, our results demonstrate that dnNFAT inhibits the production of IL-2. Thus, the NFAT transcription factor contributes to the regulation of IL-2 gene expression and therefore plays a critical role in the initiation of immune responses.	SIGNOR-275405
P17706	P09619	1	dephosphorylation	down-regulates activity	0.564	The PDGF beta receptor is negatively regulated by protein tyrosine phosphatases (PTPs).\|In summary, our findings identify TC-PTP as a previously unrecognized negative regulator of PDGF beta receptor signaling and support the general notion that PTPs display site selectivity in their action on tyrosine kinase receptors.The fact that two of the investigated PDGF β receptor sites, Y1021 and Y771, displayed a larger increase in phosphorylation than Y579 and Y751 in TC-PTP ko MEFs indicated that these two sites are preferred substrates for TC-PTP.	SIGNOR-248389
P28702	Q07869	1	binding	up-regulates	0.564	Although the three ppar subtypes are closely related and bind to similar dna response elements as heterodimers with the 9-cis retinoic acid receptor rxr, each subserves a distinct physiology	SIGNOR-105448
Q7Z5H3	P61586	1	gtpase-activating protein	down-regulates activity	0.564	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)\|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs\| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260476
P17252	P47712	1	phosphorylation	up-regulates	0.564	Pkcalfa, but not pkcbeta, is the predominant cpkc isoenzyme required for cpla2 protein phosphorylation and maximal induction of cpla2 enzymatic activity.	SIGNOR-149406
P62873	P42336	1	binding	up-regulates	0.564	Gbetagamma subunits released from gi can activate pi3k (phosphoinositide 3-kinase), and can be therefore implicated in smo-dependent activation of akt	SIGNOR-145119
P31749	Q14457	1	phosphorylation	down-regulates activity	0.564	In addition, pharmacological inhibition of AKT1 enhanced BECN1 stability in both assays, leaving about twice the amount of BECN1 at 90 min compared to control (Fig. 4i\u2013l).\|The oncogenic kinase AKT1 phosphorylates BECN1 at positions S234, S295, which leads to sequestration of this peripheral membrane binding protein xref to the cytoskeleton with the result of inhibition of autophagy xref .	SIGNOR-279666
P56524	Q02078	1	binding	down-regulates	0.564	We discovered that mef2 interacts with histone deacetylases (hdacs) 4 and 5, resulting in repression of the transcriptional activity of mef2.	SIGNOR-76231
O43318	Q99558	1	phosphorylation	up-regulates activity	0.564	The kinase TAK1 can activate the NIK-I kappaB as well as the MAP kinase cascade in the IL-1 signalling pathway\|Activated TAK1 phosphorylates NIK, which stimulates IKK-alpha activity. Our results indicate that TAK1 links TRAF6 to the NIK-IKK cascade in the IL-1 signalling pathway.	SIGNOR-262833
P31749	Q01813	1	phosphorylation	up-regulates quantity	0.564	A reduction in AKT expression as a result of AKT1 shRNA expression or MK-2206 treatment decreased the half-life of endogenous PFKP, while the expression of active Myr-AKT1 prolonged the half-life of PFKP.\|In addition, depletion of endogenous PFKP and reconstitution of RNAi resistant WT Flag-rPFKP or Flag-rPFKP S386A expression in U251 or U87 and EGFRvIII cells revealed that the S386A mutation abolished PFKP phosphorylation induced by EGF, constitutively active Myr-AKT1, and EGFRvIII.	SIGNOR-279788
Q8WXE9	P63027	1	binding	up-regulates quantity	0.564	the monomeric adaptor proteins AP180/CALM and stonin-2 are required for the efficient retrieval of synaptobrevin II (sybII) and synaptotagmin-1 respectively. Furthermore, recent studies have revealed that sybII and synaptotagmin-1 interact with other SV cargoes to ensure a high fidelity of retrieval.	SIGNOR-264113
Q15120	P29803	1	phosphorylation	down-regulates	0.563	Pdh2 was found to be very similar to pdh1 / in the mechanism of inactivation by phosphorylation of three sites;and (iv) in the phosphorylation of sites 1 and 2 by pdk3 / (ser-264 (site 1), ser-271 (site 2), and ser-203 (site 3)	SIGNOR-143974
Q8N0Z6	Q09472	1	binding	up-regulates activity	0.563	DNA damage activates ATM kinase which then phosphorylates Strap at Ser 203 (red circles). Phosphorylated Strap is stabilized and undergoes nuclear accumulation where it assembles into a co-activator complex, which includes p300 and cofactors such as JMY	SIGNOR-262646
Q15466	O00482	1	binding	down-regulates	0.563	Modulation of human nuclear receptor lrh-1 activity by phospholipids and shpthe human nuclear receptor liver receptor homolog 1 (hlrh-1) plays an important role in the development of breast carcinomas. This orphan receptor is efficiently downregulated by the unusual co-repressor shp	SIGNOR-134202
Q9UH77	Q9H4A3	1	binding	down-regulates quantity by destabilization	0.563	CUL3 assembles with BTB proteins to form Cullin-RING E3 ubiquitin ligase complexes. To explore how a CUL3-KLHL3 complex might operate, we immunoprecipitated KLHL3 and found that it associated strongly with WNK isoforms and CUL3. These results suggest that the CUL3-KLHL3 E3 ligase complex regulates blood pressure via its ability to interact with and ubiquitylate WNK isoforms.	SIGNOR-272099
P28482	P19419	1	phosphorylation	up-regulates activity	0.563	We demonstrate that elk-1, a protein closely related to p62tcf in function, is a nuclear target of two members of the map kinase family, erk1 and erk2, erk1 phosphorylates five c-terminal sites in elk-1 (s324,t336, s383, s389 and s422) with varying degrees of efficiency.	SIGNOR-235455
P06493	Q8NFH5	1	phosphorylation	down-regulates activity	0.563	Collectively, these data show that mitotic hyperphosphorylation of Nup53 by CDK1 and PLK1 contributes to its removal from NPCs.\|The combined mutation of the CDK1 and PLK1 sites to phosphomimetic residues almost completely abolished NPC integration of Nup53, indicating that hyperphosphorylation of Nup53 might be incompatible with its NPC association.	SIGNOR-278917
Q00535	P17600	1	phosphorylation	up-regulates	0.563	Synapsin i (syni), a major sv phosphoprotein involved in the regulation of sv trafficking and neurotransmitter release, is one of the presynaptic substrates of cdk5, which phosphorylates it in its c-terminal region at ser(549) (site 6) and ser(551) (site 7). Phosphorylation of syni by cdk5 is physiologically regulated and enhances its binding to f-actin.	SIGNOR-78883
Q02548	Q04727	1	binding	down-regulates activity	0.563	Grg4 efficiently represses the transcriptional activity of Pax5 in an octapeptide-dependent manner. Similar protein interactions resulting in transcriptional repression were also observed between distantly related members of both the Pax2/5/8 and Groucho protein families	SIGNOR-269083
P56945	P27986	1	binding	up-regulates activity	0.563	One such SH2-domain containing protein is the p85 subunit of PI3K, as its docking with tyrosine-phosphorylated p130cas activates the p110alpha subunit\| tyrosine-165 and tyrosine-128 on p130cas both are phosphorylated to a greater extent in parental versus paxillin Y88F mutan	SIGNOR-263980
P43250	P25025	1	phosphorylation	down-regulates quantity	0.563	GRK2 mainly phosphorylates CXCR1, while GRK6 mediates CXCR2 phosphorylation .\|Overexpression of GRK6 or treatment with CXCR2 siRNA suppresses CXCR2 expression in dorsal root ganglion and significantly reduces pain in animal model of neuropathic pain , .	SIGNOR-279782
P12931	Q13813	1	phosphorylation	up-regulates	0.563	Using mutagenesis on recombinant peptides, we identified the residue y1176 located in the calpain cleavage site of alpha ii-spectrin, near the sh3 domain, as an in vitro substrate for src kinase and lmw-ptp a. phosphorylation of this residue decreases spectrin sensitivity to calpain in vitro.	SIGNOR-86718
P01106	O60885	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
P49841	P10070	1	phosphorylation	down-regulates quantity by destabilization	0.562	The degradation of Gli2 requires the phosphorylation of a cluster of numerous serine residues in its carboxyl terminus by protein kinase A and subsequently by casein kinase 1 and glycogen synthase kinase 3.	SIGNOR-249590
P06213	Q99704	1	phosphorylation	up-regulates activity	0.562	Insulin receptor-mediated p62dok tyrosine phosphorylation at residues 362 and 398. p62(dok) is a direct substrate for the IR tyrosine kinase and that phosphorylation at Tyr(362) and Tyr(398) plays an essential role for p62(dok) to interact with its effectors and negatively regulate the insulin signaling pathway.	SIGNOR-251307
P06241	P78352	1	phosphorylation	up-regulates	0.562	Psd-95 is phosphorylated either by purified src/fyn kinases in vitro or by co-expression of constitutively active src/fyn in cos7 cells. psd-95 tyr(523) phosphorylation contributes to the post-ischaemic over-activation of nmda receptors.	SIGNOR-180449
P04637	O15392	1	binding	down-regulates	0.562	This study identifies the anti-apoptotic survivin gene as a p53-repressed gene;notably, survivin repression by p53 is shown to be distinct from p53-dependent growth arrest.	SIGNOR-111971
Q9Y618	P10275	1	acetylation	down-regulates	0.562	In this study we assessed the effect of smrt and dax-1 on ar and pr activity in the presence of both agonists and partial antagonists. We show that smrt and dax-1 repress agonist-dependent activity of both receptors, and the mechanism of repression includes disruption of the receptor dimer interactions rather than recruitment of histone deacetylases.	SIGNOR-101286
O60885	P01106	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
Q13627	P53805	1	phosphorylation	up-regulates	0.562	In the present study, dyrk1a is shown to directly interact with and phosphorylate rcan1 at ser112 and thr192 residues. Dyrk1a-mediated phosphorylation of rcan1 at ser112 primes the protein for the gsk3_-mediated phosphorylation of ser108.	SIGNOR-102290
Q13501	Q8IZQ1	1	binding	up-regulates quantity	0.562	We show here that p62 is required to recruit the large phosphoinositide-binding protein ALFY to cytoplasmic p62 bodies generated upon amino acid starvation or puromycin-treatment. ALFY, as well as p62, is required for formation and autophagic degradation of cytoplasmic ubiquitin-positive inclusions.	SIGNOR-266792
Q16633	P09086	1	binding	up-regulates	0.562	We have shown previously that both octamer binding transcription factors, namely the ubiquitous oct-1 and the b cell-specific oct-2a protein, can be enhanced in transcriptional activity by their association with the b cell-specific coactivator protein bob1, also calledobf-1or oca-b.	SIGNOR-42278
Q86TM6	P04035	1	polyubiquitination	down-regulates quantity by destabilization	0.562	In the presence of the ubiquitin-conjugating enzyme UBC7, the RING-H2 finger has in vitro ubiquitination activity for Lys(48)-specific polyubiquitin linkage, suggesting that human HRD1 is an E3 ubiquitin ligase involved in protein degradation.Human HRD1 appears to be involved in the basal degradation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase but not in the degradation that is regulated by sterols.	SIGNOR-272594
P12931	Q13177	1	phosphorylation	up-regulates	0.562	Pak2 became tyrosine phosphorylated in its n-terminal regulatory domain, where y130 was identified as the major phosphoacceptor site. Tyrosine phosphorylation-mediated superactivation of pak2 could be induced by overexpression of different src kinases or by inhibiting cellular tyrosine phosphatases with pervanadate and could be blocked by the src kinase inhibitor pp1 or by mutating the y130 residue.	SIGNOR-92460
Q13535	Q14566	1	phosphorylation	up-regulates	0.562	Together these data strongly support the conclusion that mec1 directly targets the s/tq sites in mcm4 and mcm6, although it is formally possible that mec1 and mrc1 activate a different s/tq-directed kinase to target mcm4 and mcm6.	SIGNOR-169450

Q9ULB5

P35222

1

binding

up-regulates activity

0.568

At its C-terminus, cadherin interacts with Î²-catenin, which dynamically associates with Î±-catenin, a direct binding partner of filamentous actin

SIGNOR-265869

Q05655

P29474

1

phosphorylation

down-regulates activity

0.568

The phosphorylation of both S617 and S635 have also been shown to promote increased eNOS-derived NO release (Michell et al., 2002). The phosphorylaiton of S617 can be induced by PKA or Akt activity, and may serve to sensitize eNOS to calmodulin binding and modulate the phosphorylation of other eNOS sites

SIGNOR-251631

P28335

P50148

1

binding

up-regulates activity

0.568

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

SIGNOR-257221

Q9Y3A6

P49755

1

binding

up-regulates activity

0.568

P28 forms hetero-oligomeric complexes with p23. p23 is a major determinant for efficient targeting of p28 to the ERGIC

SIGNOR-261298

P12931

Q12879

1

phosphorylation

up-regulates activity

0.567

To gain further insight into the roles of Src and Fyn in the phosphorylation and regulation of the NMDA receptor, we have characterized the tyrosine phosphorylation of NR2A and NR2B by exogenous Src and FynIn the case of NR2A, three potential tyrosine phosphorylation sites have been proposed: Tyr1105, Tyr1267 and Tyr1387 (Zheng et al. 1998; Bi et al. 2000), all of which are similarly located in the C-terminal, cytoplasmic domain.

SIGNOR-247167

P12931

P33151

1

phosphorylation

down-regulates activity

0.567

cadherins also act to prevent epithelial cell motilityCadherin-cytoskeletal interactions occur through a number of adaptor proteins that interact with the C-terminal portion of the cadherin cytoplasmic tail, including the _-, _-, and _-catenin (6, 10). Additionally, VE-cadherin stability at the plasma membrane may be regulated by the binding of p120-catenin to the juxtamembrane region of the cytoplasmic tailWe show here that tyrosine phosphorylation of the adherens junction protein VE-cadherin at two critical tyrosines, Tyr-658 and Tyr-731, via tyrosine kinase activation or phosphatase inactivation was sufficient to prevent the binding of p120- and beta-catenin, respectively, to the cytoplasmic tail of VE-cadherinVE-cadherin becomes phosphorylated on Tyr-658 and/or Tyr-731 in response to Src kinase activity.

SIGNOR-246462

P31749

O43521

1

phosphorylation

down-regulates activity

0.567

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

SIGNOR-252487

P42345

P30622

1

phosphorylation

up-regulates activity

0.567

By contrast to the phosphorylation of p150 Glued by PKA, inhibition of mTOR by rapamycin inhibited the ability of CLIP-170 to bind to microtubules, suggesting that phosphorylation by mTOR promotes CLIP-170 microtubule binding.|The new study confirms this physical interaction in animal cells and suggests that mTOR phosphorylates CLIP-170 on some, but not all, of the sites that are phosphorylated in vivo.

SIGNOR-279231

O15530

Q16512

1

phosphorylation

up-regulates

0.567

It is shown that activation in vitro and in vivo involves the activation loop phosphorylation of prk1/2 by 3-phosphoinositide-dependent protein kinase-1 (pdk1) /pdk1 phosphorylates the prks at their conserved activation loop threonines (thr-774 and thr-816 for prk1 and prk2, respectively)

SIGNOR-76640

P25116

P30679

1

binding

up-regulates activity

0.567

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

SIGNOR-257353

Q969H0

P24864

1

binding

down-regulates quantity by destabilization

0.567

Cdk2 (S384) and GSK3 (T380) prime cyclin E for destruction. The hyper-phosphorylated T380/S384 degron has high affinity for monomeric Fbw7α, which engages the remainder of the SCF to initiate cyclin E's ubiquitination by an E2 enzyme

SIGNOR-271643

Q12923

Q9BUL8

1

dephosphorylation

down-regulates activity

0.567

In addition, our yeast two-hybrid analysis revealed that CCM3 also binds to the 270-kDa nonreceptor protein tyrosine phos- phatase FAP-1 in a region predicted to contain the C- terminal phosphatase domain [23]. We have shown that this catalytic domain is capable to dephosphorylate CCM3. By dephosphorylation, FAP-1 might therefore negatively reg- ulate CCM3 activity and downstream signaling.

SIGNOR-248714

O75385

Q13501

1

phosphorylation

down-regulates quantity by destabilization

0.567

ULK1 phosphorylates p62 at the Ser403 site.

SIGNOR-278349

Q9UI47

P12830

1

relocalization

up-regulates quantity

0.567

Overexpression of CTNNA3 in a CTNNA1 negative colon carcinoma cell line resulted in the reassembly of the adherens and tight junctions through the recruitment of CTNNA3 interacting partners such as E-cadherin, β-catenin, plakoglobin, and ZO-14

SIGNOR-265492

Q04759

P35568

1

phosphorylation

down-regulates activity

0.567

Protein kinase C Theta inhibits insulin signaling by phosphorylating IRS1 at Ser(1101).

SIGNOR-260906

P02649

P10636

1

binding

up-regulates activity

0.567

Isoform specific interactions of ApoE have been shown with the microtubule-associated protein tau, which forms the neurofibrillary tangle in this disease.|Phosphorylation of serine262 in domain I of tau decreases tau binding to microtubules and also abolishes binding by ApoE3.

SIGNOR-262588

Q8IVT5

P10398

1

binding

up-regulates activity

0.567

In mammals, RAF family kinases include three catalytically competent enzymes (ARAF, BRAF and CRAF) and two pseudokinases (KSR1 and KSR2) that have been described as scaffolds owing to their apparent ability to bridge RAF isoforms and their substrate, mitogen-activated protein kinase kinase (MEK).Kinase suppressor of Ras (KSR) pseudokinases were also shown to dimerize with kinase-competent RAFs to stimulate catalysis allosterically.

SIGNOR-273876

P45983

P40763

1

phosphorylation

up-regulates activity

0.567

Transfection of the cells with sirna specific for jnk1 revealed that jnk silencing reduced serine727 phosphorylation of stat3,

SIGNOR-235704

Q9H0K1

P35568

1

phosphorylation

down-regulates quantity

0.567

SIK2 is known to attenuate insulin signaling by phosphorylating IRS-1/Ser789

SIGNOR-265745

Q13191

P62993

1

binding

up-regulates activity

0.567

Here we show that in unstimulated Jurkat cells Cbl is co-immunoprecipitated with monoclonal antibody against Grb2.

SIGNOR-236051

P29323

P12931

1

binding

up-regulates

0.566

We propose src kinase as a downstream effector that mediates the neuron's response to eph receptor activation

SIGNOR-58142

P17706

P35968

1

dephosphorylation

down-regulates activity

0.566

We show that a TCPTP substrate-trapping mutant interacts with VEGFR2. Moreover, TCPTP dephosphorylates VEGFR2 in a phosphosite-specific manner, inhibits its kinase activity and prevents its internalization from the cell surface. |The autophosphorylation sites Tyr1054/1059 and Tyr1214 were dephosphorylated by TCPTP (Fig. 4B). Tyr996, the functional significance of which is currently uncertain (Olsson et al., 2006), was a TCPTP target as well.

SIGNOR-248399

O14672

P01133

1

cleavage

up-regulates activity

0.566

Like ADAM17, ADAM10 has also been implicated in the activation of specific EGFR ligands, especially EGF and betacellulin

SIGNOR-259840

P49336

P84022

1

phosphorylation

down-regulates

0.566

Similarly, tgf-?-Induced and cdk8/9-mediated phosphorylation of smad3 at threonine 179 (t179) is important for binding of the nedd4l e3 ubiquitin ligase, which accelerates smad3 turnover;cdk8 and cyclint-cdk9 showed a preference for s206 and s214 but also phosphorylated s186 and s195 in the case of smad1;and t179, s208 and s213 in the case of smad3.

SIGNOR-161557

O43295

P63000

1

gtpase-activating protein

down-regulates activity

0.566

We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).

SIGNOR-260518

Q68EM7

P63000

1

guanine nucleotide exchange factor

up-regulates activity

0.566

ARHGAP17 is a Rho GTPase-activating protein of Rac1

SIGNOR-272166

Q16611

P99999

1

relocalization

up-regulates

0.566

Allosteric activation of bak induces its intramembranous oligomerization into a proposed pore for cytochrome c efflux

SIGNOR-105206

P17612

P63104

1

phosphorylation

down-regulates activity

0.566

Phosphorylation by pka leads to modulation of 14-3-3zeta dimerization and affect its interaction with partner proteins. Substitution of ser58 to ala completely abolished phosphorylation of 14-3-3zeta by pka.

SIGNOR-143373

P06239

P27361

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

P51610

O43889

1

binding

up-regulates activity

0.566

We also show that while interaction with HCF is not required for the ability of Luman to activate transcription when tethered to the GAL4 promoter, it appears to be essential for Luman to activate transcription through CRE sites.

SIGNOR-241372

Q9NVW2

Q86U70

1

polyubiquitination

down-regulates quantity by destabilization

0.566

Here we identify RLIM as a ubiquitin protein ligase that is able to target CLIM cofactors for degradation through the 26S proteasome pathway.

SIGNOR-272617

P28482

P10636

1

phosphorylation

down-regulates activity

0.566

Using nanoelectrospray mass spectrometry, we have undertaken an extensive comparison of phosphorylation in vitro by several candidate tau kinases, namely, JNK, p38, ERK2, and glycogen synthase kinase 3beta (GSK3beta). Between 10 and 15 sites were identified for each kinase. The three MAP kinases phosphorylated Ser202 and Thr205 but not detectably Ser199, whereas conversely GSK3beta phosphorylated Ser199 but not detectably Ser202 or Thr205. Phosphorylated Ser404 was found with all of these kinases except JNK. The MAP kinases may not be strictly proline specific: p38 phosphorylated the nonproline sites Ser185, Thr245, Ser305, and Ser356, whereas ERK2 was the most strict. All of the sites detected except Thr245 and Ser305 are known or suspected phosphorylation sites in paired helical filament-tau extracted from Alzheimer brains. Thus, the three MAP kinases and GSK3beta are importantly all strong candidates as tau kinases that may be involved in the pathogenic hyperphosphorylation of tau in Alzheimer's disease.

SIGNOR-249416

Q2M1Z3

P63000

1

gtpase-activating protein

down-regulates activity

0.566

We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).

SIGNOR-260489

Q07817

P21796

1

binding

down-regulates activity

0.566

The anti-apoptotic protein Bcl-x(L) closes VDAC by binding to it directly

SIGNOR-249614

P27361

P06239

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

Q13315

P15336

1

phosphorylation

up-regulates

0.566

Here, we demonstrate that the protein kinase atm phosphorylates atf2 on serines 490 and 498 following ionizing radiation (ir). dose- and time-dependent phosphorylation of atf2 by atm that results in its rapid colocalization with gamma-h2ax and mrn components into ir-induced foci (irif)

SIGNOR-137619

Q96J02

O15350

1

ubiquitination

down-regulates quantity by destabilization

0.566

Collectively, our present findings suggest that MDM2 promotes Itch-mediated degradation of p73 through the interaction with Itch in HeLa cells

SIGNOR-278699

Q08209

Q14934

1

dephosphorylation

up-regulates

0.566

Calcineurin directly dephosphorylates nfat resulting in the nuclear import of nfat.

SIGNOR-176379

P53350

Q99741

1

phosphorylation

up-regulates

0.566

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

SIGNOR-169184

P06748

P49450

1

binding

up-regulates activity

0.566

Here we demonstrate that prenucleosomal CENP-A is complexed with histone H4, nucleophosmin 1, and HJURPA minority of NPM1 cofractionated with prenucleosomal CENP-A, consistent with only a small proportion of total NPM1 stably associated with CENP-A. The partial overlap of NPM1 and HJURP with each other supports their formation of distinct prenucleosomal complexes with CENP-A. it is also possible that NPM1 plays a non essential role in the assembly of CENP-A nucleosomes or the nucleophosmin paralogues NPM2 and NPM3 may compensate for the absence of NPM1.

SIGNOR-263708

P78552

P29597

1

binding

up-regulates

0.566

IL-4R, ?c, and IL-13R1 All contain proline-rich box-1 regions that bind jak1, jak3, and tyk2, respectivelyil-4 uses the type ii receptor, and IL-13R1 Binds tyk2. Il-13 results in activation of jak1 and tyk2 in hematopoietic and nonhematopoietic cells.

SIGNOR-100756

P24394

P35568

1

phosphorylation

up-regulates

0.566

Irs-1 and a homologous protein, irs-2 (also known as 4-phosphotyrosine substrate), are recruited to phosphorylated y497 of IL-4R After ligand binding, leading to phosphorylation and activation of irs-1 and irs-2.

SIGNOR-100768

O96017

Q9UQ84

1

phosphorylation

down-regulates activity

0.565

Inhibition of Exo1 activity by the DDR kinase Rad53.|Unlike Sae2/CtIP activation by CDK, Exo1 phosphorylation by Rad53 limits extended resection of ssDNA at uncapped telomeres and consequently minimizes further activation of the DDR.

SIGNOR-279028

P28482

P53355

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

Q06413

P23409

1

transcriptional regulation

up-regulates quantity by expression

0.565

Myogenin and MEF2 function synergistically to activate the MRF4 promoter during myogenesis.

SIGNOR-238652

P12931

Q9Y4K3

1

phosphorylation

up-regulates activity

0.565

To gain further insights into the molecular mechanisms, we employed mass spectrometry to identify the specific tyrosine residues of Traf6 that are phosphorylated by c-Src.By mutating these phosphorylation sites to phenylalanine, we disrupted Traf6-mediated polyubiquitination and subsequently observed the inactivation of AEP. This finding suggests that the phosphorylation of Traf6 by c-Src is crucial for AEP activation.

SIGNOR-277866

P12931

O43597

1

phosphorylation

up-regulates

0.565

Activation of signalling by fibroblast growth factor receptor leads to phosphorylation of the signalling attenuator human sprouty 2 (hspry2) on residue y55. we show that hspry2 is a direct substrate for src family kinases, including src itself.Phosphorylation of hspry2 is required for hspry2 to inhibit activation of the extracellular signal-regulated kinase pathway.

SIGNOR-131189

P0DP25

P29474

1

binding

up-regulates activity

0.565

Electrons flow from the C-terminal reductase domain of one NOS monomer to the N-terminal oxygenase domain of the other NOS monomer (Siddhanta et al., 1998). The primary mode of enzyme activation is the binding of calcium-bound calmodulin to the N-terminal CaM-binding domain. This facilitates a structure change and the flow of electrons from NADPH through the flavins to the oxygenase domain of the other eNOS monomer

SIGNOR-266339

Q9ULT6

Q9ULV1

1

ubiquitination

down-regulates quantity

0.565

Here we show that the cell-surface transmembrane E3 ubiquitin ligase zinc and ring finger 3 (ZNRF3) and its homologue ring finger 43 (RNF43) are negative feedback regulators of Wnt signalling. ZNRF3 is associated with the Wnt receptor complex, and inhibits Wnt signalling by promoting the turnover of frizzled and LRP6.

SIGNOR-260115

P05771

P14598

1

phosphorylation

up-regulates

0.565

Phosphopeptide mapping of p47(phox) showed that, as opposed to pkc zeta, pkc alpha, beta ii, and delta are able to phosphorylate all the major pkc sites. The use of p47(phox) mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc alpha, beta ii, and delta.Taken together, these results suggest that pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation.

SIGNOR-89197

Q12851

Q13233

1

binding

up-regulates

0.565

The mekk1 associated with the gck carboxyl terminus is catalytically active.

SIGNOR-59682

P17655

Q15078

1

cleavage

up-regulates activity

0.565

Calpains also modulate the activity of CDK5. Physiologically, CDK 5 is activated by p35 and its cleaved product p25. The latter has a longer half life than p35 and therefore it is a more potent activator of CDK5. The cleavage of p35 to p25 is mediated by calpain

SIGNOR-251610

P53355

P28482

2

binding

down-regulates

0.565

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

SIGNOR-132610

P27361

Q13950

1

phosphorylation

up-regulates

0.565

In this study, we identified two phosphorylation sites in runx2 at ser301 and ser319 that are required for mapk-dependent activation of runx2 transcriptional activity and osteoblast differentiation.

SIGNOR-188347

O43586

Q99952

1

binding

up-regulates activity

0.565

These data confirm the importance of these residues to the binding interaction, and they suggest that much of the COOH-terminal region of PTP HSCF may be required for highest affinity binding to PST PIP.|Because this protein-protein interaction appears to be required for the dephosphorylation of PST PIP phosphotyrosines (20), it may be a potentially important new mechanism for the regulation of the cytoskeleton.

SIGNOR-262594

P27361

P17655

1

phosphorylation

up-regulates

0.565

Epidermal growth factor activates m-calpain (calpain ii), at least in part, by extracellular signal-regulated kinase-mediated phosphorylation.We now show that erk directly phosphorylates and activates m-calpain both in vitro and in vivo. We identified serine 50 as required for epidermal growth factor (egf)-induced calpain activation in vitro and in vivo.

SIGNOR-123083

P25116

Q03113

1

binding

up-regulates activity

0.565

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

SIGNOR-257403

Q96FW1

P04637

1

deubiquitination

up-regulates quantity by stabilization

0.565

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

SIGNOR-276528

P23443

Q9BPZ7

1

phosphorylation

down-regulates activity

0.565

Consistently, we detected in vivo Sin1 phosphorylation triggered by S6K1 and to a lesser extent, Akt1, but not other characterized AGC kinases (XREF_FIG and XREF_SUPPLEMENTARY).|Here we report that phosphorylation of Sin1 at Thr 86 and Thr 398 suppresses mTORC2 kinase activity by dissociating Sin1 from mTORC2.

SIGNOR-279568

B2RTY4

P61586

1

gtpase-activating protein

down-regulates activity

0.565

We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).

SIGNOR-260508

P78536

O14944

1

cleavage

up-regulates activity

0.565

ADAM17 is involved in the release and activation of several growth factors and cytokine receptor ligands. Among the growth factors activated by ADAM17 are TGF-alpha, amphiregulin, epiregulin and HB-EGF

SIGNOR-259843

Q9C004

Q15569

1

binding

down-regulates activity

0.565

Spry4 negatively regulates the kinase activity of TESK1 by associating with it through the C-terminal cysteine-rich region of Spry4

SIGNOR-253032

P63279

O75030

1

ubiquitination

down-regulates

0.565

Furthermore, we identified lysine 201 as a potential ubiquitination site. A lysine to arginine mutation abolished mitf (k201r) degradation by hubc9 in vivo.

SIGNOR-75117

Q14318

P42345

1

binding

down-regulates

0.565

Fkbp38 binds to mtor and inhibits its activity in a manner similar to that of the fkbp12-rapamycin complex.

SIGNOR-159013

P12931

P78352

1

phosphorylation

up-regulates

0.565

These results indicate that psd-95 phosphorylation by src facilitates the integration of pyk2 to psd-95 signal complex, the activation of pyk2/src, as well as the subsequent tyrosine phosphorylation of nr2a, which ultimately results in the upregulation of nmda receptor function and synaptic transmission.

SIGNOR-205120

O95644

P60568

1

transcriptional regulation

up-regulates quantity by expression

0.565

Together, our results demonstrate that dnNFAT inhibits the production of IL-2. Thus, the NFAT transcription factor contributes to the regulation of IL-2 gene expression and therefore plays a critical role in the initiation of immune responses.

SIGNOR-275405

P17706

P09619

1

dephosphorylation

down-regulates activity

0.564

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

SIGNOR-248389

P28702

Q07869

1

binding

up-regulates

0.564

Although the three ppar subtypes are closely related and bind to similar dna response elements as heterodimers with the 9-cis retinoic acid receptor rxr, each subserves a distinct physiology

SIGNOR-105448

Q7Z5H3

P61586

1

gtpase-activating protein

down-regulates activity

0.564

We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).

SIGNOR-260476

P17252

P47712

1

phosphorylation

up-regulates

0.564

Pkcalfa, but not pkcbeta, is the predominant cpkc isoenzyme required for cpla2 protein phosphorylation and maximal induction of cpla2 enzymatic activity.

SIGNOR-149406

P62873

P42336

1

binding

up-regulates

0.564

Gbetagamma subunits released from gi can activate pi3k (phosphoinositide 3-kinase), and can be therefore implicated in smo-dependent activation of akt

SIGNOR-145119

P31749

Q14457

1

phosphorylation

down-regulates activity

0.564

In addition, pharmacological inhibition of AKT1 enhanced BECN1 stability in both assays, leaving about twice the amount of BECN1 at 90 min compared to control (Fig. 4i\u2013l).|The oncogenic kinase AKT1 phosphorylates BECN1 at positions S234, S295, which leads to sequestration of this peripheral membrane binding protein xref to the cytoskeleton with the result of inhibition of autophagy xref .

SIGNOR-279666

P56524

Q02078

1

binding

down-regulates

0.564

We discovered that mef2 interacts with histone deacetylases (hdacs) 4 and 5, resulting in repression of the transcriptional activity of mef2.

SIGNOR-76231

O43318

Q99558

1

phosphorylation

up-regulates activity

0.564

The kinase TAK1 can activate the NIK-I kappaB as well as the MAP kinase cascade in the IL-1 signalling pathway|Activated TAK1 phosphorylates NIK, which stimulates IKK-alpha activity. Our results indicate that TAK1 links TRAF6 to the NIK-IKK cascade in the IL-1 signalling pathway.

SIGNOR-262833

P31749

Q01813

1

phosphorylation

up-regulates quantity

0.564

A reduction in AKT expression as a result of AKT1 shRNA expression or MK-2206 treatment decreased the half-life of endogenous PFKP, while the expression of active Myr-AKT1 prolonged the half-life of PFKP.|In addition, depletion of endogenous PFKP and reconstitution of RNAi resistant WT Flag-rPFKP or Flag-rPFKP S386A expression in U251 or U87 and EGFRvIII cells revealed that the S386A mutation abolished PFKP phosphorylation induced by EGF, constitutively active Myr-AKT1, and EGFRvIII.

SIGNOR-279788

Q8WXE9

P63027

1

binding

up-regulates quantity

0.564

the monomeric adaptor proteins AP180/CALM and stonin-2 are required for the efficient retrieval of synaptobrevin II (sybII) and synaptotagmin-1 respectively. Furthermore, recent studies have revealed that sybII and synaptotagmin-1 interact with other SV cargoes to ensure a high fidelity of retrieval.

SIGNOR-264113

Q15120

P29803

1

phosphorylation

down-regulates

0.563

Pdh2 was found to be very similar to pdh1 / in the mechanism of inactivation by phosphorylation of three sites;and (iv) in the phosphorylation of sites 1 and 2 by pdk3 / (ser-264 (site 1), ser-271 (site 2), and ser-203 (site 3)

SIGNOR-143974

Q8N0Z6

Q09472

1

binding

up-regulates activity

0.563

DNA damage activates ATM kinase which then phosphorylates Strap at Ser 203 (red circles). Phosphorylated Strap is stabilized and undergoes nuclear accumulation where it assembles into a co-activator complex, which includes p300 and cofactors such as JMY

SIGNOR-262646

Q15466

O00482

1

binding

down-regulates

0.563

Modulation of human nuclear receptor lrh-1 activity by phospholipids and shpthe human nuclear receptor liver receptor homolog 1 (hlrh-1) plays an important role in the development of breast carcinomas. This orphan receptor is efficiently downregulated by the unusual co-repressor shp

SIGNOR-134202

Q9UH77

Q9H4A3

1

binding

down-regulates quantity by destabilization

0.563

CUL3 assembles with BTB proteins to form Cullin-RING E3 ubiquitin ligase complexes. To explore how a CUL3-KLHL3 complex might operate, we immunoprecipitated KLHL3 and found that it associated strongly with WNK isoforms and CUL3. These results suggest that the CUL3-KLHL3 E3 ligase complex regulates blood pressure via its ability to interact with and ubiquitylate WNK isoforms.

SIGNOR-272099

P28482

P19419

1

phosphorylation

up-regulates activity

0.563

We demonstrate that elk-1, a protein closely related to p62tcf in function, is a nuclear target of two members of the map kinase family, erk1 and erk2, erk1 phosphorylates five c-terminal sites in elk-1 (s324,t336, s383, s389 and s422) with varying degrees of efficiency.

SIGNOR-235455

P06493

Q8NFH5

1

phosphorylation

down-regulates activity

0.563

Collectively, these data show that mitotic hyperphosphorylation of Nup53 by CDK1 and PLK1 contributes to its removal from NPCs.|The combined mutation of the CDK1 and PLK1 sites to phosphomimetic residues almost completely abolished NPC integration of Nup53, indicating that hyperphosphorylation of Nup53 might be incompatible with its NPC association.

SIGNOR-278917

Q00535

P17600

1

phosphorylation

up-regulates

0.563

Synapsin i (syni), a major sv phosphoprotein involved in the regulation of sv trafficking and neurotransmitter release, is one of the presynaptic substrates of cdk5, which phosphorylates it in its c-terminal region at ser(549) (site 6) and ser(551) (site 7). Phosphorylation of syni by cdk5 is physiologically regulated and enhances its binding to f-actin.

SIGNOR-78883

Q02548

Q04727

1

binding

down-regulates activity

0.563

Grg4 efficiently represses the transcriptional activity of Pax5 in an octapeptide-dependent manner. Similar protein interactions resulting in transcriptional repression were also observed between distantly related members of both the Pax2/5/8 and Groucho protein families

SIGNOR-269083

P56945

P27986

1

binding

up-regulates activity

0.563

One such SH2-domain containing protein is the p85 subunit of PI3K, as its docking with tyrosine-phosphorylated p130cas activates the p110alpha subunit| tyrosine-165 and tyrosine-128 on p130cas both are phosphorylated to a greater extent in parental versus paxillin Y88F mutan

SIGNOR-263980

P43250

P25025

1

phosphorylation

down-regulates quantity

0.563

GRK2 mainly phosphorylates CXCR1, while GRK6 mediates CXCR2 phosphorylation .|Overexpression of GRK6 or treatment with CXCR2 siRNA suppresses CXCR2 expression in dorsal root ganglion and significantly reduces pain in animal model of neuropathic pain , .

SIGNOR-279782

P12931

Q13813

1

phosphorylation

up-regulates

0.563

Using mutagenesis on recombinant peptides, we identified the residue y1176 located in the calpain cleavage site of alpha ii-spectrin, near the sh3 domain, as an in vitro substrate for src kinase and lmw-ptp a. phosphorylation of this residue decreases spectrin sensitivity to calpain in vitro.

SIGNOR-86718

P01106

O60885

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

P49841

P10070

1

phosphorylation

down-regulates quantity by destabilization

0.562

The degradation of Gli2 requires the phosphorylation of a cluster of numerous serine residues in its carboxyl terminus by protein kinase A and subsequently by casein kinase 1 and glycogen synthase kinase 3.

SIGNOR-249590

P06213

Q99704

1

phosphorylation

up-regulates activity

0.562

Insulin receptor-mediated p62dok tyrosine phosphorylation at residues 362 and 398. p62(dok) is a direct substrate for the IR tyrosine kinase and that phosphorylation at Tyr(362) and Tyr(398) plays an essential role for p62(dok) to interact with its effectors and negatively regulate the insulin signaling pathway.

SIGNOR-251307

P06241

P78352

1

phosphorylation

up-regulates

0.562

Psd-95 is phosphorylated either by purified src/fyn kinases in vitro or by co-expression of constitutively active src/fyn in cos7 cells. psd-95 tyr(523) phosphorylation contributes to the post-ischaemic over-activation of nmda receptors.

SIGNOR-180449

P04637

O15392

1

binding

down-regulates

0.562

This study identifies the anti-apoptotic survivin gene as a p53-repressed gene;notably, survivin repression by p53 is shown to be distinct from p53-dependent growth arrest.

SIGNOR-111971

Q9Y618

P10275

1

acetylation

down-regulates

0.562

In this study we assessed the effect of smrt and dax-1 on ar and pr activity in the presence of both agonists and partial antagonists. We show that smrt and dax-1 repress agonist-dependent activity of both receptors, and the mechanism of repression includes disruption of the receptor dimer interactions rather than recruitment of histone deacetylases.

SIGNOR-101286

O60885

P01106

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

Q13627

P53805

1

phosphorylation

up-regulates

0.562

In the present study, dyrk1a is shown to directly interact with and phosphorylate rcan1 at ser112 and thr192 residues. Dyrk1a-mediated phosphorylation of rcan1 at ser112 primes the protein for the gsk3_-mediated phosphorylation of ser108.

SIGNOR-102290

Q13501

Q8IZQ1

1

binding

up-regulates quantity

0.562

We show here that p62 is required to recruit the large phosphoinositide-binding protein ALFY to cytoplasmic p62 bodies generated upon amino acid starvation or puromycin-treatment. ALFY, as well as p62, is required for formation and autophagic degradation of cytoplasmic ubiquitin-positive inclusions.

SIGNOR-266792

Q16633

P09086

1

binding

up-regulates

0.562

We have shown previously that both octamer binding transcription factors, namely the ubiquitous oct-1 and the b cell-specific oct-2a protein, can be enhanced in transcriptional activity by their association with the b cell-specific coactivator protein bob1, also calledobf-1or oca-b.

SIGNOR-42278

Q86TM6

P04035

1

polyubiquitination

down-regulates quantity by destabilization

0.562

In the presence of the ubiquitin-conjugating enzyme UBC7, the RING-H2 finger has in vitro ubiquitination activity for Lys(48)-specific polyubiquitin linkage, suggesting that human HRD1 is an E3 ubiquitin ligase involved in protein degradation.Human HRD1 appears to be involved in the basal degradation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase but not in the degradation that is regulated by sterols.

SIGNOR-272594

P12931

Q13177

1

phosphorylation

up-regulates

0.562

Pak2 became tyrosine phosphorylated in its n-terminal regulatory domain, where y130 was identified as the major phosphoacceptor site. Tyrosine phosphorylation-mediated superactivation of pak2 could be induced by overexpression of different src kinases or by inhibiting cellular tyrosine phosphatases with pervanadate and could be blocked by the src kinase inhibitor pp1 or by mutating the y130 residue.

SIGNOR-92460

Q13535

Q14566

1

phosphorylation

up-regulates

0.562

Together these data strongly support the conclusion that mec1 directly targets the s/tq sites in mcm4 and mcm6, although it is formally possible that mec1 and mrc1 activate a different s/tq-directed kinase to target mcm4 and mcm6.

SIGNOR-169450