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
P42566	P00533	2	phosphorylation	up-regulates	0.755	Earlier studies have shown that eps15 at tyr-849 is phosphorylated in egf-stimulated cells and partly controls the internalization of mono-ubiquitinated egfr via uim domains of eps15 [10]. It has also been shown that active egfr phosphorylates tyr-849 directly;	SIGNOR-203311
P42345	Q8TB45	2	binding	down-regulates activity	0.755	DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival	SIGNOR-251657
Q8TB45	P42345	2	phosphorylation	down-regulates	0.755	Our data reveal critical roles for mtor itself as well as cki in generating a degron in deptor that is recognized by _-trcp, and promotes deptor turnover by the proteasome.	SIGNOR-176849
P00533	P42566	2	binding	down-regulates activity	0.755	We suggest that the ubiquitinated EGFR or another c-Cbl substrate that is ubiquitinated upon EGFR activation recruits Eps15 to the plasma membrane via its UIM. This event would facilitate EGFR internalization via a clathrin-dependent route in which Eps15 plays a role	SIGNOR-243278
Q9Y572	Q13546	2	phosphorylation	up-regulates activity	0.754	In the current scenario, RIPK1 phosphorylates and activates RIPK3, and activated RIPK3 then phosphorylates MLKL.	SIGNOR-278429
Q13546	Q9Y572	2	phosphorylation	up-regulates activity	0.754	Collectively, TAK1 activates RIPK3, RIPK3 activates TAK1, and RIPK1 activates RIPK3 and facilitates interaction between TAK1 and RIPK3.\|RIPK1 kinase activity is required for RIPK3 phosphorylation, and reciprocally RIPK3 phosphorylates RIPK1.	SIGNOR-280106
Q9BVA0	O75449	2	binding	up-regulates activity	0.753	In its active ATP-bound state, KATNA1 forms hexameric rings capable of binding to and severing microtubule polymers. Typically, KATNA1 binding to KATNB1 enhances severing, likely due to KATNB1 increasing the stability of the KATNA1 hexamer	SIGNOR-267174
O75449	Q9BVA0	2	binding	up-regulates quantity by stabilization	0.753	In its active ATP-bound state, KATNA1 forms hexameric rings capable of binding to and severing microtubule polymers. Typically, KATNA1 binding to KATNB1 enhances severing, likely due to KATNB1 increasing the stability of the KATNA1 hexamer	SIGNOR-267173
Q99640	P06493	2	phosphorylation	down-regulates activity	0.752	Active Cdk1 phosphorylates and inhibits Wee1 and Myt1 kinases and phosphorylates and activates the Cdc25 phosphatases.	SIGNOR-279600
P06493	Q99640	2	phosphorylation	down-regulates	0.752	Myt1hu preferentially phosphorylates cdc2 on threonine 14 in a cyclin-dependent manner;phosphorylation of threonine 14 and tyrosine 15 is inhibitory.	SIGNOR-45729
O75143	Q8IYT8	2	phosphorylation	up-regulates	0.75	Ulks directly phosphorylates atg13.	SIGNOR-184126
P28482	Q02750	2	phosphorylation	up-regulates activity	0.75	Mapk1 is phosphorylated by map2k1/mek1 and map2k2/mek2 on thr-185 and tyr-187 in response to external stimuli like insulin or ngf. Both phosphorylations are required for activity.	SIGNOR-236447
Q02750	P28482	2	phosphorylation	down-regulates activity	0.75	We propose that activation of erk during adhesion creates a feedback system in which erk phosphorylates mek1 on t292, and this in turn blocks additional s298 phosphorylation in response to integrin signaling.	SIGNOR-236335
Q8IYT8	O75143	2	binding	up-regulates	0.75	He mammalian atg13 binds both ulk1 and ulk2 and mediates the interaction of the ulk proteins with fip200. The binding of atg13 stabilizes and activates ulk and facilitates the phosphorylation of fip200 by ulk	SIGNOR-184123
Q02750	P04049	2	phosphorylation	up-regulates activity	0.749	Among other effectors, active ras binds and activates the raf kinase, iniziating a kinase cascade involving serine phosporylation of mek1/2 (mapkk) and tyrosine and threonine phosphorylation of erk1/2 active raf phosphorylates mek phospholpeptide analysis demostrated that serine residues 218 and 222 of human mek1 are the primary sites for phosphorylation by c-raf.	SIGNOR-235987
P09619	Q06124	2	dephosphorylation	down-regulates activity	0.749	Upon activation, the βPDGFR is phosphorylated at multiple tyrosine residues and thereby becomes a docking site for SH2-domain-containing signal transduction proteins.\|While all phosphotyrosine sites on the βPDGFR are equally good targets for rPTP1B, maps of the βPDGFR dephosphorylated by rSyp showed that rSyp had a distinct preference for certain sites (Fig. 4 D-F). The low dose of rSyp primarily dephosphorylated spots 1, 6, 7, 9, and to a lesser extent 8a\|Spot 1 corresponds to tyrosine 751; spot 3 corresponds to tyrosine 1009; spot 6 corresponds to tyrosine 740; spot 8b corresponds to tyrosine 1021; spot 9 corresponds to tyrosine 771, and spots 2, 7, and 8a are as yet unidentified phosphopeptides	SIGNOR-248669
Q06124	P09619	2	phosphorylation	up-regulates activity	0.749	Upon PDGF stimulation, SHPTP2 binds to the PDGFR and becomes tyrosine-phosphorylated. We have identified tyrosine-542 (pY542TNI) as the major in vivo site of SHPTP2 tyrosine phosphorylation. phosphorylation of SHPTP2 couples Grb2 to PDGFR in vivo, providing a mechanism for Ras activation by PDGFR and for positive signaling via SHPTP2 and Csw.	SIGNOR-250260
P04049	Q02750	2	phosphorylation	up-regulates activity	0.749	In addition, though MEK-1 was able to induce C-Raf phosphorylation at the S338 site, which was shown to play a role in C-Raf activation by certain growth factors [ xref ], MEK-1 was able to bind and activate the S338/339A C-Raf mutant, suggesting that the MEK-1-induced C-Raf activation does not require phosphorylation at these sites ( xref , lanes 4, 5, left panel and lanes 6\u20139, right panel).\|MEK-1-induced C-Raf activation is Ras independent.	SIGNOR-279627
P49767	O60462	2	binding	up-regulates	0.748	By in vitro binding studies we found that both vegf-c and vegf-d interact with np2, vegf-c in a heparin-independent and vegf-d in a heparin-dependent manner.	SIGNOR-147530
O60462	P49767	2	binding	up-regulates	0.748	The functional importance of the interaction of np2 with the lymphangiogenic growth factors was demonstrated by cointernalization of np2 along with vegfr-3 in endocytic vesicles of lymphatic endothelial cells upon stimulation with vegf-c or vegf-d.	SIGNOR-147611
Q969J5	Q9GZX6	2	binding	down-regulates	0.746	We identified a gene encoding a protein of 231 aa, showing 33 and 34% amino acid identity with the extracellular domains of the il-22 receptor and of the il-20r/cytokine receptor family 2-8,the recombinant protein was found to bind il-10-related t cell-derived inducible factor/il-22, and to inhibit the activity of this cytokine on hepatocytes and intestinal epithelial cells. We propose to name this natural cytokine antagonist il-22bp for il-22 binding protein. respectively, but lacking the transmembrane and cytoplasmic domains	SIGNOR-86110
Q9GZX6	Q969J5	2	binding	up-regulates	0.746	Il-22 mediates inflammation and binds class ii cytokine receptor heterodimers il-22 ra1/crf2-4.	SIGNOR-86113
Q9UPT6	P53779	2	phosphorylation	up-regulates	0.745	Phosphoamino acid analysis confirmed that jnk caused thr phosphorylation of jip3 (fig. _(fig.3c).3c). This phosphorylation on thr was markedly decreased when thr266, thr276, and thr287 were replaced with ala. These data indicate that jnk phosphorylated jip3 on thr266, thr276, and thr287 in vitro.	SIGNOR-134533
P53779	Q9UPT6	2	binding	up-regulates	0.745	The c-jun nh2-terminal kinase (jnk)-interacting protein (jip) group of scaffold proteins (jip1, jip2, and jip3) can interact with components of the jnk signaling pathway and potently activate jnk.	SIGNOR-134555
P12931	P18433	2	dephosphorylation	up-regulates activity	0.743	Several protein tyrosine phosphatases are capable of activating Src by dephosphorylating Y530 (reviewed in ref. 9). These include PTP-α, PTP-λ, SHP-1, SHP-2, and PTP1B	SIGNOR-248437
P18433	P12931	2	phosphorylation	up-regulates activity	0.743	Transient overexpression of c-src together with rptp alpha in human embryonic kidney 293 cells increased phosphorylation of tyr789, suggesting that c-src may phosphorylate rptp alpha in vivo.	SIGNOR-111306
P31749	P18031	2	dephosphorylation	down-regulates	0.742	Whereas insulin-induced phosphatidylinositol 3-kinase/akt signaling was prolonged in both tcptp-/- and ptp1b-/- immortalized mouse embryo fibroblasts (mefs), mitogen-activated protein kinase erk1/2 signaling was elevated only in ptp1b- mefs	SIGNOR-252639
P18031	P31749	2	phosphorylation	down-regulates activity	0.742	Phosphorylation of ptp1b at ser(50) by akt impairs its ability to dephosphorylate the insulin receptor.	SIGNOR-252542
Q14790	P55212	2	cleavage	up-regulates	0.735	This pathway can either be ampli?ed By caspase- 8-mediated cleavage of bid and by the downstream, caspase-6- mediated cleavage of caspase-8.	SIGNOR-109411
P55212	Q14790	2	cleavage	up-regulates	0.735	Casp8 can activate downstream caspases like caspase-6, and caspase-7 by directly cleaving them.	SIGNOR-59857
P07948	P29350	2	dephosphorylation	down-regulates activity	0.734	SHP-1 efficiently inhibits Lyn autophosphorylation and suppresses FcϵRI stimulation\|We found that PTPα and SHP-1 both dephosphorylate Lyn exclusively at Tyr-397	SIGNOR-248471
P29350	P07948	2	phosphorylation	up-regulates activity	0.734	Lyn phosphorylates SHPTP1 at the C-terminal Tyr-564 site. Lyn-mediated phosphorylation of SHPTP1 stimulates SHPTP1 tyrosine phosphatase activity.	SIGNOR-251409
O15151	Q00987	2	ubiquitination	down-regulates	0.733	The mdm2 homolog mdmx is an important regulator of p53 during mouse embryonic development. Dna damage promotes mdmx phosphorylation, nuclear translocation, and degradation by mdm2.	SIGNOR-144970
Q00987	O15151	2	binding	up-regulates quantity by stabilization	0.733	MDM2 has been shown to be degraded by the ubiquitin-proteasome pathway, while MDMX was a stable protein. Interaction of MDMX with MDM2 through the C-terminal RING finger domains resulted in inhibiting degradation of MDM2. These data indicate that MDMX functions as a regulator of MDM2.	SIGNOR-272932
Q9NPH3	P14778	2	binding	up-regulates activity	0.73	Binding of IL-1 to its receptor results in rapid assembly of a membrane-proximal signalling complex that consists of two different receptor chains (IL-1Rs), IL-1RI and IL-1RAcP, the adaptor protein MyD88, the serine/threonine kinase IRAK and a new protein, which we have named Tollip. Here we show that, before IL-1β treatment, Tollip is present in a complex with IRAK, and that recruitment of Tollip–IRAK complexes to the activated receptor complex occurs through association of Tollip with IL-1RAcP. Co-recruited MyD88 then triggers IRAK autophosphorylation, which in turn leads to rapid dissociation of IRAK from Tollip (and IL-1Rs)	SIGNOR-251981
P14778	Q9NPH3	2	binding	up-regulates	0.73	Here we report that the soluble form of the il-1 receptor accessory protein (acp) increases the affinity of binding of human il-1alpha and il-1beta to the soluble human type ii il-1 receptor by approximately 100-fold,	SIGNOR-97396
Q8N2H9	P51617	2	phosphorylation	up-regulates	0.729	Pellino3 physically interacts with il-1r-associated kinase-1, tnf receptor-associated factor-6, tgf-beta-activated kinase-1, and nf-kappab-inducing kinase in an il-1-dependent manner in the present study, we demonstrate that irak1 and irak4 phosphorylate pellino isoforms in vitro and that phosphorylation greatly enhances pellino's e3 ubiquitin ligase activity.	SIGNOR-103983
P51617	Q8N2H9	2	ubiquitination	up-regulates	0.729	These studies suggest that pellino isoforms may be the e3 ubiquitin ligases that mediate the il-1-stimulated formation of k63-pub-irak1 in cells, which may contribute to the activation of ikkbeta and the transcription factor nf-kappab, as well as other pathways dependent on irak1/4.	SIGNOR-159061
Q9Y2J4	Q9NRM7	2	phosphorylation	down-regulates activity	0.728	The N-terminal regions of Amot proteins contain a conserved HXRXXS consensus site for LATS1/2-mediated phosphorylation.\|Amot family members. Knockdown of LATS1 and LATS2 endogenously reduced the phosphorylation of Amots detected by the phospho-specific antibodies. Mutation of the serine to alanine within this HXRXXS site in Amot and AmotL2 established that this site was essential for Hippo core kinase-mediated phosphorylation. Wild-type and non-phosphorylated Amot (Amot-S175A) were targeted to actin filaments, whereas phospho-mimic Amot (Amot-S175D) failed to be localized with actin.	SIGNOR-272084
Q9NRM7	Q9Y2J4	2	relocalization	up-regulates activity	0.728	Ubiquitinated AMOTL2 then serves as a physical docking site for LATS2, which phosphorylates YAP to promote its cytoplasmic retention and degradation.	SIGNOR-271875
P23443	O15530	2	phosphorylation	up-regulates	0.727	A regulatory link between p70s6k and pkb was demonstrated, as pdk1 was found to selectively phosphorylate p70s6k at thr229. More importantly, pdk1 activated p70s6k in vitro and in vivo, whereas the catalytically inactive pdk1 blocked insulin-induced activation of p70s6k. One of the most studied events controlled by ptdins(3,4,5)p3, comprises the activation of a of agc family protein kinases, including isoforms of protein kinase b (pkb)/akt, p70 ribosomal s6 kinase (s6k), serum- and glucocorticoid-induced protein kinase (sgk) and protein kinase c (pkc), which play crucial roles in regulating physiological processes relevant to metabolism, growth, proliferation and survival. Here, we review recent biochemical, genetic and structural studies on the 3-phosphoinositide-dependent protein kinase-1 (pdk1), which phosphorylates and activates the agc kinase members regulated by pi 3-kinase. We also discuss whether inhibitors of pdk1 might have chemotherapeutic potential in the treatment of cancers in which the pdk1-regulated agc kinases are constitutively activated. Phosphorylation and activation of p70s6k by pdk1.	SIGNOR-188907
O15530	P23443	2	phosphorylation	down-regulates activity	0.727	Here we report that ribosomal protein S6 kinase beta 1 (S6K1), a member of AGC kinases and downstream target of mechanistic target of rapamycin complex 1 (mTORC1), directly phosphorylates PDK1 at its pleckstrin homology (PH) domain, and impairs PDK1 interaction with and activation of AKT.	SIGNOR-273844
P19793	P10276	2	binding	up-regulates	0.725	Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins	SIGNOR-16433
P10276	P19793	2	binding	up-regulates	0.725	Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins	SIGNOR-16665
O14578	Q15058	2	binding	up-regulates activity	0.723	We find that KIF14 targets to the central spindle via its interaction with PRC1 and has an essential function in cytokinesis. In KIF14-depleted cells, citron kinase but not other components of the central spindle and cleavage furrow fail to localize. Furthermore, the localization of KIF14 and citron kinase to the central spindle and midbody is codependent, and they form a complex depending on the activation state of citron kinase.	SIGNOR-266422
Q15058	O14578	2	binding	up-regulates activity	0.723	We find that KIF14 targets to the central spindle via its interaction with PRC1 and has an essential function in cytokinesis. In KIF14-depleted cells, citron kinase but not other components of the central spindle and cleavage furrow fail to localize. Furthermore, the localization of KIF14 and citron kinase to the central spindle and midbody is codependent, and they form a complex depending on the activation state of citron kinase.	SIGNOR-266424
Q9UPT6	P45983	2	phosphorylation	up-regulates	0.722	Phosphoamino acid analysis confirmed that jnk caused thr phosphorylation of jip3 (fig. _(fig.3c).3c). This phosphorylation on thr was markedly decreased when thr266, thr276, and thr287 were replaced with ala. These data indicate that jnk phosphorylated jip3 on thr266, thr276, and thr287 in vitro.	SIGNOR-134545
P45983	Q9UPT6	2	binding	up-regulates	0.722	The c-jun nh2-terminal kinase (jnk)-interacting protein (jip) group of scaffold proteins (jip1, jip2, and jip3) can interact with components of the jnk signaling pathway and potently activate jnk.	SIGNOR-134558
Q18PE1	O15146	2	phosphorylation	up-regulates activity	0.721	Here, we demonstrate that Dok-7 also functions downstream from MuSK, and we identify the proteins that are recruited to the C-terminal domain of Dok-7. We show that Agrin stimulates phosphorylation of two tyrosine residues in the C-terminal domain of Dok-7, which leads to recruitment of two adapter proteins: Crk and Crk-L. Y396 and Y406 are the major tyrosine phosphorylation sites in Dok-7 expressed in C2 myotubes.	SIGNOR-273845
O15146	Q18PE1	2	binding	up-regulates	0.721	In addition, dok7, a cytoplasmic adaptor protein, is also required for musk activation in vivo. This review focuses on the physical interplay between these proteins and musk for activation and downstream signaling, which culminates in nmj formation.	SIGNOR-192264
P13631	P28702	2	binding	up-regulates	0.714	Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins.	SIGNOR-16683
O60674	P15260	2	binding	up-regulates	0.714	The only type ii ifn, ifn-, binds a distinct cell-surface receptor, which is known as the type ii ifn receptor. This receptor is also composed of two subunits, ifngr1 and ifngr2, which are associated with jak1 and jak2, respectively. Activation of the jaks that are associated with the type i ifn receptor results in tyrosine phosphorylation of stat2	SIGNOR-135955
P15260	O60674	2	phosphorylation	up-regulates activity	0.714	In the classical model of IFNgamma signaling, dimeric IFNgamma cross-links the IFNGR1 receptor subunit that results in allosteric changes in receptor cytoplasmic domain. This results in movement of JAK2 from receptor subunit IFNGR2 to IFNGR1. The JAKs autophosphorylate and then phosphorylate IFNGR1 cytoplasmic domain. This results in binding, phosphorylation, and dimer formation of STAT1_. The dimeric STAT1_ dissociates from receptor and undergoes nuclear translocation via an intrinsic NLS for specific gene activation	SIGNOR-249490
P28702	P13631	2	binding	up-regulates	0.714	Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins.	SIGNOR-16662
P00533	P40818	2	deubiquitination	up-regulates quantity by stabilization	0.711	Here, we describe the role of a deubiquitinating enzyme UBPY/USP8 in the down-regulation of epidermal growth factor (EGF) receptor (EGFR). Overexpression of UBPY reduced the ubiquitination level of EGFR and delayed its degradation in EGF-stimulated cells.	SIGNOR-259103
P40818	P00533	2	phosphorylation	up-regulates activity	0.711	EGFR activates USP8 by phosphorylating Tyr-717 and Tyr-810.\|Here, we report that epidermal growth factor receptor (EGFR) kinase suppresses ciliogenesis by directly phosphorylating the deubiquitinase USP8 on Tyr 717 and Tyr 810 in RPE1 cells.	SIGNOR-279037
O14640	O75581	2	binding	up-regulates activity	0.707	The Wnt–FZD–LRP5/6 trimeric complex recruits Dishevelled (DVL) and Axin through the intracellular domains of FZD and LRP5/6, resulting in inhibition of β-catenin phosphorylation and thus ensuing β-catenin stabilization.	SIGNOR-262526
O75581	O14640	2	binding	up-regulates activity	0.707	The scaffold protein dishevelled (dvl) is required for lrp6 phosphorylation and aggregation. We propose that wnts induce coclustering of receptors and dvl in lrp6-signalosomes, which in turn triggers lrp6 phosphorylation to promote axin recruitment and beta-catenin stabilization.	SIGNOR-156072
P23458	P15260	2	binding	up-regulates	0.703	Interferon- (ifn;type ii ifn) induces reorganization of the ifn-receptor subunits, ifngr1 and ifngr2, activating the janus kinases jak1 and jak2, which are constitutively associated with each subunit, respectively	SIGNOR-150194
Q13164	Q13163	2	phosphorylation	up-regulates	0.703	Mek5 is the mapk kinase that phosphorylates and activates erk5 in response to growth factors, oxidative stress, and hyperosmotic conditions.	SIGNOR-104631
Q13163	Q13164	2	phosphorylation	up-regulates	0.703	Phosphorylation and activation of extracellular-signal-regulated protein kinase 5 (erk5) by mitogen-activated protein kinase kinase 5 (mkk5)activated erk5 also phosphorylated mitogen-activated protein kinase kinase 5 (mkk5) extensively at ser(129), ser(137), ser(142) and ser(149)	SIGNOR-99127
P15260	P23458	2	phosphorylation	up-regulates	0.703	Interferon gamma activation of stat1alpha requires both jak1 and jak2 as well as tyrosine phosphorylation of the alpha chain of the ifngamma receptor.	SIGNOR-29866
Q13315	P78527	2	phosphorylation	down-regulates activity	0.702	It has also been reported that DNA-PKcs could inhibit ATM activity by directly phosphorylating ATM at T86 / T373 and T1985 / S1987 / S1988 sites .\|It has also been reported that DNA-PKcs could inhibit ATM activity by directly phosphorylating ATM at T86 and T373 and T1985/S1987/S1988 sites.	SIGNOR-278324
P78527	Q13315	2	phosphorylation	up-regulates	0.702	Atm mediates dna-pkcs phosphorylation at thr-2609 as well as at the adjacent (s/t)q motifs within the thr-2609 cluster. In addition, our data suggest that dna-pkcs- and atm-mediated dna-pkcs phosphorylations are cooperative and required for the full activation of dna-pkcs and the subsequent dsb repair.	SIGNOR-151441
O60674	P38484	2	binding	up-regulates activity	0.7	In the classical model of IFNgamma signaling, dimeric IFNgamma cross-links the IFNGR1 receptor subunit that results in allosteric changes in receptor cytoplasmic domain. This results in movement of JAK2 from receptor subunit IFNGR2 to IFNGR1. The JAKs autophosphorylate and then phosphorylate IFNGR1 cytoplasmic domain. This results in binding, phosphorylation, and dimer formation of STAT1_. The dimeric STAT1_ dissociates from receptor and undergoes nuclear translocation via an intrinsic NLS for specific gene activation	SIGNOR-249504
P38484	O60674	2	binding	up-regulates activity	0.7	In the classical model of IFNgamma signaling, dimeric IFNgamma cross-links the IFNGR1 receptor subunit that results in allosteric changes in receptor cytoplasmic domain. This results in movement of JAK2 from receptor subunit IFNGR2 to IFNGR1. The JAKs autophosphorylate and then phosphorylate IFNGR1 cytoplasmic domain. This results in binding, phosphorylation, and dimer formation of STAT1_. The dimeric STAT1_ dissociates from receptor and undergoes nuclear translocation via an intrinsic NLS for specific gene activation	SIGNOR-249489
O15111	Q99558	2	phosphorylation	up-regulates activity	0.698	Once activated by autophosphorylation, nik activates ikkalpha, which in turn phosphorylates nf-kb2. This stimulates limited proteasome-mediated proteolysis of nf-kb2 to p52. Removal of the carboxy-terminal ankyrin repeats from nf-kb2 releases the p52/RELB heterodimer, allowing its translocation to the nucleus where it instigates the expression of nf-kb target genes.	SIGNOR-167060
Q99558	O15111	2	phosphorylation	down-regulates quantity by destabilization	0.698	Upon activation by nik, ikkalfa phosphorylates nik, triggering its proteolysis.	SIGNOR-165622
O14965	Q9NQS7	2	binding	up-regulates activity	0.693	INCENP is phosphorylated by Aurora B and activates the kinase in a positive feedback loop	SIGNOR-252048
Q9NQS7	O14965	2	phosphorylation	up-regulates activity	0.693	INCENP is phosphorylated by Aurora B and activates the kinase in a positive feedback loop	SIGNOR-252047
P13631	P19793	2	binding	up-regulates	0.686	Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins	SIGNOR-16671
P43146	Q9HD67	2	relocalization	up-regulates quantity	0.686	Here, we provide evidence for the involvement of the unconventional myosin X (Myo X) in netrin-1 function. We find that Myo X interacts with the netrin receptor deleted in colorectal cancer (DCC) and neogenin, a DCC-related protein. Expression of Myo X redistributes DCC to the cell periphery or to the tips of neurites, whereas its silencing prevents DCC distribution in neurites. Moreover, expression of DCC, but not neogenin, stimulates Myo X-mediated formation and elongation of filopodia, suggesting that Myo X function may be differentially regulated by DCC and neogenin.	SIGNOR-268282
Q9HD67	P43146	2	binding	up-regulates activity	0.686	Here, we provide evidence for the involvement of the unconventional myosin X (Myo X) in netrin-1 function. We find that Myo X interacts with the netrin receptor deleted in colorectal cancer (DCC) and neogenin, a DCC-related protein. Expression of Myo X redistributes DCC to the cell periphery or to the tips of neurites, whereas its silencing prevents DCC distribution in neurites. Moreover, expression of DCC, but not neogenin, stimulates Myo X-mediated formation and elongation of filopodia, suggesting that Myo X function may be differentially regulated by DCC and neogenin.	SIGNOR-268281
P19793	P13631	2	binding	up-regulates	0.686	Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins.	SIGNOR-16659
P01106	P84022	2	transcriptional regulation	down-regulates quantity by repression	0.685	Down-regulation of c-Myc is a critical event for growth inhibition induced by transforming growth factor-β (TGF-β) and is frequently impaired in cancer cells. We determined a Smad-responsive element in the c-mycpromoter.	SIGNOR-251494
P84022	P01106	2	binding	down-regulates activity	0.685	Through its direct interaction with smads, c-myc binds to the sp1-smad complex on the promoter of the p15(ink4b) gene, thereby inhibiting the tgf-beta-induced transcriptional activity of sp1 and smad/sp1-dependent transcription of the p15(ink4b) gene. These results suggest that oncogenic c-myc promotes cell growth and cancer development partly by inhibiting the growth inhibitory functions of smads.	SIGNOR-114284
P10826	P19793	2	binding	up-regulates	0.682	Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins	SIGNOR-16668
P19793	P10826	2	binding	up-regulates	0.682	Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins.	SIGNOR-16519
Q92997	P49674	2	phosphorylation	down-regulates activity	0.669	Co-expression of CK1ϵ with FLAG-Dvl3 retards electrophoretic migration and induces phosphorylation-dependent shift of Dvl (PS-Dvl3). mutations of Ser-280 and Ser-311 prevent efficient activation of Wnt/β-catenin by Dvl3.	SIGNOR-276645
P49674	Q92997	2	binding	up-regulates	0.669	Ckiepsilon was in a complex with axin and other downstream components of the wnt pathway, including dishevelled.	SIGNOR-71759
P30291	P24941	2	null	down-regulates quantity by destabilization	0.666	PS123 primes CK2 to phosphorylate S121, resulting in creation of a β-TrCP phosphodegron (EEGFGpS121) that is responsible for the instability of Wee1A during interphase.	SIGNOR-276039
P24941	P30291	2	phosphorylation	down-regulates	0.666	Identification and characterization of human wee1b, a new member of the wee1 family of cdk-inhibitory kinases.	SIGNOR-83139
P28702	P10826	2	binding	up-regulates	0.666	Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins.	SIGNOR-16581
P10826	P28702	2	binding	up-regulates	0.666	Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins.	SIGNOR-16677
P45984	Q9UPT6	2	binding	up-regulates	0.663	The c-jun nh2-terminal kinase (jnk)-interacting protein (jip) group of scaffold proteins (jip1, jip2, and jip3) can interact with components of the jnk signaling pathway and potently activate jnk.	SIGNOR-134561
Q9UPT6	P45984	2	phosphorylation	up-regulates	0.663	Phosphoamino acid analysis confirmed that jnk caused thr phosphorylation of jip3 (fig. _(fig.3c).3c). This phosphorylation on thr was markedly decreased when thr266, thr276, and thr287 were replaced with ala. These data indicate that jnk phosphorylated jip3 on thr266, thr276, and thr287 in vitro.	SIGNOR-134576
P46527	P06493	2	phosphorylation	down-regulates	0.655	Phosphorylation of kip1 on thr-187, by cdk1 and cdk2 leads to protein ubiquitination and proteasomal degradation.	SIGNOR-80230
P06493	P46527	2	binding	down-regulates	0.655	P21 and p27 are key inhibitors of both cdk1 and cdk2.	SIGNOR-128445
Q09472	Q92585	2	binding	up-regulates	0.651	Maml-1 is preassociated with other components of the transcriptional machinery, such as p300	SIGNOR-145057
Q92585	Q09472	2	acetylation	up-regulates	0.651	The n-terminal domain of maml1 directly interacts with both p300 and histones, and the p300-maml1 complex specifically acetylates histone h3 and h4 tails in chromatin. Furthermore, p300 acetylates maml1 and evolutionarily conserved lysine residues in the maml1 n-terminus are direct substrates for p300-mediated acetylation.	SIGNOR-153035
Q13546	P25445	2	binding	up-regulates activity	0.651	Fas associates with rip. Rip is a novel form of apoptosis-inducing protein	SIGNOR-235430
P25445	Q13546	2	binding	up-regulates activity	0.651	The death domain of the rip1 kinase binds to death receptors such as fas that is required for caspase 8 activation and apoptosis	SIGNOR-177949
Q05397	P12931	2	phosphorylation	up-regulates	0.649	Surprisingly, we found that expression of SrcMF or Src251 resulted in increased tyrosine phosphorylation of FAK on Tyr(407), Tyr(576), Tyr(577), and Tyr(861), which are considered to be Src kinase substrates	SIGNOR-150484
P12931	Q05397	2	phosphorylation	up-regulates activity	0.649	Cell reconstitution showed that FAK catalytic activity is required for alpha5beta1-stimulated Src activation in part through direct FAK phosphorylation of Src at Tyr-418.	SIGNOR-278452
Q9UHD2	Q14164	2	binding	up-regulates activity	0.646	STING recruits TBK1 and IKKε and forms the TBK1-IKKε complex via the association with TRAF3. The TBK1 complex induces the phosphorylation, dimerization, and nuclear translocation of IRF3.	SIGNOR-260155
Q14164	Q9UHD2	2	binding	up-regulates activity	0.646	Whereas nemo assembles some but not all ikk complexes [12,13], recent reports provide strong experimental evidence for a role of tank [also called traf-interacting protein (i-traf)], nak-associated protein (nap1) and similar to nap1 tbk1 adaptor (sintbad) in the assembly of tbk1 and ikk-e kinase complexes that phosphorylate irf3 and irf7 and promote type i ifn gene induction	SIGNOR-178053
P00533	Q9UJM3	2	binding	down-regulates activity	0.641	The cytoplasmic protein MIG6 (mitogen-induced gene 6; also known as ERRFI1) interacts with and inhibits the kinase domains of EGFR and ERBB2	SIGNOR-252076
Q9UJM3	P00533	2	phosphorylation	up-regulates activity	0.641	here we found that the epidermal growth factor receptor (EGFR) phosphorylates Mig6 on Y394 and that this phosphorylation is primed by prior phosphorylation of an adjacent residue, Y395, by Src.	SIGNOR-252091
P07949	Q05397	2	phosphorylation	up-regulates	0.639	Focal adhesion kinase (fak) binds ret kinase via its ferm domain, priming a direct and reciprocal ret-fak transactivation mechanism. following gdnf stimulation, increased phosphorylation of fak at tyr-576/577 as well as phosphorylation of ret at tyr-905 was observed.	SIGNOR-173009
Q05397	P07949	2	phosphorylation	up-regulates	0.639	The identification of focal adhesion kinase (fak) as a direct substrate for ret kinase revealed (i) a ret-fak transactivation mechanism consisting of direct phosphorylation of fak tyr-576/577 by ret and a reciprocal phosphorylation of ret by fak, which crucially is able to rescue the kinase-impaired ret k758m mutant and (ii) that fak binds ret via its ferm domain. Interestingly, this interaction is abolished upon ret phosphorylation, indicating that ret binding to the ferm domain of fak is a priming step for ret-fak transactivation.	SIGNOR-173013

P42566

P00533

2

phosphorylation

up-regulates

0.755

Earlier studies have shown that eps15 at tyr-849 is phosphorylated in egf-stimulated cells and partly controls the internalization of mono-ubiquitinated egfr via uim domains of eps15 [10]. It has also been shown that active egfr phosphorylates tyr-849 directly;

SIGNOR-203311

P42345

Q8TB45

2

binding

down-regulates activity

0.755

DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival

SIGNOR-251657

Q8TB45

P42345

2

phosphorylation

down-regulates

0.755

Our data reveal critical roles for mtor itself as well as cki in generating a degron in deptor that is recognized by _-trcp, and promotes deptor turnover by the proteasome.

SIGNOR-176849

P00533

P42566

2

binding

down-regulates activity

0.755

We suggest that the ubiquitinated EGFR or another c-Cbl substrate that is ubiquitinated upon EGFR activation recruits Eps15 to the plasma membrane via its UIM. This event would facilitate EGFR internalization via a clathrin-dependent route in which Eps15 plays a role

SIGNOR-243278

Q9Y572

Q13546

2

phosphorylation

up-regulates activity

0.754

In the current scenario, RIPK1 phosphorylates and activates RIPK3, and activated RIPK3 then phosphorylates MLKL.

SIGNOR-278429

Q13546

Q9Y572

2

phosphorylation

up-regulates activity

0.754

Collectively, TAK1 activates RIPK3, RIPK3 activates TAK1, and RIPK1 activates RIPK3 and facilitates interaction between TAK1 and RIPK3.|RIPK1 kinase activity is required for RIPK3 phosphorylation, and reciprocally RIPK3 phosphorylates RIPK1.

SIGNOR-280106

Q9BVA0

O75449

2

binding

up-regulates activity

0.753

In its active ATP-bound state, KATNA1 forms hexameric rings capable of binding to and severing microtubule polymers. Typically, KATNA1 binding to KATNB1 enhances severing, likely due to KATNB1 increasing the stability of the KATNA1 hexamer

SIGNOR-267174

O75449

Q9BVA0

2

binding

up-regulates quantity by stabilization

0.753

In its active ATP-bound state, KATNA1 forms hexameric rings capable of binding to and severing microtubule polymers. Typically, KATNA1 binding to KATNB1 enhances severing, likely due to KATNB1 increasing the stability of the KATNA1 hexamer

SIGNOR-267173

Q99640

P06493

2

phosphorylation

down-regulates activity

0.752

Active Cdk1 phosphorylates and inhibits Wee1 and Myt1 kinases and phosphorylates and activates the Cdc25 phosphatases.

SIGNOR-279600

P06493

Q99640

2

phosphorylation

down-regulates

0.752

Myt1hu preferentially phosphorylates cdc2 on threonine 14 in a cyclin-dependent manner;phosphorylation of threonine 14 and tyrosine 15 is inhibitory.

SIGNOR-45729

O75143

Q8IYT8

2

phosphorylation

up-regulates

0.75

Ulks directly phosphorylates atg13.

SIGNOR-184126

P28482

Q02750

2

phosphorylation

up-regulates activity

0.75

Mapk1 is phosphorylated by map2k1/mek1 and map2k2/mek2 on thr-185 and tyr-187 in response to external stimuli like insulin or ngf. Both phosphorylations are required for activity.

SIGNOR-236447

Q02750

P28482

2

phosphorylation

down-regulates activity

0.75

We propose that activation of erk during adhesion creates a feedback system in which erk phosphorylates mek1 on t292, and this in turn blocks additional s298 phosphorylation in response to integrin signaling.

SIGNOR-236335

Q8IYT8

O75143

2

binding

up-regulates

0.75

He mammalian atg13 binds both ulk1 and ulk2 and mediates the interaction of the ulk proteins with fip200. The binding of atg13 stabilizes and activates ulk and facilitates the phosphorylation of fip200 by ulk

SIGNOR-184123

Q02750

P04049

2

phosphorylation

up-regulates activity

0.749

Among other effectors, active ras binds and activates the raf kinase, iniziating a kinase cascade involving serine phosporylation of mek1/2 (mapkk) and tyrosine and threonine phosphorylation of erk1/2 active raf phosphorylates mek phospholpeptide analysis demostrated that serine residues 218 and 222 of human mek1 are the primary sites for phosphorylation by c-raf.

SIGNOR-235987

P09619

Q06124

2

dephosphorylation

down-regulates activity

0.749

Upon activation, the βPDGFR is phosphorylated at multiple tyrosine residues and thereby becomes a docking site for SH2-domain-containing signal transduction proteins.|While all phosphotyrosine sites on the βPDGFR are equally good targets for rPTP1B, maps of the βPDGFR dephosphorylated by rSyp showed that rSyp had a distinct preference for certain sites (Fig. 4 D-F). The low dose of rSyp primarily dephosphorylated spots 1, 6, 7, 9, and to a lesser extent 8a|Spot 1 corresponds to tyrosine 751; spot 3 corresponds to tyrosine 1009; spot 6 corresponds to tyrosine 740; spot 8b corresponds to tyrosine 1021; spot 9 corresponds to tyrosine 771, and spots 2, 7, and 8a are as yet unidentified phosphopeptides

SIGNOR-248669

Q06124

P09619

2

phosphorylation

up-regulates activity

0.749

Upon PDGF stimulation, SHPTP2 binds to the PDGFR and becomes tyrosine-phosphorylated. We have identified tyrosine-542 (pY542TNI) as the major in vivo site of SHPTP2 tyrosine phosphorylation. phosphorylation of SHPTP2 couples Grb2 to PDGFR in vivo, providing a mechanism for Ras activation by PDGFR and for positive signaling via SHPTP2 and Csw.

SIGNOR-250260

P04049

Q02750

2

phosphorylation

up-regulates activity

0.749

In addition, though MEK-1 was able to induce C-Raf phosphorylation at the S338 site, which was shown to play a role in C-Raf activation by certain growth factors [ xref ], MEK-1 was able to bind and activate the S338/339A C-Raf mutant, suggesting that the MEK-1-induced C-Raf activation does not require phosphorylation at these sites ( xref , lanes 4, 5, left panel and lanes 6\u20139, right panel).|MEK-1-induced C-Raf activation is Ras independent.

SIGNOR-279627

P49767

O60462

2

binding

up-regulates

0.748

By in vitro binding studies we found that both vegf-c and vegf-d interact with np2, vegf-c in a heparin-independent and vegf-d in a heparin-dependent manner.

SIGNOR-147530

O60462

P49767

2

binding

up-regulates

0.748

The functional importance of the interaction of np2 with the lymphangiogenic growth factors was demonstrated by cointernalization of np2 along with vegfr-3 in endocytic vesicles of lymphatic endothelial cells upon stimulation with vegf-c or vegf-d.

SIGNOR-147611

Q969J5

Q9GZX6

2

binding

down-regulates

0.746

We identified a gene encoding a protein of 231 aa, showing 33 and 34% amino acid identity with the extracellular domains of the il-22 receptor and of the il-20r/cytokine receptor family 2-8,the recombinant protein was found to bind il-10-related t cell-derived inducible factor/il-22, and to inhibit the activity of this cytokine on hepatocytes and intestinal epithelial cells. We propose to name this natural cytokine antagonist il-22bp for il-22 binding protein. respectively, but lacking the transmembrane and cytoplasmic domains

SIGNOR-86110

Q9GZX6

Q969J5

2

binding

up-regulates

0.746

Il-22 mediates inflammation and binds class ii cytokine receptor heterodimers il-22 ra1/crf2-4.

SIGNOR-86113

Q9UPT6

P53779

2

phosphorylation

up-regulates

0.745

Phosphoamino acid analysis confirmed that jnk caused thr phosphorylation of jip3 (fig. _(fig.3c).3c). This phosphorylation on thr was markedly decreased when thr266, thr276, and thr287 were replaced with ala. These data indicate that jnk phosphorylated jip3 on thr266, thr276, and thr287 in vitro.

SIGNOR-134533

P53779

Q9UPT6

2

binding

up-regulates

0.745

The c-jun nh2-terminal kinase (jnk)-interacting protein (jip) group of scaffold proteins (jip1, jip2, and jip3) can interact with components of the jnk signaling pathway and potently activate jnk.

SIGNOR-134555

P12931

P18433

2

dephosphorylation

up-regulates activity

0.743

Several protein tyrosine phosphatases are capable of activating Src by dephosphorylating Y530 (reviewed in ref. 9). These include PTP-α, PTP-λ, SHP-1, SHP-2, and PTP1B

SIGNOR-248437

P18433

P12931

2

phosphorylation

up-regulates activity

0.743

Transient overexpression of c-src together with rptp alpha in human embryonic kidney 293 cells increased phosphorylation of tyr789, suggesting that c-src may phosphorylate rptp alpha in vivo.

SIGNOR-111306

P31749

P18031

2

dephosphorylation

down-regulates

0.742

Whereas insulin-induced phosphatidylinositol 3-kinase/akt signaling was prolonged in both tcptp-/- and ptp1b-/- immortalized mouse embryo fibroblasts (mefs), mitogen-activated protein kinase erk1/2 signaling was elevated only in ptp1b- mefs

SIGNOR-252639

P18031

P31749

2

phosphorylation

down-regulates activity

0.742

Phosphorylation of ptp1b at ser(50) by akt impairs its ability to dephosphorylate the insulin receptor.

SIGNOR-252542

Q14790

P55212

2

cleavage

up-regulates

0.735

This pathway can either be ampli?ed By caspase- 8-mediated cleavage of bid and by the downstream, caspase-6- mediated cleavage of caspase-8.

SIGNOR-109411

P55212

Q14790

2

cleavage

up-regulates

0.735

Casp8 can activate downstream caspases like caspase-6, and caspase-7 by directly cleaving them.

SIGNOR-59857

P07948

P29350

2

dephosphorylation

down-regulates activity

0.734

SHP-1 efficiently inhibits Lyn autophosphorylation and suppresses FcϵRI stimulation|We found that PTPα and SHP-1 both dephosphorylate Lyn exclusively at Tyr-397

SIGNOR-248471

P29350

P07948

2

phosphorylation

up-regulates activity

0.734

Lyn phosphorylates SHPTP1 at the C-terminal Tyr-564 site. Lyn-mediated phosphorylation of SHPTP1 stimulates SHPTP1 tyrosine phosphatase activity.

SIGNOR-251409

O15151

Q00987

2

ubiquitination

down-regulates

0.733

The mdm2 homolog mdmx is an important regulator of p53 during mouse embryonic development. Dna damage promotes mdmx phosphorylation, nuclear translocation, and degradation by mdm2.

SIGNOR-144970

Q00987

O15151

2

binding

up-regulates quantity by stabilization

0.733

MDM2 has been shown to be degraded by the ubiquitin-proteasome pathway, while MDMX was a stable protein. Interaction of MDMX with MDM2 through the C-terminal RING finger domains resulted in inhibiting degradation of MDM2. These data indicate that MDMX functions as a regulator of MDM2.

SIGNOR-272932

Q9NPH3

P14778

2

binding

up-regulates activity

0.73

Binding of IL-1 to its receptor results in rapid assembly of a membrane-proximal signalling complex that consists of two different receptor chains (IL-1Rs), IL-1RI and IL-1RAcP, the adaptor protein MyD88, the serine/threonine kinase IRAK and a new protein, which we have named Tollip. Here we show that, before IL-1β treatment, Tollip is present in a complex with IRAK, and that recruitment of Tollip–IRAK complexes to the activated receptor complex occurs through association of Tollip with IL-1RAcP. Co-recruited MyD88 then triggers IRAK autophosphorylation, which in turn leads to rapid dissociation of IRAK from Tollip (and IL-1Rs)

SIGNOR-251981

P14778

Q9NPH3

2

binding

up-regulates

0.73

Here we report that the soluble form of the il-1 receptor accessory protein (acp) increases the affinity of binding of human il-1alpha and il-1beta to the soluble human type ii il-1 receptor by approximately 100-fold,

SIGNOR-97396

Q8N2H9

P51617

2

phosphorylation

up-regulates

0.729

Pellino3 physically interacts with il-1r-associated kinase-1, tnf receptor-associated factor-6, tgf-beta-activated kinase-1, and nf-kappab-inducing kinase in an il-1-dependent manner in the present study, we demonstrate that irak1 and irak4 phosphorylate pellino isoforms in vitro and that phosphorylation greatly enhances pellino's e3 ubiquitin ligase activity.

SIGNOR-103983

P51617

Q8N2H9

2

ubiquitination

up-regulates

0.729

These studies suggest that pellino isoforms may be the e3 ubiquitin ligases that mediate the il-1-stimulated formation of k63-pub-irak1 in cells, which may contribute to the activation of ikkbeta and the transcription factor nf-kappab, as well as other pathways dependent on irak1/4.

SIGNOR-159061

Q9Y2J4

Q9NRM7

2

phosphorylation

down-regulates activity

0.728

The N-terminal regions of Amot proteins contain a conserved HXRXXS consensus site for LATS1/2-mediated phosphorylation.|Amot family members. Knockdown of LATS1 and LATS2 endogenously reduced the phosphorylation of Amots detected by the phospho-specific antibodies. Mutation of the serine to alanine within this HXRXXS site in Amot and AmotL2 established that this site was essential for Hippo core kinase-mediated phosphorylation. Wild-type and non-phosphorylated Amot (Amot-S175A) were targeted to actin filaments, whereas phospho-mimic Amot (Amot-S175D) failed to be localized with actin.

SIGNOR-272084

Q9NRM7

Q9Y2J4

2

relocalization

up-regulates activity

0.728

Ubiquitinated AMOTL2 then serves as a physical docking site for LATS2, which phosphorylates YAP to promote its cytoplasmic retention and degradation.

SIGNOR-271875

P23443

O15530

2

phosphorylation

up-regulates

0.727

A regulatory link between p70s6k and pkb was demonstrated, as pdk1 was found to selectively phosphorylate p70s6k at thr229. More importantly, pdk1 activated p70s6k in vitro and in vivo, whereas the catalytically inactive pdk1 blocked insulin-induced activation of p70s6k. One of the most studied events controlled by ptdins(3,4,5)p3, comprises the activation of a of agc family protein kinases, including isoforms of protein kinase b (pkb)/akt, p70 ribosomal s6 kinase (s6k), serum- and glucocorticoid-induced protein kinase (sgk) and protein kinase c (pkc), which play crucial roles in regulating physiological processes relevant to metabolism, growth, proliferation and survival. Here, we review recent biochemical, genetic and structural studies on the 3-phosphoinositide-dependent protein kinase-1 (pdk1), which phosphorylates and activates the agc kinase members regulated by pi 3-kinase. We also discuss whether inhibitors of pdk1 might have chemotherapeutic potential in the treatment of cancers in which the pdk1-regulated agc kinases are constitutively activated. Phosphorylation and activation of p70s6k by pdk1.

SIGNOR-188907

O15530

P23443

2

phosphorylation

down-regulates activity

0.727

Here we report that ribosomal protein S6 kinase beta 1 (S6K1), a member of AGC kinases and downstream target of mechanistic target of rapamycin complex 1 (mTORC1), directly phosphorylates PDK1 at its pleckstrin homology (PH) domain, and impairs PDK1 interaction with and activation of AKT.

SIGNOR-273844

P19793

P10276

2

binding

up-regulates

0.725

Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins

SIGNOR-16433

P10276

P19793

2

binding

up-regulates

0.725

Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins

SIGNOR-16665

O14578

Q15058

2

binding

up-regulates activity

0.723

We find that KIF14 targets to the central spindle via its interaction with PRC1 and has an essential function in cytokinesis. In KIF14-depleted cells, citron kinase but not other components of the central spindle and cleavage furrow fail to localize. Furthermore, the localization of KIF14 and citron kinase to the central spindle and midbody is codependent, and they form a complex depending on the activation state of citron kinase.

SIGNOR-266422

Q15058

O14578

2

binding

up-regulates activity

0.723

We find that KIF14 targets to the central spindle via its interaction with PRC1 and has an essential function in cytokinesis. In KIF14-depleted cells, citron kinase but not other components of the central spindle and cleavage furrow fail to localize. Furthermore, the localization of KIF14 and citron kinase to the central spindle and midbody is codependent, and they form a complex depending on the activation state of citron kinase.

SIGNOR-266424

Q9UPT6

P45983

2

phosphorylation

up-regulates

0.722

Phosphoamino acid analysis confirmed that jnk caused thr phosphorylation of jip3 (fig. _(fig.3c).3c). This phosphorylation on thr was markedly decreased when thr266, thr276, and thr287 were replaced with ala. These data indicate that jnk phosphorylated jip3 on thr266, thr276, and thr287 in vitro.

SIGNOR-134545

P45983

Q9UPT6

2

binding

up-regulates

0.722

The c-jun nh2-terminal kinase (jnk)-interacting protein (jip) group of scaffold proteins (jip1, jip2, and jip3) can interact with components of the jnk signaling pathway and potently activate jnk.

SIGNOR-134558

Q18PE1

O15146

2

phosphorylation

up-regulates activity

0.721

Here, we demonstrate that Dok-7 also functions downstream from MuSK, and we identify the proteins that are recruited to the C-terminal domain of Dok-7. We show that Agrin stimulates phosphorylation of two tyrosine residues in the C-terminal domain of Dok-7, which leads to recruitment of two adapter proteins: Crk and Crk-L. Y396 and Y406 are the major tyrosine phosphorylation sites in Dok-7 expressed in C2 myotubes.

SIGNOR-273845

O15146

Q18PE1

2

binding

up-regulates

0.721

In addition, dok7, a cytoplasmic adaptor protein, is also required for musk activation in vivo. This review focuses on the physical interplay between these proteins and musk for activation and downstream signaling, which culminates in nmj formation.

SIGNOR-192264

P13631

P28702

2

binding

up-regulates

0.714

Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins.

SIGNOR-16683

O60674

P15260

2

binding

up-regulates

0.714

The only type ii ifn, ifn-, binds a distinct cell-surface receptor, which is known as the type ii ifn receptor. This receptor is also composed of two subunits, ifngr1 and ifngr2, which are associated with jak1 and jak2, respectively. Activation of the jaks that are associated with the type i ifn receptor results in tyrosine phosphorylation of stat2

SIGNOR-135955

P15260

O60674

2

phosphorylation

up-regulates activity

0.714

In the classical model of IFNgamma signaling, dimeric IFNgamma cross-links the IFNGR1 receptor subunit that results in allosteric changes in receptor cytoplasmic domain. This results in movement of JAK2 from receptor subunit IFNGR2 to IFNGR1. The JAKs autophosphorylate and then phosphorylate IFNGR1 cytoplasmic domain. This results in binding, phosphorylation, and dimer formation of STAT1_. The dimeric STAT1_ dissociates from receptor and undergoes nuclear translocation via an intrinsic NLS for specific gene activation

SIGNOR-249490

P28702

P13631

2

binding

up-regulates

0.714

Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins.

SIGNOR-16662

P00533

P40818

2

deubiquitination

up-regulates quantity by stabilization

0.711

Here, we describe the role of a deubiquitinating enzyme UBPY/USP8 in the down-regulation of epidermal growth factor (EGF) receptor (EGFR). Overexpression of UBPY reduced the ubiquitination level of EGFR and delayed its degradation in EGF-stimulated cells.

SIGNOR-259103

P40818

P00533

2

phosphorylation

up-regulates activity

0.711

EGFR activates USP8 by phosphorylating Tyr-717 and Tyr-810.|Here, we report that epidermal growth factor receptor (EGFR) kinase suppresses ciliogenesis by directly phosphorylating the deubiquitinase USP8 on Tyr 717 and Tyr 810 in RPE1 cells.

SIGNOR-279037

O14640

O75581

2

binding

up-regulates activity

0.707

The Wnt–FZD–LRP5/6 trimeric complex recruits Dishevelled (DVL) and Axin through the intracellular domains of FZD and LRP5/6, resulting in inhibition of β-catenin phosphorylation and thus ensuing β-catenin stabilization.

SIGNOR-262526

O75581

O14640

2

binding

up-regulates activity

0.707

The scaffold protein dishevelled (dvl) is required for lrp6 phosphorylation and aggregation. We propose that wnts induce coclustering of receptors and dvl in lrp6-signalosomes, which in turn triggers lrp6 phosphorylation to promote axin recruitment and beta-catenin stabilization.

SIGNOR-156072

P23458

P15260

2

binding

up-regulates

0.703

Interferon- (ifn;type ii ifn) induces reorganization of the ifn-receptor subunits, ifngr1 and ifngr2, activating the janus kinases jak1 and jak2, which are constitutively associated with each subunit, respectively

SIGNOR-150194

Q13164

Q13163

2

phosphorylation

up-regulates

0.703

Mek5 is the mapk kinase that phosphorylates and activates erk5 in response to growth factors, oxidative stress, and hyperosmotic conditions.

SIGNOR-104631

Q13163

Q13164

2

phosphorylation

up-regulates

0.703

Phosphorylation and activation of extracellular-signal-regulated protein kinase 5 (erk5) by mitogen-activated protein kinase kinase 5 (mkk5)activated erk5 also phosphorylated mitogen-activated protein kinase kinase 5 (mkk5) extensively at ser(129), ser(137), ser(142) and ser(149)

SIGNOR-99127

P15260

P23458

2

phosphorylation

up-regulates

0.703

Interferon gamma activation of stat1alpha requires both jak1 and jak2 as well as tyrosine phosphorylation of the alpha chain of the ifngamma receptor.

SIGNOR-29866

Q13315

P78527

2

phosphorylation

down-regulates activity

0.702

It has also been reported that DNA-PKcs could inhibit ATM activity by directly phosphorylating ATM at T86 / T373 and T1985 / S1987 / S1988 sites .|It has also been reported that DNA-PKcs could inhibit ATM activity by directly phosphorylating ATM at T86 and T373 and T1985/S1987/S1988 sites.

SIGNOR-278324

P78527

Q13315

2

phosphorylation

up-regulates

0.702

Atm mediates dna-pkcs phosphorylation at thr-2609 as well as at the adjacent (s/t)q motifs within the thr-2609 cluster. In addition, our data suggest that dna-pkcs- and atm-mediated dna-pkcs phosphorylations are cooperative and required for the full activation of dna-pkcs and the subsequent dsb repair.

SIGNOR-151441

O60674

P38484

2

binding

up-regulates activity

0.7

In the classical model of IFNgamma signaling, dimeric IFNgamma cross-links the IFNGR1 receptor subunit that results in allosteric changes in receptor cytoplasmic domain. This results in movement of JAK2 from receptor subunit IFNGR2 to IFNGR1. The JAKs autophosphorylate and then phosphorylate IFNGR1 cytoplasmic domain. This results in binding, phosphorylation, and dimer formation of STAT1_. The dimeric STAT1_ dissociates from receptor and undergoes nuclear translocation via an intrinsic NLS for specific gene activation

SIGNOR-249504

P38484

O60674

2

binding

up-regulates activity

0.7

In the classical model of IFNgamma signaling, dimeric IFNgamma cross-links the IFNGR1 receptor subunit that results in allosteric changes in receptor cytoplasmic domain. This results in movement of JAK2 from receptor subunit IFNGR2 to IFNGR1. The JAKs autophosphorylate and then phosphorylate IFNGR1 cytoplasmic domain. This results in binding, phosphorylation, and dimer formation of STAT1_. The dimeric STAT1_ dissociates from receptor and undergoes nuclear translocation via an intrinsic NLS for specific gene activation

SIGNOR-249489

O15111

Q99558

2

phosphorylation

up-regulates activity

0.698

Once activated by autophosphorylation, nik activates ikkalpha, which in turn phosphorylates nf-kb2. This stimulates limited proteasome-mediated proteolysis of nf-kb2 to p52. Removal of the carboxy-terminal ankyrin repeats from nf-kb2 releases the p52/RELB heterodimer, allowing its translocation to the nucleus where it instigates the expression of nf-kb target genes.

SIGNOR-167060

Q99558

O15111

2

phosphorylation

down-regulates quantity by destabilization

0.698

Upon activation by nik, ikkalfa phosphorylates nik, triggering its proteolysis.

SIGNOR-165622

O14965

Q9NQS7

2

binding

up-regulates activity

0.693

INCENP is phosphorylated by Aurora B and activates the kinase in a positive feedback loop

SIGNOR-252048

Q9NQS7

O14965

2

phosphorylation

up-regulates activity

0.693

INCENP is phosphorylated by Aurora B and activates the kinase in a positive feedback loop

SIGNOR-252047

P13631

P19793

2

binding

up-regulates

0.686

Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins

SIGNOR-16671

P43146

Q9HD67

2

relocalization

up-regulates quantity

0.686

Here, we provide evidence for the involvement of the unconventional myosin X (Myo X) in netrin-1 function. We find that Myo X interacts with the netrin receptor deleted in colorectal cancer (DCC) and neogenin, a DCC-related protein. Expression of Myo X redistributes DCC to the cell periphery or to the tips of neurites, whereas its silencing prevents DCC distribution in neurites. Moreover, expression of DCC, but not neogenin, stimulates Myo X-mediated formation and elongation of filopodia, suggesting that Myo X function may be differentially regulated by DCC and neogenin.

SIGNOR-268282

Q9HD67

P43146

2

binding

up-regulates activity

0.686

Here, we provide evidence for the involvement of the unconventional myosin X (Myo X) in netrin-1 function. We find that Myo X interacts with the netrin receptor deleted in colorectal cancer (DCC) and neogenin, a DCC-related protein. Expression of Myo X redistributes DCC to the cell periphery or to the tips of neurites, whereas its silencing prevents DCC distribution in neurites. Moreover, expression of DCC, but not neogenin, stimulates Myo X-mediated formation and elongation of filopodia, suggesting that Myo X function may be differentially regulated by DCC and neogenin.

SIGNOR-268281

P19793

P13631

2

binding

up-regulates

0.686

Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins.

SIGNOR-16659

P01106

P84022

2

transcriptional regulation

down-regulates quantity by repression

0.685

Down-regulation of c-Myc is a critical event for growth inhibition induced by transforming growth factor-β (TGF-β) and is frequently impaired in cancer cells. We determined a Smad-responsive element in the c-mycpromoter.

SIGNOR-251494

P84022

P01106

2

binding

down-regulates activity

0.685

Through its direct interaction with smads, c-myc binds to the sp1-smad complex on the promoter of the p15(ink4b) gene, thereby inhibiting the tgf-beta-induced transcriptional activity of sp1 and smad/sp1-dependent transcription of the p15(ink4b) gene. These results suggest that oncogenic c-myc promotes cell growth and cancer development partly by inhibiting the growth inhibitory functions of smads.

SIGNOR-114284

P10826

P19793

2

binding

up-regulates

0.682

Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins

SIGNOR-16668

P19793

P10826

2

binding

up-regulates

0.682

Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins.

SIGNOR-16519

Q92997

P49674

2

phosphorylation

down-regulates activity

0.669

Co-expression of CK1ϵ with FLAG-Dvl3 retards electrophoretic migration and induces phosphorylation-dependent shift of Dvl (PS-Dvl3). mutations of Ser-280 and Ser-311 prevent efficient activation of Wnt/β-catenin by Dvl3.

SIGNOR-276645

P49674

Q92997

2

binding

up-regulates

0.669

Ckiepsilon was in a complex with axin and other downstream components of the wnt pathway, including dishevelled.

SIGNOR-71759

P30291

P24941

2

null

down-regulates quantity by destabilization

0.666

PS123 primes CK2 to phosphorylate S121, resulting in creation of a β-TrCP phosphodegron (EEGFGpS121) that is responsible for the instability of Wee1A during interphase.

SIGNOR-276039

P24941

P30291

2

phosphorylation

down-regulates

0.666

Identification and characterization of human wee1b, a new member of the wee1 family of cdk-inhibitory kinases.

SIGNOR-83139

P28702

P10826

2

binding

up-regulates

0.666

Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins.

SIGNOR-16581

P10826

P28702

2

binding

up-regulates

0.666

Here we report that the transcriptional activity of rar and rxr can be reciprocally modulated by direct interactions between the two proteins.

SIGNOR-16677

P45984

Q9UPT6

2

binding

up-regulates

0.663

The c-jun nh2-terminal kinase (jnk)-interacting protein (jip) group of scaffold proteins (jip1, jip2, and jip3) can interact with components of the jnk signaling pathway and potently activate jnk.

SIGNOR-134561

Q9UPT6

P45984

2

phosphorylation

up-regulates

0.663

Phosphoamino acid analysis confirmed that jnk caused thr phosphorylation of jip3 (fig. _(fig.3c).3c). This phosphorylation on thr was markedly decreased when thr266, thr276, and thr287 were replaced with ala. These data indicate that jnk phosphorylated jip3 on thr266, thr276, and thr287 in vitro.

SIGNOR-134576

P46527

P06493

2

phosphorylation

down-regulates

0.655

Phosphorylation of kip1 on thr-187, by cdk1 and cdk2 leads to protein ubiquitination and proteasomal degradation.

SIGNOR-80230

P06493

P46527

2

binding

down-regulates

0.655

P21 and p27 are key inhibitors of both cdk1 and cdk2.

SIGNOR-128445

Q09472

Q92585

2

binding

up-regulates

0.651

Maml-1 is preassociated with other components of the transcriptional machinery, such as p300

SIGNOR-145057

Q92585

Q09472

2

acetylation

up-regulates

0.651

The n-terminal domain of maml1 directly interacts with both p300 and histones, and the p300-maml1 complex specifically acetylates histone h3 and h4 tails in chromatin. Furthermore, p300 acetylates maml1 and evolutionarily conserved lysine residues in the maml1 n-terminus are direct substrates for p300-mediated acetylation.

SIGNOR-153035

Q13546

P25445

2

binding

up-regulates activity

0.651

Fas associates with rip. Rip is a novel form of apoptosis-inducing protein

SIGNOR-235430

P25445

Q13546

2

binding

up-regulates activity

0.651

The death domain of the rip1 kinase binds to death receptors such as fas that is required for caspase 8 activation and apoptosis

SIGNOR-177949

Q05397

P12931

2

phosphorylation

up-regulates

0.649

Surprisingly, we found that expression of SrcMF or Src251 resulted in increased tyrosine phosphorylation of FAK on Tyr(407), Tyr(576), Tyr(577), and Tyr(861), which are considered to be Src kinase substrates

SIGNOR-150484

P12931

Q05397

2

phosphorylation

up-regulates activity

0.649

Cell reconstitution showed that FAK catalytic activity is required for alpha5beta1-stimulated Src activation in part through direct FAK phosphorylation of Src at Tyr-418.

SIGNOR-278452

Q9UHD2

Q14164

2

binding

up-regulates activity

0.646

STING recruits TBK1 and IKKε and forms the TBK1-IKKε complex via the association with TRAF3. The TBK1 complex induces the phosphorylation, dimerization, and nuclear translocation of IRF3.

SIGNOR-260155

Q14164

Q9UHD2

2

binding

up-regulates activity

0.646

Whereas nemo assembles some but not all ikk complexes [12,13], recent reports provide strong experimental evidence for a role of tank [also called traf-interacting protein (i-traf)], nak-associated protein (nap1) and similar to nap1 tbk1 adaptor (sintbad) in the assembly of tbk1 and ikk-e kinase complexes that phosphorylate irf3 and irf7 and promote type i ifn gene induction

SIGNOR-178053

P00533

Q9UJM3

2

binding

down-regulates activity

0.641

The cytoplasmic protein MIG6 (mitogen-induced gene 6; also known as ERRFI1) interacts with and inhibits the kinase domains of EGFR and ERBB2

SIGNOR-252076

Q9UJM3

P00533

2

phosphorylation

up-regulates activity

0.641

here we found that the epidermal growth factor receptor (EGFR) phosphorylates Mig6 on Y394 and that this phosphorylation is primed by prior phosphorylation of an adjacent residue, Y395, by Src.

SIGNOR-252091

P07949

Q05397

2

phosphorylation

up-regulates

0.639

Focal adhesion kinase (fak) binds ret kinase via its ferm domain, priming a direct and reciprocal ret-fak transactivation mechanism. following gdnf stimulation, increased phosphorylation of fak at tyr-576/577 as well as phosphorylation of ret at tyr-905 was observed.

SIGNOR-173009

Q05397

P07949

2

phosphorylation

up-regulates

0.639

The identification of focal adhesion kinase (fak) as a direct substrate for ret kinase revealed (i) a ret-fak transactivation mechanism consisting of direct phosphorylation of fak tyr-576/577 by ret and a reciprocal phosphorylation of ret by fak, which crucially is able to rescue the kinase-impaired ret k758m mutant and (ii) that fak binds ret via its ferm domain. Interestingly, this interaction is abolished upon ret phosphorylation, indicating that ret binding to the ferm domain of fak is a priming step for ret-fak transactivation.

SIGNOR-173013