GleghornLab/Signor_processed · Datasets at Hugging Face

IdA stringlengths 6 21	IdB stringlengths 6 21	mechanism stringclasses 40 values	effect stringclasses 10 values	score float64 0.1 0.99 ⌀	sentence stringlengths 10 1.63k ⌀	signor_id stringlengths 12 14
O00213	P00519	phosphorylation	up-regulates	0.415	The c-abl tyrosine kinase phosphorylates the fe65 adaptor protein to stimulate fe65/amyloid precursor protein nuclear signaling. Here, we show that active c-abl stimulates app/fe65-mediated gene transcription and that this effect is mediated by phosphorylation of fe65 on tyrosine 547 within its second ptb domain.	SIGNOR-123476
Q3KR16	P53350	phosphorylation	up-regulates	0.415	We reported previously that a guanine nucleotide exchange factor, myogef, localizes to the central spindle, activates rhoa, and is required for cytokinesis. In this study, we have found that plk1 (polo-like kinase 1) can phosphorylate myogef, thereby recruiting myogef to the central spindle as well as enhancing myogef activity toward rhoa. The in vitro kinase assay shows that plk1 can phosphorylate myogef on threonine 574.	SIGNOR-179954
Q13490	Q6GPH4	binding	down-regulates	0.415	Immunoprecipitation studies indicate that xaf1 binds to xiap,birc2,birc3.	SIGNOR-156843
P00533	P29350	dephosphorylation	down-regulates	0.415	The sh2-domain ptpase shp-1 binds to and dephosphorylates autophosphorylated egfr and may participate in modulation of egfr signaling in epithelial cells. Reduced shp-1 binding to the egfr y1173f mutant resulted in a reduced receptor dephosphorylation by coexpressed shp-1 and less interference with egf-dependent mitogen-activated protein kinase stimulation.	SIGNOR-59965
Q96J92	O00141	phosphorylation	up-regulates activity	0.415	In addition, we identified a novel SGK1 phosphorylation site (S1201) in WNK4, and phosphorylation at this site is reduced by Ca(2+)/CaM.	SIGNOR-276421
Q8IVM0	P00533	phosphorylation	down-regulates activity	0.415	We also detected tyrosine phosphorylation of Ymer by EGF stimulation as previously reported (Fig. 1A). Furthermore, we verified that EGF receptor-mediated tyrosine phosphorylation of Ymer is inhibited by AG1478, which is known as an EGF receptor tyrosine kinase inhibitor (Fig. 1B). A luciferase reporter assay showed that mutation of tyrosines on Ymer (YmerY217/279/304F) results in loss of the inhibitory activity for NF-kappaB signaling.	SIGNOR-262851
Q92974	P12931	phosphorylation	up-regulates activity	0.415	Src activates GEF-H1.	SIGNOR-277478
P10415	Q99933	binding	up-regulates activity	0.415	Cloning and functional analysis of BAG-1: A novel Bcl-2-binding protein with anti-cell death activity\|	SIGNOR-254118
Q8N6T7	Q00987	ubiquitination	down-regulates quantity	0.415	These results suggest that MDM2 degrades SIRT6 in a proteasome dependent manner.\|USP10 has been shown to deubiquitinate and stabilize p53, a well-known substrate of MDM2, suggesting a mechanism whereby SIRT6 is ubiquitinated and destabilized by MDM2, which could be reversed by USP10 mediated deubiquitination.	SIGNOR-278702
Q9NQT8	Q7KZI7	phosphorylation	down-regulates activity	0.415	We report here the identification of GAKIN/KIF13B as a novel in vivo substrate for Par1b and present evidence that GAKIN/KIF13B plays a critical role in axon formation in neurons, which is negatively regulated by Par1b-mediated phosphorylation. Par1b phosphorylates GAKIN/KIF13B at both Ser1381 and Ser1410.	SIGNOR-262956
Q14457	Q13464	phosphorylation	up-regulates activity	0.415	Beclin1 is phosphorylated by ROCK1 at T119.	SIGNOR-278198
Q9Y4C1	Q16665	transcriptional regulation	up-regulates quantity by expression	0.415	To this end, we confirm that KDM3A, KDM4B, KDM4C, KDM5B, KDM5C, and KDM62 are direct targets of HIF-1a while extent the list of known targets to KDM2A, KDM2B, KDM4D, KDM5A, and KDM6A. The results demonstrated that majority of the KDMs were similarly induced (KDM2A, KDM2B, KDM3A, KDM4B, KDM4C, KDM4D, KDM5A, KDM5B, KDM5C, KDM6B, and KDM7A) or repressed (KDM NO66 and KDM1A) by both HIF-1a and HIF-2a.	SIGNOR-271568
O43524	P04150	transcriptional regulation	up-regulates quantity	0.415	We show that FOXO3 is an immediate early glucocorticoid receptor (GR) target, whose transcription is even further enhanced by conditions that mimic metabolic stress.	SIGNOR-255759
Q14814	Q00535	phosphorylation	down-regulates activity	0.415	In this case, cdk5 phosphorylates MEF2D on Ser444 suppressing its transcriptional activity.	SIGNOR-279509
Q05469	P27361	phosphorylation	up-regulates activity	0.415	Thus, activation of the ERK pathway appears to be able to regulate adipocyte lipolysis by phosphorylating HSL on Ser(600) and increasing the activity of HSL.	SIGNOR-249470
P41594	P05129	phosphorylation	up-regulates activity	0.415	Thus, we showed that it is phosphorylation of Ser-839, not Thr-840, that is absolutely required for the unique Ca2+ oscillations produced by mGluR5 activation. The Thr-840 residue is important only in that it is permissive for the PKC-dependent phosphorylation of Ser-839.	SIGNOR-249289
P35222	P04629	phosphorylation	up-regulates activity	0.415	EGFR and TRKA effect on WNT3a mediated Topflash induction was abolished by U0126 or expression of dominant negative LRP6-5A mutant (XREF_FIG), demonstrating that both EGFR and TRKA signal via ERK and LRP6 pathway to upregulate WNT and beta-catenin signaling.\|FGFR2, FGFR3, EGFR and TRKA Phosphorylate \u03b2-catenin at Tyr142.	SIGNOR-279240
Q8NFH5	P53350	phosphorylation	down-regulates activity	0.415	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-279252
O15492	P00533	phosphorylation	up-regulates	0.415	Phosphorylation on tyr(168) was mediated by the epidermal growth factor receptor (egfr). We show here that endogenous rgs16 is phosphorylated after epidermal growth factor stimulation of mcf-7 cells.	SIGNOR-98267
P43003	O00141	phosphorylation	up-regulates activity	0.415	Site‐directed mutagenesis of the SGK1 phosphorylation sites in the Nedd4‐2 protein (S382A,S468ANedd4‐2) and in the EAAT1 protein (T482AEAAT1, T482DEAAT1) significantly blunts the effect of S422DSGK1. Introduction of a negative charge at the SGK phosphorylation site in the EAAT1 protein leads to a strong stimulation of the carrier, whereas replacement with alanine markedly decreases the EAAT1‐mediated current. These observations suggest that SGK1 exerts its effect not only by phosphorylation of Nedd4‐2 but also by phosphorylation of EAAT1.	SIGNOR-263075
Q68DK2	Q9H1H9	binding	up-regulates activity	0.415	We show that PtdIns(3)P localizes to the midbody during cytokinesis and recruits a centrosomal protein, FYVE-CENT (ZFYVE26), and its binding partner TTC19, which in turn interacts with CHMP4B, an endosomal sorting complex required for transport (ESCRT)-III subunit implicated in the abscission step of cytokinesis. On the basis of these data and the high-content microscopy described above, we propose that PtdIns(3)P controls the KIF13A-dependent recruitment of FYVE-CENT and TTC19 to the midbody, and that TTC19 is the most downstream effector of the three, possibly controlling the function of CHMP4B.	SIGNOR-265539
Q9HBH9	Q16539	phosphorylation	up-regulates	0.415	Erk and p38 phosphorylate mnk1 and mnk2, which stimulates their in vitro kinase activity	SIGNOR-48349
Q13315	Q00535	phosphorylation	up-regulates	0.415	Here we show that cdk5 (cyclin-dependent kinase 5), activated by dna damage, directly phosphorylates atm at ser 794 in post-mitotic neurons. Phosphorylation at ser 794 precedes, and is required for, atm autophosphorylation at ser 1981, and activates atm kinase activity	SIGNOR-183454
P36897	P07900	binding	up-regulates	0.415	The data in fig. 5 suggest that hsp90 specifically interacts with t?RI And t?RII In vitro and in vivo. Coupled with our data showing that loss of hsp90 function decreases t?R Levels and blocks tgf?-Induced smad2/3 activation and transcription, this result suggests that hsp90 controls tgf? Signaling as an essential component for stabilizing t?Rs.	SIGNOR-179268
P05231	O95644	transcriptional regulation	up-regulates quantity by expression	0.415	The calcineurin/nuclear factor of activated T cells (NFAT) signaling pathway has been found to play a role in regulating growth and differentiation in several cell types. However, the functional significance of NFAT in the vasculature is largely unclear. Here we show that NFATc1, NFATc3, and NFATc4 are expressed in human myometrial arteries. \|Chronic inhibition of NFAT significantly reduced IL-6 production in intact myometrial arteries and inhibited cell proliferation in vascular smooth muscle cells cultured from explants from the same arteries.	SIGNOR-251730
Q15942	P31749	phosphorylation	down-regulates	0.415	Akt binds and phosphorylates zyxin on serine 142, leading to its association with acinus zyxin is a substrate of caspases, but akt phosphorylation fails to protect its proteolytic degradation	SIGNOR-156122
Q9Y253	Q13535	phosphorylation	up-regulates	0.415	Atr-mediated phosphorylation of dna polymerase _ is needed for efficient recovery from uv damage. We show that, after uv irradiation, pol_ becomes phosphorylated at ser601 by the ataxia-telangiectasia mutated and rad3-related (atr) kinase. Atr-dependent phosphorylation of pol_ is necessary to restore normal survival and postreplication repair	SIGNOR-171290
P10275	Q15466	binding	down-regulates	0.415	We demonstrated that shp inhibited both ar-lbd and ntd-dependent transactivation, which evidenced for the first time a protein capable of inhibiting a steroid receptor amino-terminal-dependent transactivation. We further characterized the shp mechanism of action by showing that shp reversed ar coactivator-mediated activation	SIGNOR-112589
Q7RTU7	Q8IYA7	transcriptional regulation	up-regulates quantity by expression	0.415	MKX is a meniscus-enriched transcription factor. In human meniscus cells, MKX regulates the expression of meniscus marker genes, OA-related genes, and other transcription factors, including Scleraxis (SCX), SRY Box 5 (SOX5), and Runt domain-related transcription factor 2 (RUNX2).	SIGNOR-267213
Q13541	Q9P1W9	phosphorylation	up-regulates activity	0.414	Further, PIM2 triggered phosphorylation of AKT and 4EBP1 (XREF_FIG) clearly demonstrating the activation of PI3K pathway.	SIGNOR-279091
Q99626	Q16539	phosphorylation	down-regulates quantity by destabilization	0.414	ERK2, p38alpha and GSK-3beta can phosphorylate Cdx2 in vitro and that the 4S motif is required for phosphorylation by GSK-3beta and p38alpha\|Phosphorylation of the homeotic tumor suppressor Cdx2 mediates its ubiquitin-dependent proteasome degradation	SIGNOR-250092
P46531	Q92993	acetylation	down-regulates	0.414	This result implies that the residues k2019, k2039, k2044, and k2068 of notch1-ic are the major targets of the acetyltransferase activity of tip60.	SIGNOR-156923
Q9UJM3	P12931	phosphorylation	down-regulates activity	0.414	Prior phosphorylation of Y395 dramatically increases the rate of EGFR phosphorylation of Mig6 on Y394 in vitro, and suppression of Src activity pharmacologically or by shRNA decreased phosphorylation of Mig6 on this site in cells, impairing EGFR binding and inhibition.\|We further found that Mig6 inhibition of EGFR is modulated by Src via phosphorylation of Mig6 on Y395.	SIGNOR-279116
Q00987	Q6K0P9	binding	down-regulates quantity by destabilization	0.414	Here, we show that IFIXalpha1 downregulates HDM2, a principal negative regulator of p53, at the posttranslational level. IFIXalpha1 destabilizes HDM2 protein and promotes its ubiquitination. The E3 ligase activity of HDM2 appears to be required for this IFIXalpha1 effect. Importantly, HDM2 downregulation is required for the IFIXalpha1-mediated increase of p53 protein levels, transcriptional activity, and nuclear localization, suggesting that IFIXalpha1 positively regulates p53 by acting as a negative regulator of HDM2.	SIGNOR-268493
Q9NRY4	Q13464	phosphorylation	down-regulates activity	0.414	these results indicate that Rho-kinase can phosphorylate p190A RhoGAP at Ser1150 in COS7 cells. Similarly, the immunoblot analysis, through the use of the anti-p190A RhoGAP-pT1226 and -pS1236 antibodies, revealed that Rho-kinase can phosphorylate p190A RhoGAP at Thr1226 and Ser1236 in COS7 cells	SIGNOR-276177
P29350	P00519	phosphorylation	up-regulates activity	0.414	The results demonstrate that the SH3 domain of ABL1 interacts with a WPDHGVPSEP motif (residues 417-426) in the catalytic domain of SHPTP1 and that ABL1 phosphorylates C terminal Y536 and Y564 sites.	SIGNOR-260820
P16949	O15264	phosphorylation	down-regulates	0.414	Serine 25 of oncoprotein 18 is a major cytosolic target for the mitogen-activated protein kinase.	SIGNOR-36362
P29317	Q13239	binding	down-regulates quantity by destabilization	0.414	These data are consistent with a model where SLAP induces Ephrin-independent EPHA2 degradation. \| This activity is independent from CBL but requires SLAP SH3 interaction with the ubiquitination factor UBE4A and SLAP SH2 interaction with pTyr594-EPHA2.	SIGNOR-262964
O14522	P06241	phosphorylation	down-regulates activity	0.414	Synapse formation by PTPRT was inhibited by phosphorylation of tyrosine 912 within the membrane-proximal catalytic domain of PTPRT by Fyn. This tyrosine phosphorylation reduced phosphatase activity of PTPRT	SIGNOR-275543
Q9UNN4	P19784	phosphorylation	up-regulates activity	0.414	ALF was able to stabilize the binding of TBP to DNA, but it could not stabilize TBP mutants A184E, N189E, E191R, and R205E nor could it facilitate binding of the TBP-like factor TRF2/TLF to a consensus TATA element. However, phosphorylation of ALF with casein kinase II resulted in the partial restoration of complex formation using mutant TBPs. \| Because the residues involved (Ser-280, Ser-281, Ser-316, and Ser-321) are conserved in ALF (Ser-356, Ser-357, Ser-418, and Ser-423), we tested whether its activity might also be affected by this modification. We first showed that ALF and TFIIAα/β polypeptides incubated with casein kinase II and [γ-32P]ATP could be labeled.	SIGNOR-250993
Q14012	Q8N5S9	phosphorylation	up-regulates activity	0.414	Human calcium-calmodulin dependent protein kinase I: cDNA cloning, domain structure and activation by phosphorylation at threonine-177 by calcium-calmodulin dependent protein kinase I kinase.	SIGNOR-250717
P19634	P51812	phosphorylation	up-regulates activity	0.414	In pressured arteries, RSK2 dependent activation of NHE-1 was associated with increased intracellular Ca 2+ transients, which would be expected to increase MLCK activity, thereby contributing to basal tone and myogenic responses.\|Together, these data indicate that Ser 703 in NHE-1 is phosphorylated by RSK2, that RSK2 is associated with NHE-1, and that the time course of NHE-1 phosphorylation in response to intraluminal pressure is fast enough for this phosphorylation event to contribute to myogenic vasoconstriction.	SIGNOR-280119
Q9Y294	O14757	phosphorylation	up-regulates activity	0.414	Chk1 activated by ataxia telangiectasia mutated (ATM) kinase on DNA breaks in G1 promotes NHEJ through direct phosphorylation of ASF1A at Ser-166. ASF1A phosphorylated at Ser-166 interacts with the repair protein MDC1 and thus enhances MDC1's interaction with ATM and the stable localization of ATM at DNA breaks.	SIGNOR-277620
Q9NZQ3	P12931	phosphorylation	up-regulates activity	0.414	These results indicate that phosphorylation of SPIN90 by Src is essential for its synaptic targeting.	SIGNOR-279387
P42336	O43561	binding	up-regulates activity	0.414	By substituting these tyrosine residues in LAT with phenylalanine and by utilizing phosphorylated peptides derived from these sites, we mapped the tyrosine residues in LAT required for the direct interaction and activation of Vav, p85/p110alpha and phospholipase Cgamma1 (PLCgamma1). Our results indicate that Tyr(226) and Tyr(191) are required for Vav binding, whereas Tyr(171) and Tyr(132) are necessary for association and activation of phosphoinositide 3-kinase activity and PLCgamma1 respectively.	SIGNOR-246065
P61224	P52306	binding	up-regulates	0.414	Smggds has been previously shown to activate a wide variety of small gtpases, including the ras family members rap1a, rap1b, and k-ras, as well as the rho family members cdc42, rac1, rac2, rhoa, and rhob	SIGNOR-171552
Q02750	Q9Y2U5	phosphorylation	up-regulates	0.414	Both mekk2 and mekk3 are able to activate the jun kinase pathway in vivo. However, following routine immunoprecipitation in triton x-100, mekk2 but not mekk3 is able to effectively phosphorylate both sek-1 and mek-1 and to undergo autophosphorylation	SIGNOR-107692
Q13224	P17612	phosphorylation	up-regulates activity	0.414	Here we identify serine residue 1166 (Ser1166) in the carboxy-terminal tail of the NMDAR subunit GluN2B to be a direct molecular and functional target of PKA phosphorylation critical to NMDAR-dependent Ca(2+) permeation and Ca(2+) signaling in spines.	SIGNOR-276616
O95453	Q7Z2W4	binding	up-regulates activity	0.414	We provide evidence indicating that ZAP selectively recruits cellular poly(A)-specific ribonuclease (PARN) to shorten the poly(A) tail of target viral mRNA and recruits the RNA exosome to degrade the RNA body from the 3′ end.	SIGNOR-261296
Q9GZV1	P31751	phosphorylation	up-regulates	0.414	In vitro and in vivo studies confirmed that akt phosphorylates ankrd2 at ser-99. moreover, the forced expression of a phosphorylation-defective mutant form of ankrd2 in c2c12 myoblasts promoted a faster differentiation program, implicating akt-dependent phosphorylation at ser-99 in the negative regulation of myogenesis in response to stress conditions.	SIGNOR-236978
Q4V328	P42574	cleavage	up-regulates activity	0.414	These results suggest that the region of GRASP‐1 downstream of the Caspase‐3‐cleavage site is capable of activating the JNK signaling pathway by enhancing the phosphorylation of JNK. these results suggest that full length GRASP‐1 does not enhance JNK pathway activity, possibly due to the inhibitory effect of the N‐terminal fragment on the C‐terminal fragment. In contrast, Caspase‐3 cleavage of GRASP‐1 releases the C‐terminal fragment, which in turn activates JNK signaling by serving as a scaffold protein.	SIGNOR-260641
O15111	Q9Y243	phosphorylation	up-regulates	0.414	Although there are likely to be multiple levels of crosstalk between the pi3k-akt and nf-kb pathways, one mechanism has been attributed to direct phosphorylation of the amino acid residue t23 on ikb kinase alfa (ikkalfa) by akt, thereby leading to activation of this kinase upstream of nf-kb akt mediates ikkalpha phosphorylation at threonine 23 akt transiently associates in vivo with ikk and induces ikk activation. Akt mediates ikkalfa phosphorylation at threonine 23.Akt phosphorylates ikkalpha on t23, and this phosphorylation event is a prerequisite for the phosphorylation of p65 at s534 by ikkalpha and beta	SIGNOR-187062
P30679	O00254	binding	up-regulates activity	0.414	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-257360
Q7KZI7	Q7L7X3	phosphorylation	up-regulates activity	0.414	MARK family kinases can be activated by phosphorylation of a conserved threonine (Thr-208 in MARK2), and inactivated by phosphorylation of a serine (Ser-212), both in the activation loop of the catalytic domain. Activation is achieved by the kinases MARKK/TAO1 or LKB1, although the inactivating kinase was unknown. We show here that GSK3beta serves the role of the inhibitory kinase.	SIGNOR-276164
P63092	Q8TDV5	binding	up-regulates activity	0.414	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 ‚â• -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 ‚â• -1.0 for defining true couplings. \| The score associated to this interaction has a LogRAi ‚â• -1.0.	SIGNOR-256768
P24385	Q5XUX0	binding	down-regulates quantity by destabilization	0.413	FBXO31 serves as the substrate-recognition component of the SKP/Cullin/F-box protein class of E3 ubiquitin ligases and has been shown to direct degradation of pivotal cell-cycle regulatory proteins including cyclin D1 and the p53 antagonist MDM2.	SIGNOR-277379
Q96A00	O75116	phosphorylation	up-regulates activity	0.413	A major kinase for GPCR‐induced CPI‐17 phosphorylation is PKC which is activated by the PLCbeta‐produced signaling messenger diacylglycerol (DAG). It phosphorylates CPI‐17 at Thr38 residue that directly docks at the active site of MLCP, thereby inhibiting its activity and promoting an increase of phosphorylation of myosin and of other MLCP.\| CPI-17 can be also directly phosphorylated at Thr38 residue by MYPT1-associated kinase [222], by PAK, which is downstream of Rac and/or Cdc42 cascade [223], by Rho-associated coiled-coil kinase (ROCK) [224] and by PKN [225].	SIGNOR-96696
P30048	Q5S007	phosphorylation	down-regulates activity	0.413	Here, we show that LRRK2 interacts with human peroxiredoxin 3 (PRDX3), a mitochondrial member of the antioxidant family of thioredoxin (Trx) peroxidases. Importantly, mutations in the LRRK2 kinase domain significantly increased phosphorylation of PRDX3 compared to wild-type. The increase in PRDX3 phosphorylation was associated with decreased peroxidase activity and increased death in LRRK2-expressing but not in LRRK2-depleted or vector-transfected neuronal cells.	SIGNOR-262891
Q9UHD2	Q92630	phosphorylation	down-regulates quantity by destabilization	0.413	We further found that DYRK2 phosphorylated Ser527 of TBK1, which is essential for the recruitment of NLRP4 and for the E3 ubiquitin ligase DTX4 to degrade TBK1.	SIGNOR-276939
O95837	P25105	binding	up-regulates activity	0.413	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-257436
Q16621	Q96J02	ubiquitination	down-regulates activity	0.413	Itch regulates p45/NF-E2 in vivo by Lys63-linked ubiquitination\| Interestingly, Itch suppressed the transactivation activity of p45/NF-E2 by adding a Lys63-linked polyubiquitin chain. Confocal microscopy revealed that ubiquitinated p45/NF-E2 became localized in the cytoplasm when Itch was over-expressed. Thus, Itch-mediated ubiquitination of p45/NF-E2 does not target the protein for proteasomal degradation, but instead retains p45/NF-E2 in the cytoplasm, where it cannot function as a transactivator.	SIGNOR-275553
P35222	P17252	phosphorylation	down-regulates	0.413	As shown in Fig. 1 B, PKCalpha readily phosphorylated Ser33 and Ser37 / Thr41 on full-length beta-catenin (beta-catenin 1 - 781) and CTD deletion mutant (beta-catenin 1-682).\|To examine the effect of the armadillo repeats 1-5 on PKCalpha mediated beta-catenin degradation, DNA constructs expressing beta-catenin 1 - 781 and beta-catenin deletion mutants (beta-catenin 1-422 and beta-catenin 1-138) were transfected into HEK293 cells, followed by treatment with increasing concentrations of A23187 and CGK062, which are known activators of PKCalpha.	SIGNOR-278492
P01112	P49354	null	up-regulates activity	0.413	Major investments have been made to target Ras through indirect routes. Inhibition of farnesyl transferase to block Ras maturation has failed in large clinical trials.	SIGNOR-242568
Q14012	Q96RR4	phosphorylation	up-regulates activity	0.413	Human calcium-calmodulin dependent protein kinase I: cDNA cloning, domain structure and activation by phosphorylation at threonine-177 by calcium-calmodulin dependent protein kinase I kinase.	SIGNOR-250716
P33076	Q92769	deacetylation	down-regulates quantity by repression	0.413	We report that CIITA and histone deacetylase 2 (HDAC2) interact in smooth muscle cells and macrophages as assayed by co-immunoprecipitations. HDAC2 deacetylates CIITA whereas both the HDAC inhibitor trichostatin A (TSA) and over-expression of HDAC2 interfering RNA increase CIITA acetylation. HDAC2 down-regulates CIITA recruitment to target promoters as evidenced by chromatin immunoprecipitation assays, and suppresses MHC II activation and collagen repression mediated by CIITA in luciferase reporter assays.	SIGNOR-254231
P36952	Q13547	transcriptional regulation	down-regulates quantity by repression	0.413	We found that maspin is selectively upregulated in IFIXα-expressing cells and involved in anti-invasive activity of IFIXα. We also present evidence indicating that IFIXα downregulates histone deacetylase 1 (HDAC1), which is possibly involved in the silencing of the maspin gene in human breast cancer cells. To confirm these results, we performed a luciferase assay using a maspin-promoter-luciferase plasmid. The results showed that HDAC1 overexpression suppressed the activity of the maspin promoter (Figure 3C). Therefore, our results suggest that IFIXα enhances maspin expression through the downregulation of HDAC1.	SIGNOR-268494
P46459	P43378	dephosphorylation	down-regulates	0.413	Our results suggest that the molecular mechanism by which ptp-meg2 promotes secretory vesicle fusion involves the local release of nsf from a tyrosine-phosphorylated, inactive state.	SIGNOR-128348
O96006	P46100	binding	up-regulates activity	0.413	XNP/dATRX physically interacts with DREF. our results show that DREF is required for the proper expression of pnr and that XNP/dATRX binds to DREF at the DRE sites, resulting in the repression of pnr gene expression.	SIGNOR-239729
P19484	P28482	phosphorylation	down-regulates activity	0.413	Evidence for ERK2-mediated TFEB phosphorylation came from ERK2-TFEB coimmuno-precipitation (fig. S12C) in normal but not in starved medium and from a peptide-based kinase assay showing that mutation of Ser142 to alanine abolished ERK2-mediated phosphorylation (	SIGNOR-248279
P03372	P50613	phosphorylation	up-regulates	0.413	Activation of estrogen receptor alpha by s118 phosphorylation involves a ligand-dependent interaction with tfiih and participation of cdk7.	SIGNOR-81170
P05198	P36873	dephosphorylation	up-regulates activity	0.412	Dephosphorylation of eIF2Î± is central to ISR signal termination to restore protein synthesis and normal cell functioning. It is mediated by protein phosphatase 1 (PP1) complex that recruits a PP1 catalytic subunit (PP1c) and one of the two regulatory subunits. In mammals, phosphatase activity is regulated by either PPP1R15A (also known as growth arrest and DNA damageâ€inducible protein, GADD34), which is induced as part of the ISR. the GADD34â€“PP1 complex acts as an important negative feedback loop to restore protein synthesis once the ER stress has been resolved, and as such aids in cell survival	SIGNOR-254119
Q13099	O75665	binding	up-regulates activity	0.412	Ofd1 acts at the distal centriole to build distal appendages, recruit Ift88, and stabilize centriolar microtubules at a defined length.	SIGNOR-251973
P60709	P37802	binding	down-regulates activity	0.412	Taken together, our data propose a novel, oncogene-tumor suppressor interplay, where oncogenic PFTK1 confers HCC cell motility through inactivating the actin-binding motile suppressing function of TAGLN2 via phosphorylation.	SIGNOR-265104
Q9Y6B2	O94952	binding	down-regulates quantity by destabilization	0.412	SCFFBXO21 ubiquitylates and thereby targets EID1 for degradation.We have now applied this approach to an uncharacterized human F-box protein, FBXO21, which serves as the substrate-recognition subunit of a SKP1-CUL1-F-box protein (SCF)-type E3, thereby identifying EID1 (EP300-interacting inhibitor of differentiation 1) as a candidate substrate.Over-expression of FBXO21 resulted in the down-regulation of EID1, whereas disruption of the FBXO21 gene with the CRISPR/Cas9 system stabilized EID1 and led to its accumulation in both the cytoplasm and nucleus. An in vitro ubiquitylation assay showed that EID1 is a direct substrate of SCF(FBXO)	SIGNOR-272429
O15379	P24385	binding	up-regulates	0.412	Collectively, these studies suggest an important role of cyclin d1 in regulation of ppargamma-mediated adipocyte differentiation through recruitment of hdacs to regulate ppar response element local chromatin structure and ppargamma function.	SIGNOR-134056
P10828	P28482	phosphorylation	down-regulates activity	0.412	We concluded that serine 142 of the tr dbd is the likely site of phosphorylation by t(4)-activated mapk and that the docking site on tr for activated mapk includes residues 128-133 (kgffrr), a basic amino acid-enriched motif novel for mapk substrates. Tr mutations in the proposed mapk docking domain and at residue 142 modulated t(4)-conditioned shedding of co-repressor and recruitment of co-activator proteins by the receptor, and they altered transcriptional activity of tr in a thyroid hormone response element-luciferase reporter assay.	SIGNOR-102216
P42262	P54829	dephosphorylation	down-regulates activity	0.412	One study showed that stimulation of the metabotrophic glutamate receptor mGluR5 leads to a STEP mediated tyrosine dephosphorylation of GluA2 and internalization of GluA1 and GluA2, although the tyrosine residue on GluA2 that is dephosphorylated by STEP remains unidentified.	SIGNOR-277040
Q9NQ66	P27361	phosphorylation	up-regulates activity	0.412	Plc beta1 could be efficiently phosphorylated by activated mitogen-activated protein kinase but not by pka. The erk phosphorylation site was mapped to serine 982	SIGNOR-106565
Q8IXJ6	P06493	phosphorylation	down-regulates	0.412	Here, we demonstrate that sirt2 is phosphorylated both in vitro and in vivo on serine 368 by the cell-cycle regulator, cyclin-dependent kinase 1. Overexpression of sirt2 mediates a delay in cellular proliferation that is dependent on serine 368 phosphorylation.	SIGNOR-154681
Q8TCW9	P58294	binding	up-regulates	0.412	The present study demonstrates that eg-vegf/prokineticin 1 and a peptide closely related to eg-vegf, prokineticin 2, are cognate ligands of two orphan g-protein-coupled receptors designated zaq (=eg-vegf/pk-r1) and i5e (=eg-vegf/pk-r2)	SIGNOR-89084
P31751	Q9UBI6	binding	up-regulates	0.412	We show that pge2 stimulates colon cancer cell growth through its heterotrimeric guanine nucleotide-binding protein (g protein) coupled receptor, ep2, by a signaling route that involves the activation of phosphoinositide 3-kinase and the protein kinase akt by free g protein bg subunits and the direct association of the g protein as subunit with the regulator of g protein signaling (rgs) domain of axin. This leads to the inactivation and release of glycogen synthase kinase 3b from its complex with axin, thereby relieving the inhibitory phosphorylation of b-catenin and activating its signaling pathway.	SIGNOR-141792
P52789	P04637	transcriptional regulation	down-regulates quantity by repression	0.412	P53 regulates basal expression of AIF and SCO2 and facilitates oxidative phosphorylation. The expression of GLUT1, GLUT4, and HK2 is negatively regulated by p53, whereas TIGAR expression is induced by p53. The net result of p53-mediated regulation of these glycolytic enzymes is the suppression of glycolysis. In addition, p53 directly binds and inhibits G6PD activity and downregulates the pentose phosphate pathway.	SIGNOR-267466
O43148	P52292	binding	down-regulates activity	0.412	KPNA2 Inhibits RNMT Activity\|We report that CDK1-cyclin B1 phosphorylates the RNMT regulatory domain on T77 during G2/M phase of the cell cycle. RNMT T77 phosphorylation activates the enzyme both directly and indirectly by inhibiting interaction with KPNA2, an RNMT inhibitor.	SIGNOR-265502
Q01196	P12931	phosphorylation	up-regulates activity	0.412	Src phosphorylates Runx1 on one central and four C-terminal tyrosines.\|We find that activated Src synergizes with Runx1 to activate a Runx1 luciferase reporter.	SIGNOR-279656
Q93034	P10523	binding	up-regulates quantity by stabilization	0.412	Here we report that NEDD4-1, a HECT domain-containing E3 ubiquitin ligase, binds via its HECT domain directly with SAG's C-terminal RING domain and ubiquitylates SAG for proteasome-mediated. We also found that SAG bridges NEDD4-1 via its C-terminus and CUL-5 via its N-terminus to form a NEDD4-1/SAG/CUL-5 tri-complex. Biologically, NEDD4-1 overexpression sensitizes cancer cells to etoposide-induced apoptosis by reducing SAG levels through targeted degradation. Thus, SAG is added to a growing list of NEDD4-1 substrates and mediates its biological function. degradation.	SIGNOR-272844
O60504	P00519	phosphorylation	up-regulates activity	0.412	Abl kinase interacts with and phosphorylates vinexin.	SIGNOR-280172
Q08289	Q13557	phosphorylation	up-regulates	0.412	We recently identified ca(v)1.2 beta(2a) residues critical for camkii phosphorylation (thr 498) beta(2a) thr 498 and leu 493 are required for ca(v)1.2 activation by camkii in native cells.	SIGNOR-164067
Q12955	O00533	relocalization	up-regulates quantity	0.412	Neurofascin, L1, NrCAM, NgCAM, and neuroglian are membrane-spanning cell adhesion molecules with conserved cytoplasmic domains that are believed to play important roles in development of the nervous system. This report presents biochemical evidence that the cytoplasmic domains of these molecules associate directly with ankyrins, a family of spectrin-binding proteins located on the cytoplasmic surface of specialized plasma membrane domains.	SIGNOR-266723
Q13322	P42345	phosphorylation	up-regulates	0.412	The adaptor protein grb10 was identified as an mtorc1 substrate that mediates the phosphoinositide 3-kinase.	SIGNOR-174071
P09651	P31749	phosphorylation	down-regulates	0.412	Our data also suggest that akt negatively regulates hnrnp a1-mediated ires activity via phosphorylation at ser199.	SIGNOR-252519
P41236	P49841	phosphorylation	up-regulates activity	0.412	Protein phosphatase 1 (PP1) is complexed with inhibitor 2 (I-2) in the cytosol. In rabbit muscle extract PP1.I-2 is activated upon preincubation with ATP/Mg. This activation is caused by phosphorylation of I-2 on Thr(72) by glycogen synthase kinase 3 (GSK3).	SIGNOR-251257
Q15139	P12931	phosphorylation	up-regulates	0.411	Critical for the regulation of pkd1 activity in response to oxidative stress are src- and abl-mediated tyrosine phosphorylations that eventually lead to protein kinase cdelta (pkcdelta)-mediated activation of pkd1. our data suggest that pkd1 phosphorylation at tyr95 generates a binding motif for pkcdelta, and that oxidative stress-mediated pkcdelta/pkd interaction results in pkd1 activation loop phosphorylation and activation.	SIGNOR-157716
O95837	P20309	binding	up-regulates activity	0.411	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-257134
Q14814	Q13627	phosphorylation	down-regulates activity	0.411	DYRK1A phosphorylates MEF2D and decreases its transcriptional activity	SIGNOR-277901
P56524	Q9Y2K2	phosphorylation	down-regulates activity	0.411	They find that SIK3 phosphorylates and inhibits HDAC4 during feeding states.\|They find that SIK3 phosphorylates and inhibits HDAC4 during feeding\nstates.	SIGNOR-279430
P50148	P43657	binding	up-regulates	0.411	Lysophosphatidic acid (lpa), a major g protein coupled receptor (gpcr)-activating ligand present in serum, elicits growth factor like responses by stimulating specific gpcrs coupled to heterotrimeric g proteins such as g(i), g(q), and g12/13.	SIGNOR-135822
P30874	P31629	transcriptional regulation	up-regulates quantity by expression	0.411	Activation of somatostatin receptor II expression by transcription factors MIBP1 and SEF-2 in the murine brain.	SIGNOR-261617
Q13263	O96017	phosphorylation	down-regulates activity	0.411	In particular, Chk2 phosphorylates KAP1 on Ser473 decreasing the interaction between KAP1 and HP1 proteins: this post translational modification promotes HP1\u03b2 mobilization and the reorganization of chromatin structure favoring the repair of DNA breaks inside heterochromatin [ , ].\|Of note, phosphorylation of S473 by Chk2 decreases the interaction between KAP1 and HP1 proteins and is necessary for HP1\u03b2 mobilization, a key event for DNA repair in the heterochromatin [ - ].	SIGNOR-279730
Q13043	P35240	binding	up-regulates activity	0.411	NF2 is activated by oxidative stress in cardiomyocytes and mouse myocardium and facilitates apoptosis. NF2 promotes I/R injury through activation of Mst1 and inhibition of Yap, thereby regulating Hippo signaling in the adult heart.	SIGNOR-261956
P04637	Q96Q15	phosphorylation	up-regulates	0.411	Hsmg-1 is a stress-activated kinase that phosphorylates p53 and hupf1 in vitrothe observation that hsmg-1 exhibits p53 (ser-15) kinase activity in vitro suggested that this pikk might be involved in genotoxic stress-induced p53 phosphorylation and stabilization in intact cells.	SIGNOR-125135

O00213

P00519

0

phosphorylation

up-regulates

0.415

The c-abl tyrosine kinase phosphorylates the fe65 adaptor protein to stimulate fe65/amyloid precursor protein nuclear signaling. Here, we show that active c-abl stimulates app/fe65-mediated gene transcription and that this effect is mediated by phosphorylation of fe65 on tyrosine 547 within its second ptb domain.

SIGNOR-123476

Q3KR16

P53350

0

phosphorylation

up-regulates

0.415

We reported previously that a guanine nucleotide exchange factor, myogef, localizes to the central spindle, activates rhoa, and is required for cytokinesis. In this study, we have found that plk1 (polo-like kinase 1) can phosphorylate myogef, thereby recruiting myogef to the central spindle as well as enhancing myogef activity toward rhoa. The in vitro kinase assay shows that plk1 can phosphorylate myogef on threonine 574.

SIGNOR-179954

Q13490

Q6GPH4

0

binding

down-regulates

0.415

Immunoprecipitation studies indicate that xaf1 binds to xiap,birc2,birc3.

SIGNOR-156843

P00533

P29350

0

dephosphorylation

down-regulates

0.415

The sh2-domain ptpase shp-1 binds to and dephosphorylates autophosphorylated egfr and may participate in modulation of egfr signaling in epithelial cells. Reduced shp-1 binding to the egfr y1173f mutant resulted in a reduced receptor dephosphorylation by coexpressed shp-1 and less interference with egf-dependent mitogen-activated protein kinase stimulation.

SIGNOR-59965

Q96J92

O00141

0

phosphorylation

up-regulates activity

0.415

In addition, we identified a novel SGK1 phosphorylation site (S1201) in WNK4, and phosphorylation at this site is reduced by Ca(2+)/CaM.

SIGNOR-276421

Q8IVM0

P00533

0

phosphorylation

down-regulates activity

0.415

We also detected tyrosine phosphorylation of Ymer by EGF stimulation as previously reported (Fig. 1A). Furthermore, we verified that EGF receptor-mediated tyrosine phosphorylation of Ymer is inhibited by AG1478, which is known as an EGF receptor tyrosine kinase inhibitor (Fig. 1B). A luciferase reporter assay showed that mutation of tyrosines on Ymer (YmerY217/279/304F) results in loss of the inhibitory activity for NF-kappaB signaling.

SIGNOR-262851

Q92974

P12931

0

phosphorylation

up-regulates activity

0.415

Src activates GEF-H1.

SIGNOR-277478

P10415

Q99933

0

binding

up-regulates activity

0.415

Cloning and functional analysis of BAG-1: A novel Bcl-2-binding protein with anti-cell death activity|

SIGNOR-254118

Q8N6T7

Q00987

0

ubiquitination

down-regulates quantity

0.415

These results suggest that MDM2 degrades SIRT6 in a proteasome dependent manner.|USP10 has been shown to deubiquitinate and stabilize p53, a well-known substrate of MDM2, suggesting a mechanism whereby SIRT6 is ubiquitinated and destabilized by MDM2, which could be reversed by USP10 mediated deubiquitination.

SIGNOR-278702

Q9NQT8

Q7KZI7

0

phosphorylation

down-regulates activity

0.415

We report here the identification of GAKIN/KIF13B as a novel in vivo substrate for Par1b and present evidence that GAKIN/KIF13B plays a critical role in axon formation in neurons, which is negatively regulated by Par1b-mediated phosphorylation. Par1b phosphorylates GAKIN/KIF13B at both Ser1381 and Ser1410.

SIGNOR-262956

Q14457

Q13464

0

phosphorylation

up-regulates activity

0.415

Beclin1 is phosphorylated by ROCK1 at T119.

SIGNOR-278198

Q9Y4C1

Q16665

0

transcriptional regulation

up-regulates quantity by expression

0.415

To this end, we confirm that KDM3A, KDM4B, KDM4C, KDM5B, KDM5C, and KDM62 are direct targets of HIF-1a while extent the list of known targets to KDM2A, KDM2B, KDM4D, KDM5A, and KDM6A. The results demonstrated that majority of the KDMs were similarly induced (KDM2A, KDM2B, KDM3A, KDM4B, KDM4C, KDM4D, KDM5A, KDM5B, KDM5C, KDM6B, and KDM7A) or repressed (KDM NO66 and KDM1A) by both HIF-1a and HIF-2a.

SIGNOR-271568

O43524

P04150

0

transcriptional regulation

up-regulates quantity

0.415

We show that FOXO3 is an immediate early glucocorticoid receptor (GR) target, whose transcription is even further enhanced by conditions that mimic metabolic stress.

SIGNOR-255759

Q14814

Q00535

0

phosphorylation

down-regulates activity

0.415

In this case, cdk5 phosphorylates MEF2D on Ser444 suppressing its transcriptional activity.

SIGNOR-279509

Q05469

P27361

0

phosphorylation

up-regulates activity

0.415

Thus, activation of the ERK pathway appears to be able to regulate adipocyte lipolysis by phosphorylating HSL on Ser(600) and increasing the activity of HSL.

SIGNOR-249470

P41594

P05129

0

phosphorylation

up-regulates activity

0.415

Thus, we showed that it is phosphorylation of Ser-839, not Thr-840, that is absolutely required for the unique Ca2+ oscillations produced by mGluR5 activation. The Thr-840 residue is important only in that it is permissive for the PKC-dependent phosphorylation of Ser-839.

SIGNOR-249289

P35222

P04629

0

phosphorylation

up-regulates activity

0.415

EGFR and TRKA effect on WNT3a mediated Topflash induction was abolished by U0126 or expression of dominant negative LRP6-5A mutant (XREF_FIG), demonstrating that both EGFR and TRKA signal via ERK and LRP6 pathway to upregulate WNT and beta-catenin signaling.|FGFR2, FGFR3, EGFR and TRKA Phosphorylate \u03b2-catenin at Tyr142.

SIGNOR-279240

Q8NFH5

P53350

0

phosphorylation

down-regulates activity

0.415

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-279252

O15492

P00533

0

phosphorylation

up-regulates

0.415

Phosphorylation on tyr(168) was mediated by the epidermal growth factor receptor (egfr). We show here that endogenous rgs16 is phosphorylated after epidermal growth factor stimulation of mcf-7 cells.

SIGNOR-98267

P43003

O00141

0

phosphorylation

up-regulates activity

0.415

Site‐directed mutagenesis of the SGK1 phosphorylation sites in the Nedd4‐2 protein (S382A,S468ANedd4‐2) and in the EAAT1 protein (T482AEAAT1, T482DEAAT1) significantly blunts the effect of S422DSGK1. Introduction of a negative charge at the SGK phosphorylation site in the EAAT1 protein leads to a strong stimulation of the carrier, whereas replacement with alanine markedly decreases the EAAT1‐mediated current. These observations suggest that SGK1 exerts its effect not only by phosphorylation of Nedd4‐2 but also by phosphorylation of EAAT1.

SIGNOR-263075

Q68DK2

Q9H1H9

0

binding

up-regulates activity

0.415

We show that PtdIns(3)P localizes to the midbody during cytokinesis and recruits a centrosomal protein, FYVE-CENT (ZFYVE26), and its binding partner TTC19, which in turn interacts with CHMP4B, an endosomal sorting complex required for transport (ESCRT)-III subunit implicated in the abscission step of cytokinesis. On the basis of these data and the high-content microscopy described above, we propose that PtdIns(3)P controls the KIF13A-dependent recruitment of FYVE-CENT and TTC19 to the midbody, and that TTC19 is the most downstream effector of the three, possibly controlling the function of CHMP4B.

SIGNOR-265539

Q9HBH9

Q16539

0

phosphorylation

up-regulates

0.415

Erk and p38 phosphorylate mnk1 and mnk2, which stimulates their in vitro kinase activity

SIGNOR-48349

Q13315

Q00535

0

phosphorylation

up-regulates

0.415

Here we show that cdk5 (cyclin-dependent kinase 5), activated by dna damage, directly phosphorylates atm at ser 794 in post-mitotic neurons. Phosphorylation at ser 794 precedes, and is required for, atm autophosphorylation at ser 1981, and activates atm kinase activity

SIGNOR-183454

P36897

P07900

0

binding

up-regulates

0.415

The data in fig. 5 suggest that hsp90 specifically interacts with t?RI And t?RII In vitro and in vivo. Coupled with our data showing that loss of hsp90 function decreases t?R Levels and blocks tgf?-Induced smad2/3 activation and transcription, this result suggests that hsp90 controls tgf? Signaling as an essential component for stabilizing t?Rs.

SIGNOR-179268

P05231

O95644

0

transcriptional regulation

up-regulates quantity by expression

0.415

The calcineurin/nuclear factor of activated T cells (NFAT) signaling pathway has been found to play a role in regulating growth and differentiation in several cell types. However, the functional significance of NFAT in the vasculature is largely unclear. Here we show that NFATc1, NFATc3, and NFATc4 are expressed in human myometrial arteries. |Chronic inhibition of NFAT significantly reduced IL-6 production in intact myometrial arteries and inhibited cell proliferation in vascular smooth muscle cells cultured from explants from the same arteries.

SIGNOR-251730

Q15942

P31749

0

phosphorylation

down-regulates

0.415

Akt binds and phosphorylates zyxin on serine 142, leading to its association with acinus zyxin is a substrate of caspases, but akt phosphorylation fails to protect its proteolytic degradation

SIGNOR-156122

Q9Y253

Q13535

0

phosphorylation

up-regulates

0.415

Atr-mediated phosphorylation of dna polymerase _ is needed for efficient recovery from uv damage. We show that, after uv irradiation, pol_ becomes phosphorylated at ser601 by the ataxia-telangiectasia mutated and rad3-related (atr) kinase. Atr-dependent phosphorylation of pol_ is necessary to restore normal survival and postreplication repair

SIGNOR-171290

P10275

Q15466

0

binding

down-regulates

0.415

We demonstrated that shp inhibited both ar-lbd and ntd-dependent transactivation, which evidenced for the first time a protein capable of inhibiting a steroid receptor amino-terminal-dependent transactivation. We further characterized the shp mechanism of action by showing that shp reversed ar coactivator-mediated activation

SIGNOR-112589

Q7RTU7

Q8IYA7

0

transcriptional regulation

up-regulates quantity by expression

0.415

MKX is a meniscus-enriched transcription factor. In human meniscus cells, MKX regulates the expression of meniscus marker genes, OA-related genes, and other transcription factors, including Scleraxis (SCX), SRY Box 5 (SOX5), and Runt domain-related transcription factor 2 (RUNX2).

SIGNOR-267213

Q13541

Q9P1W9

0

phosphorylation

up-regulates activity

0.414

Further, PIM2 triggered phosphorylation of AKT and 4EBP1 (XREF_FIG) clearly demonstrating the activation of PI3K pathway.

SIGNOR-279091

Q99626

Q16539

0

phosphorylation

down-regulates quantity by destabilization

0.414

ERK2, p38alpha and GSK-3beta can phosphorylate Cdx2 in vitro and that the 4S motif is required for phosphorylation by GSK-3beta and p38alpha|Phosphorylation of the homeotic tumor suppressor Cdx2 mediates its ubiquitin-dependent proteasome degradation

SIGNOR-250092

P46531

Q92993

0

acetylation

down-regulates

0.414

This result implies that the residues k2019, k2039, k2044, and k2068 of notch1-ic are the major targets of the acetyltransferase activity of tip60.

SIGNOR-156923

Q9UJM3

P12931

0

phosphorylation

down-regulates activity

0.414

Prior phosphorylation of Y395 dramatically increases the rate of EGFR phosphorylation of Mig6 on Y394 in vitro, and suppression of Src activity pharmacologically or by shRNA decreased phosphorylation of Mig6 on this site in cells, impairing EGFR binding and inhibition.|We further found that Mig6 inhibition of EGFR is modulated by Src via phosphorylation of Mig6 on Y395.

SIGNOR-279116

Q00987

Q6K0P9

0

binding

down-regulates quantity by destabilization

0.414

Here, we show that IFIXalpha1 downregulates HDM2, a principal negative regulator of p53, at the posttranslational level. IFIXalpha1 destabilizes HDM2 protein and promotes its ubiquitination. The E3 ligase activity of HDM2 appears to be required for this IFIXalpha1 effect. Importantly, HDM2 downregulation is required for the IFIXalpha1-mediated increase of p53 protein levels, transcriptional activity, and nuclear localization, suggesting that IFIXalpha1 positively regulates p53 by acting as a negative regulator of HDM2.

SIGNOR-268493

Q9NRY4

Q13464

0

phosphorylation

down-regulates activity

0.414

these results indicate that Rho-kinase can phosphorylate p190A RhoGAP at Ser1150 in COS7 cells. Similarly, the immunoblot analysis, through the use of the anti-p190A RhoGAP-pT1226 and -pS1236 antibodies, revealed that Rho-kinase can phosphorylate p190A RhoGAP at Thr1226 and Ser1236 in COS7 cells

SIGNOR-276177

P29350

P00519

0

phosphorylation

up-regulates activity

0.414

The results demonstrate that the SH3 domain of ABL1 interacts with a WPDHGVPSEP motif (residues 417-426) in the catalytic domain of SHPTP1 and that ABL1 phosphorylates C terminal Y536 and Y564 sites.

SIGNOR-260820

P16949

O15264

0

phosphorylation

down-regulates

0.414

Serine 25 of oncoprotein 18 is a major cytosolic target for the mitogen-activated protein kinase.

SIGNOR-36362

P29317

Q13239

0

binding

down-regulates quantity by destabilization

0.414

These data are consistent with a model where SLAP induces Ephrin-independent EPHA2 degradation. | This activity is independent from CBL but requires SLAP SH3 interaction with the ubiquitination factor UBE4A and SLAP SH2 interaction with pTyr594-EPHA2.

SIGNOR-262964

O14522

P06241

0

phosphorylation

down-regulates activity

0.414

Synapse formation by PTPRT was inhibited by phosphorylation of tyrosine 912 within the membrane-proximal catalytic domain of PTPRT by Fyn. This tyrosine phosphorylation reduced phosphatase activity of PTPRT

SIGNOR-275543

Q9UNN4

P19784

0

phosphorylation

up-regulates activity

0.414

ALF was able to stabilize the binding of TBP to DNA, but it could not stabilize TBP mutants A184E, N189E, E191R, and R205E nor could it facilitate binding of the TBP-like factor TRF2/TLF to a consensus TATA element. However, phosphorylation of ALF with casein kinase II resulted in the partial restoration of complex formation using mutant TBPs. | Because the residues involved (Ser-280, Ser-281, Ser-316, and Ser-321) are conserved in ALF (Ser-356, Ser-357, Ser-418, and Ser-423), we tested whether its activity might also be affected by this modification. We first showed that ALF and TFIIAα/β polypeptides incubated with casein kinase II and [γ-32P]ATP could be labeled.

SIGNOR-250993

Q14012

Q8N5S9

0

phosphorylation

up-regulates activity

0.414

Human calcium-calmodulin dependent protein kinase I: cDNA cloning, domain structure and activation by phosphorylation at threonine-177 by calcium-calmodulin dependent protein kinase I kinase.

SIGNOR-250717

P19634

P51812

0

phosphorylation

up-regulates activity

0.414

In pressured arteries, RSK2 dependent activation of NHE-1 was associated with increased intracellular Ca 2+ transients, which would be expected to increase MLCK activity, thereby contributing to basal tone and myogenic responses.|Together, these data indicate that Ser 703 in NHE-1 is phosphorylated by RSK2, that RSK2 is associated with NHE-1, and that the time course of NHE-1 phosphorylation in response to intraluminal pressure is fast enough for this phosphorylation event to contribute to myogenic vasoconstriction.

SIGNOR-280119

Q9Y294

O14757

0

phosphorylation

up-regulates activity

0.414

Chk1 activated by ataxia telangiectasia mutated (ATM) kinase on DNA breaks in G1 promotes NHEJ through direct phosphorylation of ASF1A at Ser-166. ASF1A phosphorylated at Ser-166 interacts with the repair protein MDC1 and thus enhances MDC1's interaction with ATM and the stable localization of ATM at DNA breaks.

SIGNOR-277620

Q9NZQ3

P12931

0

phosphorylation

up-regulates activity

0.414

These results indicate that phosphorylation of SPIN90 by Src is essential for its synaptic targeting.

SIGNOR-279387

P42336

O43561

0

binding

up-regulates activity

0.414

By substituting these tyrosine residues in LAT with phenylalanine and by utilizing phosphorylated peptides derived from these sites, we mapped the tyrosine residues in LAT required for the direct interaction and activation of Vav, p85/p110alpha and phospholipase Cgamma1 (PLCgamma1). Our results indicate that Tyr(226) and Tyr(191) are required for Vav binding, whereas Tyr(171) and Tyr(132) are necessary for association and activation of phosphoinositide 3-kinase activity and PLCgamma1 respectively.

SIGNOR-246065

P61224

P52306

0

binding

up-regulates

0.414

Smggds has been previously shown to activate a wide variety of small gtpases, including the ras family members rap1a, rap1b, and k-ras, as well as the rho family members cdc42, rac1, rac2, rhoa, and rhob

SIGNOR-171552

Q02750

Q9Y2U5

0

phosphorylation

up-regulates

0.414

Both mekk2 and mekk3 are able to activate the jun kinase pathway in vivo. However, following routine immunoprecipitation in triton x-100, mekk2 but not mekk3 is able to effectively phosphorylate both sek-1 and mek-1 and to undergo autophosphorylation

SIGNOR-107692

Q13224

P17612

0

phosphorylation

up-regulates activity

0.414

Here we identify serine residue 1166 (Ser1166) in the carboxy-terminal tail of the NMDAR subunit GluN2B to be a direct molecular and functional target of PKA phosphorylation critical to NMDAR-dependent Ca(2+) permeation and Ca(2+) signaling in spines.

SIGNOR-276616

O95453

Q7Z2W4

0

binding

up-regulates activity

0.414

We provide evidence indicating that ZAP selectively recruits cellular poly(A)-specific ribonuclease (PARN) to shorten the poly(A) tail of target viral mRNA and recruits the RNA exosome to degrade the RNA body from the 3′ end.

SIGNOR-261296

Q9GZV1

P31751

0

phosphorylation

up-regulates

0.414

In vitro and in vivo studies confirmed that akt phosphorylates ankrd2 at ser-99. moreover, the forced expression of a phosphorylation-defective mutant form of ankrd2 in c2c12 myoblasts promoted a faster differentiation program, implicating akt-dependent phosphorylation at ser-99 in the negative regulation of myogenesis in response to stress conditions.

SIGNOR-236978

Q4V328

P42574

0

cleavage

up-regulates activity

0.414

These results suggest that the region of GRASP‐1 downstream of the Caspase‐3‐cleavage site is capable of activating the JNK signaling pathway by enhancing the phosphorylation of JNK. these results suggest that full length GRASP‐1 does not enhance JNK pathway activity, possibly due to the inhibitory effect of the N‐terminal fragment on the C‐terminal fragment. In contrast, Caspase‐3 cleavage of GRASP‐1 releases the C‐terminal fragment, which in turn activates JNK signaling by serving as a scaffold protein.

SIGNOR-260641

O15111

Q9Y243

0

phosphorylation

up-regulates

0.414

Although there are likely to be multiple levels of crosstalk between the pi3k-akt and nf-kb pathways, one mechanism has been attributed to direct phosphorylation of the amino acid residue t23 on ikb kinase alfa (ikkalfa) by akt, thereby leading to activation of this kinase upstream of nf-kb akt mediates ikkalpha phosphorylation at threonine 23 akt transiently associates in vivo with ikk and induces ikk activation. Akt mediates ikkalfa phosphorylation at threonine 23.Akt phosphorylates ikkalpha on t23, and this phosphorylation event is a prerequisite for the phosphorylation of p65 at s534 by ikkalpha and beta

SIGNOR-187062

P30679

O00254

0

binding

up-regulates activity

0.414

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-257360

Q7KZI7

Q7L7X3

0

phosphorylation

up-regulates activity

0.414

MARK family kinases can be activated by phosphorylation of a conserved threonine (Thr-208 in MARK2), and inactivated by phosphorylation of a serine (Ser-212), both in the activation loop of the catalytic domain. Activation is achieved by the kinases MARKK/TAO1 or LKB1, although the inactivating kinase was unknown. We show here that GSK3beta serves the role of the inhibitory kinase.

SIGNOR-276164

P63092

Q8TDV5

0

binding

up-regulates activity

0.414

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 ‚â• -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 ‚â• -1.0 for defining true couplings. | The score associated to this interaction has a LogRAi ‚â• -1.0.

SIGNOR-256768

P24385

Q5XUX0

0

binding

down-regulates quantity by destabilization

0.413

FBXO31 serves as the substrate-recognition component of the SKP/Cullin/F-box protein class of E3 ubiquitin ligases and has been shown to direct degradation of pivotal cell-cycle regulatory proteins including cyclin D1 and the p53 antagonist MDM2.

SIGNOR-277379

Q96A00

O75116

0

phosphorylation

up-regulates activity

0.413

A major kinase for GPCR‐induced CPI‐17 phosphorylation is PKC which is activated by the PLCbeta‐produced signaling messenger diacylglycerol (DAG). It phosphorylates CPI‐17 at Thr38 residue that directly docks at the active site of MLCP, thereby inhibiting its activity and promoting an increase of phosphorylation of myosin and of other MLCP.| CPI-17 can be also directly phosphorylated at Thr38 residue by MYPT1-associated kinase [222], by PAK, which is downstream of Rac and/or Cdc42 cascade [223], by Rho-associated coiled-coil kinase (ROCK) [224] and by PKN [225].

SIGNOR-96696

P30048

Q5S007

0

phosphorylation

down-regulates activity

0.413

Here, we show that LRRK2 interacts with human peroxiredoxin 3 (PRDX3), a mitochondrial member of the antioxidant family of thioredoxin (Trx) peroxidases. Importantly, mutations in the LRRK2 kinase domain significantly increased phosphorylation of PRDX3 compared to wild-type. The increase in PRDX3 phosphorylation was associated with decreased peroxidase activity and increased death in LRRK2-expressing but not in LRRK2-depleted or vector-transfected neuronal cells.

SIGNOR-262891

Q9UHD2

Q92630

0

phosphorylation

down-regulates quantity by destabilization

0.413

We further found that DYRK2 phosphorylated Ser527 of TBK1, which is essential for the recruitment of NLRP4 and for the E3 ubiquitin ligase DTX4 to degrade TBK1.

SIGNOR-276939

O95837

P25105

0

binding

up-regulates activity

0.413

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-257436

Q16621

Q96J02

0

ubiquitination

down-regulates activity

0.413

Itch regulates p45/NF-E2 in vivo by Lys63-linked ubiquitination| Interestingly, Itch suppressed the transactivation activity of p45/NF-E2 by adding a Lys63-linked polyubiquitin chain. Confocal microscopy revealed that ubiquitinated p45/NF-E2 became localized in the cytoplasm when Itch was over-expressed. Thus, Itch-mediated ubiquitination of p45/NF-E2 does not target the protein for proteasomal degradation, but instead retains p45/NF-E2 in the cytoplasm, where it cannot function as a transactivator.

SIGNOR-275553

P35222

P17252

0

phosphorylation

down-regulates

0.413

As shown in Fig. 1 B, PKCalpha readily phosphorylated Ser33 and Ser37 / Thr41 on full-length beta-catenin (beta-catenin 1 - 781) and CTD deletion mutant (beta-catenin 1-682).|To examine the effect of the armadillo repeats 1-5 on PKCalpha mediated beta-catenin degradation, DNA constructs expressing beta-catenin 1 - 781 and beta-catenin deletion mutants (beta-catenin 1-422 and beta-catenin 1-138) were transfected into HEK293 cells, followed by treatment with increasing concentrations of A23187 and CGK062, which are known activators of PKCalpha.

SIGNOR-278492

P01112

P49354

0

null

up-regulates activity

0.413

Major investments have been made to target Ras through indirect routes. Inhibition of farnesyl transferase to block Ras maturation has failed in large clinical trials.

SIGNOR-242568

Q14012

Q96RR4

0

phosphorylation

up-regulates activity

0.413

Human calcium-calmodulin dependent protein kinase I: cDNA cloning, domain structure and activation by phosphorylation at threonine-177 by calcium-calmodulin dependent protein kinase I kinase.

SIGNOR-250716

P33076

Q92769

0

deacetylation

down-regulates quantity by repression

0.413

We report that CIITA and histone deacetylase 2 (HDAC2) interact in smooth muscle cells and macrophages as assayed by co-immunoprecipitations. HDAC2 deacetylates CIITA whereas both the HDAC inhibitor trichostatin A (TSA) and over-expression of HDAC2 interfering RNA increase CIITA acetylation. HDAC2 down-regulates CIITA recruitment to target promoters as evidenced by chromatin immunoprecipitation assays, and suppresses MHC II activation and collagen repression mediated by CIITA in luciferase reporter assays.

SIGNOR-254231

P36952

Q13547

0

transcriptional regulation

down-regulates quantity by repression

0.413

We found that maspin is selectively upregulated in IFIXα-expressing cells and involved in anti-invasive activity of IFIXα. We also present evidence indicating that IFIXα downregulates histone deacetylase 1 (HDAC1), which is possibly involved in the silencing of the maspin gene in human breast cancer cells. To confirm these results, we performed a luciferase assay using a maspin-promoter-luciferase plasmid. The results showed that HDAC1 overexpression suppressed the activity of the maspin promoter (Figure 3C). Therefore, our results suggest that IFIXα enhances maspin expression through the downregulation of HDAC1.

SIGNOR-268494

P46459

P43378

0

dephosphorylation

down-regulates

0.413

Our results suggest that the molecular mechanism by which ptp-meg2 promotes secretory vesicle fusion involves the local release of nsf from a tyrosine-phosphorylated, inactive state.

SIGNOR-128348

O96006

P46100

0

binding

up-regulates activity

0.413

XNP/dATRX physically interacts with DREF. our results show that DREF is required for the proper expression of pnr and that XNP/dATRX binds to DREF at the DRE sites, resulting in the repression of pnr gene expression.

SIGNOR-239729

P19484

P28482

0

phosphorylation

down-regulates activity

0.413

Evidence for ERK2-mediated TFEB phosphorylation came from ERK2-TFEB coimmuno-precipitation (fig. S12C) in normal but not in starved medium and from a peptide-based kinase assay showing that mutation of Ser142 to alanine abolished ERK2-mediated phosphorylation (

SIGNOR-248279

P03372

P50613

0

phosphorylation

up-regulates

0.413

Activation of estrogen receptor alpha by s118 phosphorylation involves a ligand-dependent interaction with tfiih and participation of cdk7.

SIGNOR-81170

P05198

P36873

0

dephosphorylation

up-regulates activity

0.412

Dephosphorylation of eIF2Î± is central to ISR signal termination to restore protein synthesis and normal cell functioning. It is mediated by protein phosphatase 1 (PP1) complex that recruits a PP1 catalytic subunit (PP1c) and one of the two regulatory subunits. In mammals, phosphatase activity is regulated by either PPP1R15A (also known as growth arrest and DNA damageâ€inducible protein, GADD34), which is induced as part of the ISR. the GADD34â€“PP1 complex acts as an important negative feedback loop to restore protein synthesis once the ER stress has been resolved, and as such aids in cell survival

SIGNOR-254119

Q13099

O75665

0

binding

up-regulates activity

0.412

Ofd1 acts at the distal centriole to build distal appendages, recruit Ift88, and stabilize centriolar microtubules at a defined length.

SIGNOR-251973

P60709

P37802

0

binding

down-regulates activity

0.412

Taken together, our data propose a novel, oncogene-tumor suppressor interplay, where oncogenic PFTK1 confers HCC cell motility through inactivating the actin-binding motile suppressing function of TAGLN2 via phosphorylation.

SIGNOR-265104

Q9Y6B2

O94952

0

binding

down-regulates quantity by destabilization

0.412

SCFFBXO21 ubiquitylates and thereby targets EID1 for degradation.We have now applied this approach to an uncharacterized human F-box protein, FBXO21, which serves as the substrate-recognition subunit of a SKP1-CUL1-F-box protein (SCF)-type E3, thereby identifying EID1 (EP300-interacting inhibitor of differentiation 1) as a candidate substrate.Over-expression of FBXO21 resulted in the down-regulation of EID1, whereas disruption of the FBXO21 gene with the CRISPR/Cas9 system stabilized EID1 and led to its accumulation in both the cytoplasm and nucleus. An in vitro ubiquitylation assay showed that EID1 is a direct substrate of SCF(FBXO)

SIGNOR-272429

O15379

P24385

0

binding

up-regulates

0.412

Collectively, these studies suggest an important role of cyclin d1 in regulation of ppargamma-mediated adipocyte differentiation through recruitment of hdacs to regulate ppar response element local chromatin structure and ppargamma function.

SIGNOR-134056

P10828

P28482

0

phosphorylation

down-regulates activity

0.412

We concluded that serine 142 of the tr dbd is the likely site of phosphorylation by t(4)-activated mapk and that the docking site on tr for activated mapk includes residues 128-133 (kgffrr), a basic amino acid-enriched motif novel for mapk substrates. Tr mutations in the proposed mapk docking domain and at residue 142 modulated t(4)-conditioned shedding of co-repressor and recruitment of co-activator proteins by the receptor, and they altered transcriptional activity of tr in a thyroid hormone response element-luciferase reporter assay.

SIGNOR-102216

P42262

P54829

0

dephosphorylation

down-regulates activity

0.412

One study showed that stimulation of the metabotrophic glutamate receptor mGluR5 leads to a STEP mediated tyrosine dephosphorylation of GluA2 and internalization of GluA1 and GluA2, although the tyrosine residue on GluA2 that is dephosphorylated by STEP remains unidentified.

SIGNOR-277040

Q9NQ66

P27361

0

phosphorylation

up-regulates activity

0.412

Plc beta1 could be efficiently phosphorylated by activated mitogen-activated protein kinase but not by pka. The erk phosphorylation site was mapped to serine 982

SIGNOR-106565

Q8IXJ6

P06493

0

phosphorylation

down-regulates

0.412

Here, we demonstrate that sirt2 is phosphorylated both in vitro and in vivo on serine 368 by the cell-cycle regulator, cyclin-dependent kinase 1. Overexpression of sirt2 mediates a delay in cellular proliferation that is dependent on serine 368 phosphorylation.

SIGNOR-154681

Q8TCW9

P58294

0

binding

up-regulates

0.412

The present study demonstrates that eg-vegf/prokineticin 1 and a peptide closely related to eg-vegf, prokineticin 2, are cognate ligands of two orphan g-protein-coupled receptors designated zaq (=eg-vegf/pk-r1) and i5e (=eg-vegf/pk-r2)

SIGNOR-89084

P31751

Q9UBI6

0

binding

up-regulates

0.412

We show that pge2 stimulates colon cancer cell growth through its heterotrimeric guanine nucleotide-binding protein (g protein) coupled receptor, ep2, by a signaling route that involves the activation of phosphoinositide 3-kinase and the protein kinase akt by free g protein bg subunits and the direct association of the g protein as subunit with the regulator of g protein signaling (rgs) domain of axin. This leads to the inactivation and release of glycogen synthase kinase 3b from its complex with axin, thereby relieving the inhibitory phosphorylation of b-catenin and activating its signaling pathway.

SIGNOR-141792

P52789

P04637

0

transcriptional regulation

down-regulates quantity by repression

0.412

P53 regulates basal expression of AIF and SCO2 and facilitates oxidative phosphorylation. The expression of GLUT1, GLUT4, and HK2 is negatively regulated by p53, whereas TIGAR expression is induced by p53. The net result of p53-mediated regulation of these glycolytic enzymes is the suppression of glycolysis. In addition, p53 directly binds and inhibits G6PD activity and downregulates the pentose phosphate pathway.

SIGNOR-267466

O43148

P52292

0

binding

down-regulates activity

0.412

KPNA2 Inhibits RNMT Activity|We report that CDK1-cyclin B1 phosphorylates the RNMT regulatory domain on T77 during G2/M phase of the cell cycle. RNMT T77 phosphorylation activates the enzyme both directly and indirectly by inhibiting interaction with KPNA2, an RNMT inhibitor.

SIGNOR-265502

Q01196

P12931

0

phosphorylation

up-regulates activity

0.412

Src phosphorylates Runx1 on one central and four C-terminal tyrosines.|We find that activated Src synergizes with Runx1 to activate a Runx1 luciferase reporter.

SIGNOR-279656

Q93034

P10523

0

binding

up-regulates quantity by stabilization

0.412

Here we report that NEDD4-1, a HECT domain-containing E3 ubiquitin ligase, binds via its HECT domain directly with SAG's C-terminal RING domain and ubiquitylates SAG for proteasome-mediated. We also found that SAG bridges NEDD4-1 via its C-terminus and CUL-5 via its N-terminus to form a NEDD4-1/SAG/CUL-5 tri-complex. Biologically, NEDD4-1 overexpression sensitizes cancer cells to etoposide-induced apoptosis by reducing SAG levels through targeted degradation. Thus, SAG is added to a growing list of NEDD4-1 substrates and mediates its biological function. degradation.

SIGNOR-272844

O60504

P00519

0

phosphorylation

up-regulates activity

0.412

Abl kinase interacts with and phosphorylates vinexin.

SIGNOR-280172

Q08289

Q13557

0

phosphorylation

up-regulates

0.412

We recently identified ca(v)1.2 beta(2a) residues critical for camkii phosphorylation (thr 498) beta(2a) thr 498 and leu 493 are required for ca(v)1.2 activation by camkii in native cells.

SIGNOR-164067

Q12955

O00533

0

relocalization

up-regulates quantity

0.412

Neurofascin, L1, NrCAM, NgCAM, and neuroglian are membrane-spanning cell adhesion molecules with conserved cytoplasmic domains that are believed to play important roles in development of the nervous system. This report presents biochemical evidence that the cytoplasmic domains of these molecules associate directly with ankyrins, a family of spectrin-binding proteins located on the cytoplasmic surface of specialized plasma membrane domains.

SIGNOR-266723

Q13322

P42345

0

phosphorylation

up-regulates

0.412

The adaptor protein grb10 was identified as an mtorc1 substrate that mediates the phosphoinositide 3-kinase.

SIGNOR-174071

P09651

P31749

0

phosphorylation

down-regulates

0.412

Our data also suggest that akt negatively regulates hnrnp a1-mediated ires activity via phosphorylation at ser199.

SIGNOR-252519

P41236

P49841

0

phosphorylation

up-regulates activity

0.412

Protein phosphatase 1 (PP1) is complexed with inhibitor 2 (I-2) in the cytosol. In rabbit muscle extract PP1.I-2 is activated upon preincubation with ATP/Mg. This activation is caused by phosphorylation of I-2 on Thr(72) by glycogen synthase kinase 3 (GSK3).

SIGNOR-251257

Q15139

P12931

0

phosphorylation

up-regulates

0.411

Critical for the regulation of pkd1 activity in response to oxidative stress are src- and abl-mediated tyrosine phosphorylations that eventually lead to protein kinase cdelta (pkcdelta)-mediated activation of pkd1. our data suggest that pkd1 phosphorylation at tyr95 generates a binding motif for pkcdelta, and that oxidative stress-mediated pkcdelta/pkd interaction results in pkd1 activation loop phosphorylation and activation.

SIGNOR-157716

O95837

P20309

0

binding

up-regulates activity

0.411

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-257134

Q14814

Q13627

0

phosphorylation

down-regulates activity

0.411

DYRK1A phosphorylates MEF2D and decreases its transcriptional activity

SIGNOR-277901

P56524

Q9Y2K2

0

phosphorylation

down-regulates activity

0.411

They find that SIK3 phosphorylates and inhibits HDAC4 during feeding states.|They find that SIK3 phosphorylates and inhibits HDAC4 during feeding\nstates.

SIGNOR-279430

P50148

P43657

0

binding

up-regulates

0.411

Lysophosphatidic acid (lpa), a major g protein coupled receptor (gpcr)-activating ligand present in serum, elicits growth factor like responses by stimulating specific gpcrs coupled to heterotrimeric g proteins such as g(i), g(q), and g12/13.

SIGNOR-135822

P30874

P31629

0

transcriptional regulation

up-regulates quantity by expression

0.411

Activation of somatostatin receptor II expression by transcription factors MIBP1 and SEF-2 in the murine brain.

SIGNOR-261617

Q13263

O96017

0

phosphorylation

down-regulates activity

0.411

In particular, Chk2 phosphorylates KAP1 on Ser473 decreasing the interaction between KAP1 and HP1 proteins: this post translational modification promotes HP1\u03b2 mobilization and the reorganization of chromatin structure favoring the repair of DNA breaks inside heterochromatin [ , ].|Of note, phosphorylation of S473 by Chk2 decreases the interaction between KAP1 and HP1 proteins and is necessary for HP1\u03b2 mobilization, a key event for DNA repair in the heterochromatin [ - ].

SIGNOR-279730

Q13043

P35240

0

binding

up-regulates activity

0.411

NF2 is activated by oxidative stress in cardiomyocytes and mouse myocardium and facilitates apoptosis. NF2 promotes I/R injury through activation of Mst1 and inhibition of Yap, thereby regulating Hippo signaling in the adult heart.

SIGNOR-261956

P04637

Q96Q15

0

phosphorylation

up-regulates

0.411

Hsmg-1 is a stress-activated kinase that phosphorylates p53 and hupf1 in vitrothe observation that hsmg-1 exhibits p53 (ser-15) kinase activity in vitro suggested that this pikk might be involved in genotoxic stress-induced p53 phosphorylation and stabilization in intact cells.

SIGNOR-125135