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
P48058	P17612	phosphorylation	up-regulates	0.429	We found that pka phosphorylation of the ampa receptor subunits glur4 and glur1 directly controlled the synaptic incorporation of ampa receptors in organotypic slices from rat hippocampus.	SIGNOR-97550
Q9Y618	P24941	phosphorylation	down-regulates activity	0.429	Cdk2 and Pin1 negatively regulate the transcriptional corepressor SMRT.\|Cdk2 phosphorylates SMRT at consensus Cdk motifs to generate Pin1 binding sites and consequently targets SMRT for degradation, the latter also requiring the PPIase activity of Pin1 (XREF_FIG).	SIGNOR-278306
P04637	O15111	phosphorylation	up-regulates activity	0.429	In the nucleus, IKKalpha enhances p53 mediated GADD45 and BAD gene expressions by phosphorylating p53 at Ser20 and stabilizing p53 protein levels , leading to the induction of apoptosis in response to ROS exposure.\|PKC-activated nuclear I\u03baB kinase\u03b1 promotes the stability of p53 protein and mediates reactive oxygen species-induced apoptosis [ ].	SIGNOR-280231
O75182	Q5VTB9	polyubiquitination	down-regulates quantity by destabilization	0.429	Here we identify RNF220 (RING finger protein 220) as a novel ubiquitin ligase for Sin3B. RNF220 specifically interacts with Sin3B both in vitro and in vivo. Sin3B can be regulated by the ubiquitin-proteasome system. Co-expression of RNF220 promotes the ubiquitination and proteasomal degradation of Sin3B.	SIGNOR-271943
O60381	Q15759	phosphorylation	up-regulates	0.428	A mutation of the p38 map kinase phosphorylation site at aa 401 [(s-a)401hbp1] also triggered hbp1 protein instability. While protein stability was compromised by mutation, the specific activities of (s-a)401hbp1 and of wild-type hbp1 appeared comparable for transcriptional repression.	SIGNOR-119134
Q8NFU7	P51608	binding	up-regulates activity	0.428	MeCP2 and its partners, splicing factor Y-box binding protein 1 (YB-1) and methylcytosine dioxygenase 1 (Tet1), bind to BDNF chromatin in naı ̈ve but dissociate during conditioning\|Knockdown of MeCP2 shows it is instrumental for splicing and inhibits Tet1 and CTCF binding thereby negatively impacting DNA methylation and conditioning-dependent splicing regulation. Thus, mutations in MECP2 can have secondary effects on DNA methylation and alternative splicing.	SIGNOR-277701
Q9Y4K3	P36897	binding	up-regulates activity	0.428	We report here that TRAF6 is specifically required for the Smad-independent activation of JNK and p38 and its carboxyl TRAF homology domain physically interacts with TGF-² receptors	SIGNOR-241918
Q14596	P49841	phosphorylation	down-regulates activity	0.428	The autophagy receptor NBR1 (neighbor of BRCA1 gene 1) binds UB/ubiquitin and the autophagosome-conjugated MAP1LC3/LC3 (microtubule-associated protein 1 light chain 3) proteins, thereby ensuring ubiquitinated protein degradation\|Here we show that NBR1 is a substrate of GSK3. NBR1 phosphorylation by GSK3 at Thr586 prevents the aggregation of ubiquitinated proteins and their selective autophagic degradation.	SIGNOR-261795
P50148	P35367	binding	up-regulates activity	0.428	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-257376
P63027	Q9ULU8	binding	up-regulates activity	0.428	CAPS interactions with N-terminal regions of the SNARE motif of VAMP2 were also detected, which suggests that CAPS might recruit VAMP2 into syntaxin-1/SNAP-25 heterodimers for RQaQbc-SNARE complex assembly.	SIGNOR-264340
Q9UQL6	Q13555	phosphorylation	down-regulates	0.428	Camk phosphorylates serines -259 and -498 in hdac5, which subsequently serve as docking sites for 14-3-3. Our studies suggest that 14-3-3 binding to hdac5 is required for camk-dependent disruption of mef2hdac complexes and nuclear export of hdac5, and implicate 14-3-3 as a signal-dependent regulator of muscle cell differentiation.	SIGNOR-85102
O95140	P45983	phosphorylation	down-regulates quantity	0.428	We demonstrate that a critical component of the mitochondrial fusion apparatus, the mitofusin Mfn2, is a target for phosphorylation in response to a variety of cellular stresses. We provide direct evidence that JNK mediates this phosphorylation.	SIGNOR-274138
P35228	P42224	transcriptional regulation	up-regulates quantity by expression	0.428	STAT1 binds as a homodimer to cis elements known as gammaactivated sequences in the promoters of the genes encoding NOS2, the MHC class II transactivator (CIITA) and IL-12, among others.	SIGNOR-249497
Q12778	Q16828	dephosphorylation	up-regulates activity	0.428	It has been previously demonstrated that MKP-3 dephosphorylates FOXO1 on Ser256 and promotes nuclear translocation of FOXO1 , which subsequentially binds to the promoters of gluconeogenic genes and turns on the gluconeogenic program.\|We also reported that MKP-3 can activate FOXO1 by at least dephosphorylating Ser 256, one of the Akt phosphorylation sites xref .	SIGNOR-276983
P35558	Q12778	transcriptional regulation	up-regulates quantity by expression	0.428	Phosphorylated foxo1 is inactive and retained in the cytosol. Mkp-3 mediated dephosphorylation activates foxo1 and subsequentially promotes its nuclear translocation and binding to the promoters of gluconeogenic genes, such as phosphoenolpyruvate carboxykinase (pepck) and glucose-6-phosphatase (g6pase).	SIGNOR-197200
Q7Z434	Q9BQ95	binding	up-regulates activity	0.428	ECSIT interacts with IPS-1\|ECSIT enhances IPS-1-mediated IFN-Beta promoter activation	SIGNOR-260371
P40763	Q14289	phosphorylation	up-regulates activity	0.428	These results imply that following EGF stimulation, PYK2 enhances a STAT3-dependent IL8 expression, thus creating a positive feedback loop between ErbB receptors, PYK2, and IL8.\|These results suggest that PYK2-induced STAT3 phosphorylation is crucial for IL8 secretion, while IL8 is crucial for EGF-induced MMP9 transcription (Figure xref ) and for SKBR3 invasion (Figure xref ).	SIGNOR-279429
Q15910	P52333	phosphorylation	up-regulates activity	0.428	These results demonstrate that phosphorylation of EZH2 by JAK3 on the Y244 increases the interaction with Polymerase II and decreases the association with PRC2 components promoting the expression of non-canonical genes.\|To explore the mechanism of JAK3 mediated EZH2 activation, the authors performed co-immunoprecipitation assays, which revealed interaction of EZH2 with JAK3 and polymerase II.	SIGNOR-278518
P05412	Q8TD08	phosphorylation	up-regulates	0.428	Up-regulation of c-jun mrna in cardiac myocytes requires the extracellular signal-regulated kinase cascade, but c-jun n-terminal kinases are required for efficient up-regulation of c-jun protein. these data suggest that erks, rather than jnks, are required for c- jun up-regulation.	SIGNOR-91375
P25054	O60566	phosphorylation	up-regulates activity	0.428	These findings support a model in which BubR1 kinase may directly regulate APC function involved in stable kinetochore microtubule attachment.\|Using purified components, BubR1 directly phosphorylates APC and forms a ternary complex with APC and microtubules.	SIGNOR-279393
Q13477	Q8TAU0	transcriptional regulation	up-regulates quantity by expression	0.428	We provide evidence that NKX2.3 can activate MAdCAM-1 transcription directly	SIGNOR-266219
Q15118	P00558	phosphorylation	up-regulates activity	0.428	Mitochondrial PGK1 acts as a protein kinase to phosphorylate pyruvate dehydrogenase kinase 1 (PDHK1) at T338, which activates PDHK1 to phosphorylate and inhibit the pyruvate dehydrogenase (PDH) complex.	SIGNOR-278365
P10828	P27361	phosphorylation	down-regulates activity	0.428	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-102224
Q16875	P31749	phosphorylation	up-regulates	0.427	We also found that AMP activated protein kinase and protein kinases A, B, and C catalyzed the phosphorylation of Ser-460 of HBP1, and that in addition both isoforms are phosphorylated at a second, as yet undetermined site by protein kinase C. However, none of the phosphorylations had any effect on the intrinsic kinetic characteristics of either enzymatic activity, and neither did point mutation (mimicking phosphorylation), deletion, and alternative-splice modification of the HBP1 carboxy-terminal region. Instead, these phosphorylations and mutations decreased the sensitivity of the 6PF2K to a potent allosteric inhibitor, phosphoenolpyruvate, which appears to be the major regulatory mechanism.	SIGNOR-252477
O95271	P53350	phosphorylation	up-regulates quantity by stabilization	0.427	Here, we report that Plk1 forms a complex with TNKS1 in vitro and in vivo, and phosphorylates TNKS1. Phosphorylation of TNKS1 by Plk1 appears to increase TNKS1 stability and telomeric poly(ADP-ribose) polymerase (PARP) activity. By contrast, targeted inhibition of Plk1 or mutation of phosphorylation sites decreased the stability and PARP activity of TNKS1, leading to distort mitotic spindle-pole assembly and telomeric ends.	SIGNOR-276245
P10636	Q13627	phosphorylation	down-regulates	0.427	Dyrk1a phosphorylates tau at least at s202, t212 and s404, but t212 phosphorylation is known to initiate tau hyperphosphorylation by gsk3b (ryoo et al., 2007;woods et al., 2001) and has been demonstrated to have a role in alternative splicing of taumrna	SIGNOR-171030
P05787	Q15759	phosphorylation	up-regulates	0.427	Keratin 8 (k8) serine 73 occurs within a relatively conserved type ii keratin motif . Here we show that ser-73 is exclusively phosphorylated in vitro by p38 mitogen-activated protein kinase. The ser-73 --> ala-associated filament reorganization defect is rescued by a ser-73 --> asp mutation. Also, disease-causing keratin mutations can modulate keratin phosphorylation and organization, which may affect disease pathogenesis.	SIGNOR-114063
P35613	Q8NEZ5	ubiquitination	down-regulates quantity by destabilization	0.427	F-Box Protein FBXO22 Mediates Polyubiquitination and Degradation of CD147 to Reverse Cisplatin Resistance of Tumor Cells	SIGNOR-273452
P14136	Q9UQM7	phosphorylation	down-regulates activity	0.427	On the other hand, GFAP was phosphorylated to approximately 1.9 mol of phosphate/mol of GFAP by Ca(2+)-CaM-dependent protein kinase II, and this phosphorylation did induce disassembly of the filament. Sequential analysis of the purified phosphopeptides revealed that only Ser8 on GFAP was phosphorylated by cdc2 kinase, whereas Ser13, Ser17, Ser34, and Ser389 on GFAP were phosphorylated by Ca(2+)-CaM-dependent protein kinase II.	SIGNOR-250626
P09874	Q96EP1	polyubiquitination	down-regulates quantity by destabilization	0.427	Here, we show that checkpoint with Forkhead-associated (FHA) and RING finger domain protein (CHFR), an E3 ubiquitin ligase, is recruited to DSBs by poly(ADP-ribose) (PAR). Moreover, CHFR ubiquitinates PAR polymerase 1 (PARP1) and regulates chromatin-associated PARP1 in vivo. Moreover, the poly-ubiquitin chain on PARP1 could be recognized by both anti-K48 and K63-linked poly-ubiquitin chain antibodies, suggesting that CHFR mediates a mixed poly-ubiquitin chain linkage on PARP1. With MG132 treatment, ubiquitinated PARP1 was significantly accumulated (Figure 4D), suggesting that the ubiquitination of PARP1 is likely involved in protein degradation. Consistently, we found that following DNA damage, PARP1 quickly dissociated from the chromatin in the wild-type cells (Figure 4F). However, in the Chfr−/− cells, the dissociation of PARP1 from the chromatin was significantly delayed.	SIGNOR-271470
P02649	Q99523	binding	up-regulates quantity	0.427	Here, we identified the pro-neurotrophin receptor sortilin as major endocytic pathway for clearance of APOE/Aβ complexes in neurons. Sortilin binds APOE with high affinity. Lack of receptor expression in mice results in accumulation of APOE and of Aβ in the brain and in aggravated plaque burden. Sortilin interacts with all human APOE isoforms.	SIGNOR-273721
P98177	Q13043	phosphorylation	up-regulates	0.427	The other major signaling modules that directly regulate the activity of the foxo factors include the stress-activated jun-n-terminal kinase (jnk), the mammalian ortholog of the ste20-like protein kinase (mst1), and the deacetylase sirt1	SIGNOR-178193
P61006	Q92834	guanine nucleotide exchange factor	up-regulates activity	0.427	PGR interacts with the small GTPase RAB8A, which participates in cilia biogenesis and maintenance. We show that RPGR primarily associates with the GDP-bound form of RAB8A and stimulates GDP/GTP nucleotide exchange. RPGR functions as a GEF for RAB8A and RPGR–RAB8A association may facilitate ciliary trafficking.	SIGNOR-253030
Q13547	P20749	binding	up-regulates	0.427	We show that bcl-3 is a substrate for the protein kinase gsk3 and that gsk3-mediated bcl-3 phosphorylation, which is inhibited by akt activation, targets its degradation through the proteasome pathway. This phosphorylation modulates its association with hdac1, -3, and -6	SIGNOR-129801
Q12965	O43426	binding	up-regulates activity	0.427	We describe binding of two PRD-containing endocytic proteins, dynamin and synaptojanin-1, to the SH3 domain of Myo1E. This interaction was detected both in vitro, using pull-downs of purified proteins, and in vivo, using immunoprecipitation of protein complexes from synapse-enriched brain extract and immunolocalization of Myo1E and dynamin. Our observation of the interaction between human Myo1E and endocytic proteins suggests that this longtailed myosin may play a role in clathrin-dependent endocytosis.Interaction between Myo1E SH3 domain and PRD-containing endocytic proteins may promote recruitment of Myo1E to clathrin-coated structures since an inactivating mutation in the SH3 domain reduced Myo1E localization to clathrin-containing puncta.	SIGNOR-265423
P01116	Q8N9B8	guanine nucleotide exchange factor	up-regulates	0.427	Gefs catalyse the transition from gdp-bound, inactive ras to gtp-bound, active ras.	SIGNOR-183826
P56524	Q5H9F3	binding	up-regulates activity	0.427	BCoR-L1 interacts with Class II HDACs, HDAC4, HDAC5, and HDAC7, suggesting that they are involved in its function as transcriptional corepressor.	SIGNOR-259112
P61586	P85298	gtpase-activating protein	down-regulates activity	0.427	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)\|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs\| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260463
Q8IVP5	P68400	phosphorylation	down-regulates activity	0.427	Here, we identify that the mitochondrially localized PGAM5 phosphatase interacts with and dephosphorylates FUNDC1 at serine 13 (Ser-13) upon hypoxia or carbonylcyanide p-trifluoromethoxyphenylhydrazone (FCCP) treatment. Dephosphorylation of FUNDC1 catalyzed by PGAM5 enhances its interaction with LC3, which is abrogated following knockdown of PGAM5 or the introduction of a cell-permeable unphosphorylated peptide encompassing the Ser-13 and LIR of FUNDC1. We further observed that CK2 phosphorylates FUNDC1 to reverse the effect of PGAM5 in mitophagy activation.	SIGNOR-273622
P03372	Q99728	ubiquitination	down-regulates quantity	0.427	As shown in xref , both FOXK2 and BARD1 enhanced the ubiquitination of ER\u03b1, with the extent of ubiquitination being enhanced when both FOXK2 and BARD1 were overexpressed.\|These findings suggested that FOXK2 might act as a negative regulator of Estrogen receptor\u03b1, and its association with both Estrogen receptor\u03b1 and BRCA1/BARD1 could lead to the down-regulation of Estrogen receptor\u03b1 transcriptional activity, effectively regulating the function of Estrogen receptor\u03b1.	SIGNOR-278803
O75460	P07237	binding	down-regulates activity	0.427	The secretory pathway kinase Fam20C phosphorylates Ser357 of PDI and responds rapidly to various ER stressors. Phosphorylation of Ser357 induces an open conformation of PDI and turns it from a "foldase" into a "holdase", which is critical for preventing protein misfolding in the ER. Phosphorylated PDI also binds to the lumenal domain of IRE1α, a major UPR signal transducer, and attenuates excessive IRE1α activity.	SIGNOR-275573
Q8NBP7	P36956	transcriptional regulation	up-regulates quantity by expression	0.427	Expression of nuclear forms of sterol-regulatory element binding protein-1 (SREBP-1) and SREBP-2 dramatically increased the promoter activity of PCSK9.	SIGNOR-255222
Q9UJU2	P23760	binding	up-regulates activity	0.427	Pax3 binds to lef1 pax3 activity may directly effect the expression of factors regulated by signal transduction pathways dependent on lef1.	SIGNOR-162100
P31749	Q07912	phosphorylation	up-regulates activity	0.427	Ack1 (also known as ACK or TNK2), which directly phosphorylates AKT at an evolutionarily conserved tyrosine 176 in the kinase domain. Tyr176-phosphorylated AKT localizes to the plasma membrane and promotes Thr308/Ser473-phosphorylation leading to AKT activation.	SIGNOR-252446
P31749	P45983	phosphorylation	up-regulates activity	0.427	We report that JNKs are necessary for the reactivation of Akt after ischemic injury. We identified Thr450 of Akt as a residue that is phosphorylated by JNKs, and the phosphorylation status of Thr450 regulates reactivation of Akt after hypoxia, apparently by priming Akt for subsequent phosphorylation by 3-phosphoinositide-dependent protein kinase.	SIGNOR-252426
P23396	P67775	dephosphorylation	down-regulates	0.427	We identified that pp2a interacts with wild-type rps3, but not with mutants (s6a/t221a) (fig. 8), and that it associates with the n-terminal region of rps3 (fig. 2). From our results presented here, we conclude that pp2a is involved in the dephosphorylation of phosphorylated rps3 by pkc, and that serine 6 on the n-terminal region of rps3 appears to mediate the pp2a recruitment.	SIGNOR-137963
P31749	P62136	dephosphorylation	down-regulates activity	0.426	Here, we identify PP1 as a serine/threonine phosphatase that associates with and dephosphorylates AKT in breast cancer cells\|The heat shock protein 90 inhibitor geldanamycin and the ErbB inhibitor ZD1839 promote rapid PP1 phosphatase-dependent inactivation of AKT in ErbB2 overexpressing breast cancer cells	SIGNOR-252603
Q09472	O60885	binding	up-regulates activity	0.426	In this study, we explored the role of Brd4 and its interaction with the p300 acetyltransferase in the regulation of Nox4 and the in vivo efficacy of a BET inhibitor to reverse established age-associated lung fibrosis. \|Together, these studies suggest that Brd4 enhances p300-mediated histone acetylation.	SIGNOR-262064
Q9UBN7	P27361	phosphorylation	up-regulates	0.426	Histone deacetylase 6 (hdac6) is well known for its ability to promote cell migrationextracellular signal-regulated kinase (erk) phosphorylates histone deacetylase 6 (hdac6) at serine 1035 to stimulate cell migrationwe have identified two novel erk-mediated phosphorylation sites: threonine 1031 and serine 1035 in hdac6. Both sites were phosphorylated by erk1	SIGNOR-202702
P35558	Q8IXJ6	deacetylation	up-regulates quantity by stabilization	0.426	Conversely, SIRT2 deacetylates and stabilizes PEPCK1.\|Furthermore, coexpression of P300 increased acetylation levels of wild-type PEPCK1, but not PEPCK13K/R, indicating that P300 acts on these lysine residues of PEPCK1	SIGNOR-267599
Q14118	Q9ULB1	binding	up-regulates activity	0.426	The DGC is potentially recruited to the postsynaptic membrane though a direct neurexin–dystroglycan interaction and an indirect interaction with NL2 via the synaptic scaffolding protein S-SCAM.	SIGNOR-265458
Q14118	P58400	binding	up-regulates activity	0.426	The DGC is potentially recruited to the postsynaptic membrane though a direct neurexin–dystroglycan interaction and an indirect interaction with NL2 via the synaptic scaffolding protein S-SCAM.	SIGNOR-265459
P29374	P24941	phosphorylation	down-regulates	0.426	In the present study we identified rbp1 as a novel cdk substrate. Rbp1 is phosphorylated by cdk2 on serines 864 and 1007, which are n- and c-terminal to the lxcxe motif, respectively. Cdk2-mediated phosphorylation of rbp1 or prb destabilizes their interaction in vitro, with concurrent phosphorylation of both proteins leading to their dissociation	SIGNOR-170455
P30679	P47900	binding	up-regulates activity	0.426	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-257339
P15336	P31751	phosphorylation	up-regulates activity	0.426	Taken together, these data suggest that AMPK regulates EC migration through phosphorylation of AKT2, which promotes ATF2 transactivation of MMP-2 during EC migration.\|Within this subgroup, we chose AKT2 for analysis because AKT2 phosphorylates activating transcription factor 2 (ATF2) [ xref , xref ].	SIGNOR-280178
P24385	Q16539	phosphorylation	up-regulates	0.426	A large number of cytosolic proteins can be phosphorylated by p38 mapks, including phospholipase a2, the microtubule-associated protein tau, nhe-1, cyclin d1, cdk inhibitors, bcl2 family proteins, growth factor receptors or keratins	SIGNOR-166594
P04040	Q16236	transcriptional regulation	up-regulates quantity by expression	0.426	BTG2 was found to up-regulate expression of antioxidant enzymes known to be regulated by NFE2L2, including catalase, SOD1, and SOD2	SIGNOR-254651
Q5VWQ8	Q13546	phosphorylation	up-regulates activity	0.426	We further show that RIP1 (the Ser/Thr protein kinase receptor-interacting protein) associates with the GAP domain of AIP1 and mediates TNF-induced AIP1 phosphorylation at Ser-604 and JNK/p38 activation as demonstrated by both overexpression and small interfering RNA knockdown of RIP1 in EC.	SIGNOR-259976
P15923	P46531	binding	down-regulates	0.426	We provide evidence that notch and deltex may act on e47 by inhibiting signaling through ras because (i) full e47 activity was found to be dependent on ras and (ii) both notch and deltex inhibited gal4-jun, a hybrid transcription factor whose activity is dependent on signaling from ras to sapk/jnk.	SIGNOR-56150
P07949	P10586	dephosphorylation	down-regulates	0.426	Lar expression significantly reduced tyrosine-1062 phosphorylation in ret-men2a but not in ret-men2b	SIGNOR-85170
P13688	P12931	phosphorylation	up-regulates activity	0.426	Recent reports have also suggested that Bgp1 behaves as a signal transduction molecule. Several physiological events promote the Tyr phosphorylation of Bgp1 on one or two Tyr residues within its cytoplasmic domain (Tyr-488 and Tyr-515). BGP becomes Tyr-phosphorylated by Src-like Tyr kinases in activated neutrophils (24) and in human colon carcinoma cellsWe have recently shown that Tyr phosphorylation of the mouse Bgp1 cytoplasmic domain in CT51 mouse colonic carcinoma cells led to its binding to the protein-Tyr phosphatase SHP-1 and that this event required the presence of both Tyr-488 and Tyr-515	SIGNOR-246471
P30679	P30411	binding	up-regulates activity	0.426	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-257281
Q99988	P18847	transcriptional regulation	up-regulates quantity by expression	0.426	In addition, DIM increased the expression of NAG-1 as well as activating transcription factor 3 (ATF3), and the induction of ATF3 was earlier than that of NAG-1. The DIM treatment increased luciferase activity of NAG-1 in HCT-116 cells transfected with NAG-1 promoter construct. The results suggest that I3C represses cell proliferation through up-regulation of NAG-1 and that ATF3 may play a pivotal role in DIM-induced NAG-1 expression in human colorectal cancer cells.	SIGNOR-253725
Q9NQS7	O14578	phosphorylation	up-regulates activity	0.426	Figure 5.CIT-K phosphorylates INCENP. (a) Schematic diagram of INCENP structure illustrating the phosphorylated sites identified by MS.	SIGNOR-280232
Q13765	Q13418	phosphorylation	up-regulates	0.426	Ilk phosphorylated alpha-nac on residue ser-43. Ilk-dependent phosphorylation of alpha-nac induced the nuclear accumulation of the coactivator and that phosphorylation of alpha-nac by ilk is required for the potentiation of c-jun-mediated responses by the kinase.	SIGNOR-127694
E9PAV3	Q13418	phosphorylation	up-regulates	0.426	The inactivation of gsk3? In response to adhesion and ilk activation (6) would then result in a thr-159-hypophosphorylated ?-Nac that would become unavailable for proteasome degradation but would become a substrate for the ilk kinase activity on residue ser-43. The ser-43-phosphorylated ?-Nac would preferentially interact with c-jun (30), translocate to the nucleus, and potentiate transcription	SIGNOR-127631
O15455	P00533	phosphorylation	up-regulates activity	0.426	Although both the ErbB1 and the ErbB2 isoforms of EGFR can bind to activated TLR3, functionally, only ErbB1 can trigger TLR3 signaling.\|There is a high degree of specificity of the targets of the two PTKs, EGFR and Src	SIGNOR-278932
P00533	P06493	phosphorylation	down-regulates	0.426	Using a synthetic peptide corresponding to the sequence surrounding ser-1002, p34cdc2 was identified as a kinase capable of phosphorylating this serine residue. phosphorylation of the egf receptor by p34cdc2 was associated with a decrease in its tyrosine protein kinase activity.	SIGNOR-38313
Q8NHV4	Q8TD19	phosphorylation	up-regulates activity	0.426	Nek9 phosphorylates NEDD1 on Ser377 driving its recruitment and thereby that of γ-tubulin to the centrosome in mitotic cells.	SIGNOR-263016
Q13873	O95476	binding	down-regulates	0.426	We show that dullard promotes the ubiquitin-mediated proteosomal degradation of bmp receptors	SIGNOR-151001
Q53EL6	Q9Y297	ubiquitination	down-regulates	0.425	Both akt and p70(s6k) phosphorylate pdcd4, allowing for binding of the e3-ubiquitin ligase beta-trcp and consequently ubiquitylation.	SIGNOR-160985
P46937	P06493	phosphorylation	up-regulates activity	0.425	Our evidence suggested that these YAP sites (Ser138, Thr143, and Ser367) were CDK1 phosphorylation sites.\|These data demonstrate that the YAP phosphorylation sites Ser138, Thr143, and Ser367 are important for proper mitosis and cytokinesis.	SIGNOR-276587
P06241	Q99835	phosphorylation	up-regulates	0.425	Instead, shh rapidly and locally stimulated phosphorylation of the src family kinase (sfk) members src and fyn in a smo-dependent fashion.	SIGNOR-199156
Q86TI0	Q13131	phosphorylation	down-regulates	0.425	In rat l6 myotubes, endogenous tbc1d1 is strongly phosphorylated on ser237 and binds to 14-3-3s in response to the ampk activators aicar	SIGNOR-159048
P06748	P53350	phosphorylation	up-regulates	0.425	Phosphorylated at ser-4 by plk1 and plk2. Phosphorylation at ser-4 by plk2 in s phase is required for centriole duplication and is sufficient to trigger centriole replication. Phosphorylation at ser-4 by plk1 takes place during mitosis.	SIGNOR-125666
P20916	P06241	phosphorylation	up-regulates activity	0.425	Fyn constitutively binds to MAG in a latent form. Ligand stimulation of L-MAG would result in activation of Fyn kinase and phosphorylation of Tyr-620. Binding and activation of PLC y through this phosphotyrosine residue would contribute to the signaling pathway involved in the regulation of myelination.	SIGNOR-251178
P08754	Q99500	binding	up-regulates activity	0.425	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-257175
Q00653	P04637	binding	up-regulates	0.425	P52 cooperates with p53 to regulate other known p53 target genes.	SIGNOR-149811
Q9UHF1	Q86V15	transcriptional regulation	up-regulates quantity	0.425	We have recently demonstrated that a novel transcriptional pathway involving activation of the Epidermal Growth Factor-like Domain 7 (Egfl7) gene by the transcription factor CASTOR (CASZ1) is required for blood vessel assembly and lumen morphogenesis.	SIGNOR-266858
P36956	Q5VTR2	ubiquitination	down-regulates activity	0.425	Here, we reveal that RNF20-induced SREBP1c ubiquitination down-regulates hepatic lipogenic activity upon PKA activation.\|Overexpression of RNF20 represses SREBP1c activity, leading to a decrease in the expression of lipogenic genes.	SIGNOR-278643
P14921	O75444	binding	down-regulates	0.425	Full-length c-maf binds to the c-myb and ets-1. / c-maf inhibits c-myb and ets-1 transcriptional activity.	SIGNOR-56808
P38405	P07550	binding	up-regulates activity	0.425	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-256952
Q14457	Q16644	phosphorylation	up-regulates activity	0.425	Taken together, these data indicate that MK2 and MK3 directly phosphorylate Beclin 1 S90 in vitro, and that MK2 like kinase activity also mediates starvation induced Beclin 1 S90 phosphorylation in cultured cells.	SIGNOR-279342
Q969H0	Q13315	phosphorylation	up-regulates activity	0.425	In response to ionizing radiation, ATM phosphorylates FBXW7 at serine 26 to recruit it to DNA double-strand break (DSB) sites, whereas activated DNA-PKcs phosphorylates XRCC4 at serines 325/326, which promotes binding of XRCC4 to FBXW7	SIGNOR-259942
P0DMV8	Q9HC98	phosphorylation	up-regulates activity	0.425	Mitotic phosphorylation of Hsp72 by the kinase NEK6 at Thr66 located in the NBD promotes the localization of Hsp72 to the mitotic spindle and is required for efficient spindle assembly and chromosome congression and segregation.	SIGNOR-273885
P51955	Q15154	relocalization	up-regulates	0.425	Recruitment of nek2 and c-nap1 to the centrosome is dependent on pcm-1	SIGNOR-133337
Q9C026	P62837	binding	up-regulates activity	0.425	Collectively, these results indicated that TRIM9 is an E3 ligase for its self-ubiquitination and that the ubiquitination of TRIM9 likely serves as a signal for proteasomal degradation. As shown in Fig. 1A, TRIM9 was ubiquitinated by itself when incubated with UbcH5b. In contrast, ubiquitination was observed when incubated with other E2 enzymes. These results suggest that TRIM9 cooperates with UbcH5b for its self-ubiquitination. N	SIGNOR-271420
P55211	Q9Y2G2	binding	down-regulates	0.425	Tucan is a recently identified card-containing protein that can complex with caspase-9 and prevent cytochrome c-induced caspase activation.	SIGNOR-146663
P21796	P00441	binding	down-regulates activity	0.425	Misfolded Mutant SOD1 Directly Inhibits VDAC1 Conductance in a Mouse Model of Inherited ALS\|With conformation-specific antibodies, we now demonstrate that misfolded mutant SOD1 binds directly to the voltage-dependent anion channel (VDAC1), an integral membrane protein imbedded in the outer mitochondrial membrane.	SIGNOR-262798
P84022	O15194	dephosphorylation	up-regulates activity	0.424	Dephosphorylation of Smad2/3 Linkers by SCP2 and SCP3\|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity	SIGNOR-248306
O75874	P36888	phosphorylation	up-regulates activity	0.424	Moreover, in an in vitro kinase assay, purified recombinant FLT3 (rFLT3) phosphorylated recombinant IDH2 R140Q mutant but did not alter its catalytic activity (Figure 1C), whereas rFLT3 phosphorylated mIDH1 protein and enhanced its catalytic activity	SIGNOR-267630
P21796	Q96PY6	phosphorylation	down-regulates	0.424	Nek1 phosphorylates vdac1 on ser193. Wild-type vdac1 assumes an open configuration, but closes and prevents cytochrome c efflux when phosphorylated by nek1. A vdac1-ser193ala mutant, which cannot be phosphorylated by nek1 under identical conditions, remains open and constitutively allows cytochrome c efflux.	SIGNOR-164222
Q9UPY5	Q16236	transcriptional regulation	up-regulates quantity by expression	0.424	NFE2L2 is stabilized and translocates to the nucleus, where it dimerizes with sMAF proteins. This complex binds to AREs to mediate the transcription of genes involved in iron metabolism, GSH metabolism, and ROS detoxification. NFE2L2 directly binds to the promoter region of SLC7A11, leading to increased expression of this transporter, which in turn contributes to the resistance to ferroptosis and to radiotherapy	SIGNOR-279867
Q9Y6B2	Q00987	polyubiquitination	down-regulates quantity by destabilization	0.424	Degradation of EID-1 occurs via ubiquitin-dependent proteolysis and correlates with MDM2 binding. These results are consistent with a model wherein destruction of EID-1 is linked to its ability to interact with MDM2 via either p300 or pRB.	SIGNOR-272582
P36956	P23443	phosphorylation	up-regulates activity	0.424	Besides promoting protein synthesis, S6K1 also phosphorylates and activates sterol regulatory element binding protein 1 and 2 (SREBP and SREBP2), which promotes de novo lipid synthesis that is critical for cell growth and proliferation.\|Besides promoting protein synthesis, S6K1 also phosphorylates and activates sterol regulatory element-binding protein 1 and 2 (SREBP and SREBP2), which promotes de novo lipid synthesis that is critical for cell growth and proliferation ( xref ).	SIGNOR-280120
Q9UNN4	P68400	phosphorylation	up-regulates activity	0.424	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-250873
Q13526	P53350	phosphorylation	up-regulates	0.424	Here we demonstrate that ser-65 in pin1 is the major site for plk1-specific phosphorylation, and the polo-box domain of plk1 is required for this phosphorylation. Interestingly, the phosphorylation of pin1 by plk1 does not affect its isomerase activity but rather is linked to its protein stability. pin1 is ubiquitinated in hela s3 cells, and substitution of glu for ser-65 reduces the ubiquitination of pin1.	SIGNOR-139919
Q9BX66	P00519	phosphorylation	up-regulates activity	0.424	We have here identified Tyr360 in CAP as a major phosphorylation site by c-Abl, although Tyr 632 also might contribute since its substitution in combination with the Y360F mutation reduced the phosphorylation of CAP to a very low level. Y360 in CAP is the major phosphorylation site of c-Abl. Since Tyr326 was not a major c-Abl phosphorylation site, we sought to identify a putative other kinase that might be involved in the phosphorylation of Y326 in CAP.	SIGNOR-278153
P78352	Q9HBW1	binding	up-regulates activity	0.424	A possible function for the NGL–PSD-95 interaction is to couple trans-synaptic adhesion events to the recruitment of PSD-95 and other PSD-95-associated postsynaptic proteins. PSD-95 and liprin-α may be key synaptic scaffolding proteins that couple trans-synaptic adhesions to the assembly of synaptic proteins/vesicles	SIGNOR-264051
P84022	O14595	dephosphorylation	up-regulates activity	0.424	Dephosphorylation of Smad2/3 Linkers by SCP2 and SCP3\|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity	SIGNOR-248293

P48058

P17612

0

phosphorylation

up-regulates

0.429

We found that pka phosphorylation of the ampa receptor subunits glur4 and glur1 directly controlled the synaptic incorporation of ampa receptors in organotypic slices from rat hippocampus.

SIGNOR-97550

Q9Y618

P24941

0

phosphorylation

down-regulates activity

0.429

Cdk2 and Pin1 negatively regulate the transcriptional corepressor SMRT.|Cdk2 phosphorylates SMRT at consensus Cdk motifs to generate Pin1 binding sites and consequently targets SMRT for degradation, the latter also requiring the PPIase activity of Pin1 (XREF_FIG).

SIGNOR-278306

P04637

O15111

0

phosphorylation

up-regulates activity

0.429

In the nucleus, IKKalpha enhances p53 mediated GADD45 and BAD gene expressions by phosphorylating p53 at Ser20 and stabilizing p53 protein levels , leading to the induction of apoptosis in response to ROS exposure.|PKC-activated nuclear I\u03baB kinase\u03b1 promotes the stability of p53 protein and mediates reactive oxygen species-induced apoptosis [ ].

SIGNOR-280231

O75182

Q5VTB9

0

polyubiquitination

down-regulates quantity by destabilization

0.429

Here we identify RNF220 (RING finger protein 220) as a novel ubiquitin ligase for Sin3B. RNF220 specifically interacts with Sin3B both in vitro and in vivo. Sin3B can be regulated by the ubiquitin-proteasome system. Co-expression of RNF220 promotes the ubiquitination and proteasomal degradation of Sin3B.

SIGNOR-271943

O60381

Q15759

0

phosphorylation

up-regulates

0.428

A mutation of the p38 map kinase phosphorylation site at aa 401 [(s-a)401hbp1] also triggered hbp1 protein instability. While protein stability was compromised by mutation, the specific activities of (s-a)401hbp1 and of wild-type hbp1 appeared comparable for transcriptional repression.

SIGNOR-119134

Q8NFU7

P51608

0

binding

up-regulates activity

0.428

MeCP2 and its partners, splicing factor Y-box binding protein 1 (YB-1) and methylcytosine dioxygenase 1 (Tet1), bind to BDNF chromatin in naı ̈ve but dissociate during conditioning|Knockdown of MeCP2 shows it is instrumental for splicing and inhibits Tet1 and CTCF binding thereby negatively impacting DNA methylation and conditioning-dependent splicing regulation. Thus, mutations in MECP2 can have secondary effects on DNA methylation and alternative splicing.

SIGNOR-277701

Q9Y4K3

P36897

0

binding

up-regulates activity

0.428

We report here that TRAF6 is specifically required for the Smad-independent activation of JNK and p38 and its carboxyl TRAF homology domain physically interacts with TGF-² receptors

SIGNOR-241918

Q14596

P49841

0

phosphorylation

down-regulates activity

0.428

The autophagy receptor NBR1 (neighbor of BRCA1 gene 1) binds UB/ubiquitin and the autophagosome-conjugated MAP1LC3/LC3 (microtubule-associated protein 1 light chain 3) proteins, thereby ensuring ubiquitinated protein degradation|Here we show that NBR1 is a substrate of GSK3. NBR1 phosphorylation by GSK3 at Thr586 prevents the aggregation of ubiquitinated proteins and their selective autophagic degradation.

SIGNOR-261795

P50148

P35367

0

binding

up-regulates activity

0.428

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-257376

P63027

Q9ULU8

0

binding

up-regulates activity

0.428

CAPS interactions with N-terminal regions of the SNARE motif of VAMP2 were also detected, which suggests that CAPS might recruit VAMP2 into syntaxin-1/SNAP-25 heterodimers for RQaQbc-SNARE complex assembly.

SIGNOR-264340

Q9UQL6

Q13555

0

phosphorylation

down-regulates

0.428

Camk phosphorylates serines -259 and -498 in hdac5, which subsequently serve as docking sites for 14-3-3. Our studies suggest that 14-3-3 binding to hdac5 is required for camk-dependent disruption of mef2hdac complexes and nuclear export of hdac5, and implicate 14-3-3 as a signal-dependent regulator of muscle cell differentiation.

SIGNOR-85102

O95140

P45983

0

phosphorylation

down-regulates quantity

0.428

We demonstrate that a critical component of the mitochondrial fusion apparatus, the mitofusin Mfn2, is a target for phosphorylation in response to a variety of cellular stresses. We provide direct evidence that JNK mediates this phosphorylation.

SIGNOR-274138

P35228

P42224

0

transcriptional regulation

up-regulates quantity by expression

0.428

STAT1 binds as a homodimer to cis elements known as gammaactivated sequences in the promoters of the genes encoding NOS2, the MHC class II transactivator (CIITA) and IL-12, among others.

SIGNOR-249497

Q12778

Q16828

0

dephosphorylation

up-regulates activity

0.428

It has been previously demonstrated that MKP-3 dephosphorylates FOXO1 on Ser256 and promotes nuclear translocation of FOXO1 , which subsequentially binds to the promoters of gluconeogenic genes and turns on the gluconeogenic program.|We also reported that MKP-3 can activate FOXO1 by at least dephosphorylating Ser 256, one of the Akt phosphorylation sites xref .

SIGNOR-276983

P35558

Q12778

0

transcriptional regulation

up-regulates quantity by expression

0.428

Phosphorylated foxo1 is inactive and retained in the cytosol. Mkp-3 mediated dephosphorylation activates foxo1 and subsequentially promotes its nuclear translocation and binding to the promoters of gluconeogenic genes, such as phosphoenolpyruvate carboxykinase (pepck) and glucose-6-phosphatase (g6pase).

SIGNOR-197200

Q7Z434

Q9BQ95

0

binding

up-regulates activity

0.428

ECSIT interacts with IPS-1|ECSIT enhances IPS-1-mediated IFN-Beta promoter activation

SIGNOR-260371

P40763

Q14289

0

phosphorylation

up-regulates activity

0.428

These results imply that following EGF stimulation, PYK2 enhances a STAT3-dependent IL8 expression, thus creating a positive feedback loop between ErbB receptors, PYK2, and IL8.|These results suggest that PYK2-induced STAT3 phosphorylation is crucial for IL8 secretion, while IL8 is crucial for EGF-induced MMP9 transcription (Figure xref ) and for SKBR3 invasion (Figure xref ).

SIGNOR-279429

Q15910

P52333

0

phosphorylation

up-regulates activity

0.428

These results demonstrate that phosphorylation of EZH2 by JAK3 on the Y244 increases the interaction with Polymerase II and decreases the association with PRC2 components promoting the expression of non-canonical genes.|To explore the mechanism of JAK3 mediated EZH2 activation, the authors performed co-immunoprecipitation assays, which revealed interaction of EZH2 with JAK3 and polymerase II.

SIGNOR-278518

P05412

Q8TD08

0

phosphorylation

up-regulates

0.428

Up-regulation of c-jun mrna in cardiac myocytes requires the extracellular signal-regulated kinase cascade, but c-jun n-terminal kinases are required for efficient up-regulation of c-jun protein. these data suggest that erks, rather than jnks, are required for c- jun up-regulation.

SIGNOR-91375

P25054

O60566

0

phosphorylation

up-regulates activity

0.428

These findings support a model in which BubR1 kinase may directly regulate APC function involved in stable kinetochore microtubule attachment.|Using purified components, BubR1 directly phosphorylates APC and forms a ternary complex with APC and microtubules.

SIGNOR-279393

Q13477

Q8TAU0

0

transcriptional regulation

up-regulates quantity by expression

0.428

We provide evidence that NKX2.3 can activate MAdCAM-1 transcription directly

SIGNOR-266219

Q15118

P00558

0

phosphorylation

up-regulates activity

0.428

Mitochondrial PGK1 acts as a protein kinase to phosphorylate pyruvate dehydrogenase kinase 1 (PDHK1) at T338, which activates PDHK1 to phosphorylate and inhibit the pyruvate dehydrogenase (PDH) complex.

SIGNOR-278365

P10828

P27361

0

phosphorylation

down-regulates activity

0.428

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-102224

Q16875

P31749

0

phosphorylation

up-regulates

0.427

We also found that AMP activated protein kinase and protein kinases A, B, and C catalyzed the phosphorylation of Ser-460 of HBP1, and that in addition both isoforms are phosphorylated at a second, as yet undetermined site by protein kinase C. However, none of the phosphorylations had any effect on the intrinsic kinetic characteristics of either enzymatic activity, and neither did point mutation (mimicking phosphorylation), deletion, and alternative-splice modification of the HBP1 carboxy-terminal region. Instead, these phosphorylations and mutations decreased the sensitivity of the 6PF2K to a potent allosteric inhibitor, phosphoenolpyruvate, which appears to be the major regulatory mechanism.

SIGNOR-252477

O95271

P53350

0

phosphorylation

up-regulates quantity by stabilization

0.427

Here, we report that Plk1 forms a complex with TNKS1 in vitro and in vivo, and phosphorylates TNKS1. Phosphorylation of TNKS1 by Plk1 appears to increase TNKS1 stability and telomeric poly(ADP-ribose) polymerase (PARP) activity. By contrast, targeted inhibition of Plk1 or mutation of phosphorylation sites decreased the stability and PARP activity of TNKS1, leading to distort mitotic spindle-pole assembly and telomeric ends.

SIGNOR-276245

P10636

Q13627

0

phosphorylation

down-regulates

0.427

Dyrk1a phosphorylates tau at least at s202, t212 and s404, but t212 phosphorylation is known to initiate tau hyperphosphorylation by gsk3b (ryoo et al., 2007;woods et al., 2001) and has been demonstrated to have a role in alternative splicing of taumrna

SIGNOR-171030

P05787

Q15759

0

phosphorylation

up-regulates

0.427

Keratin 8 (k8) serine 73 occurs within a relatively conserved type ii keratin motif . Here we show that ser-73 is exclusively phosphorylated in vitro by p38 mitogen-activated protein kinase. The ser-73 --> ala-associated filament reorganization defect is rescued by a ser-73 --> asp mutation. Also, disease-causing keratin mutations can modulate keratin phosphorylation and organization, which may affect disease pathogenesis.

SIGNOR-114063

P35613

Q8NEZ5

0

ubiquitination

down-regulates quantity by destabilization

0.427

F-Box Protein FBXO22 Mediates Polyubiquitination and Degradation of CD147 to Reverse Cisplatin Resistance of Tumor Cells

SIGNOR-273452

P14136

Q9UQM7

0

phosphorylation

down-regulates activity

0.427

On the other hand, GFAP was phosphorylated to approximately 1.9 mol of phosphate/mol of GFAP by Ca(2+)-CaM-dependent protein kinase II, and this phosphorylation did induce disassembly of the filament. Sequential analysis of the purified phosphopeptides revealed that only Ser8 on GFAP was phosphorylated by cdc2 kinase, whereas Ser13, Ser17, Ser34, and Ser389 on GFAP were phosphorylated by Ca(2+)-CaM-dependent protein kinase II.

SIGNOR-250626

P09874

Q96EP1

0

polyubiquitination

down-regulates quantity by destabilization

0.427

Here, we show that checkpoint with Forkhead-associated (FHA) and RING finger domain protein (CHFR), an E3 ubiquitin ligase, is recruited to DSBs by poly(ADP-ribose) (PAR). Moreover, CHFR ubiquitinates PAR polymerase 1 (PARP1) and regulates chromatin-associated PARP1 in vivo. Moreover, the poly-ubiquitin chain on PARP1 could be recognized by both anti-K48 and K63-linked poly-ubiquitin chain antibodies, suggesting that CHFR mediates a mixed poly-ubiquitin chain linkage on PARP1. With MG132 treatment, ubiquitinated PARP1 was significantly accumulated (Figure 4D), suggesting that the ubiquitination of PARP1 is likely involved in protein degradation. Consistently, we found that following DNA damage, PARP1 quickly dissociated from the chromatin in the wild-type cells (Figure 4F). However, in the Chfr−/− cells, the dissociation of PARP1 from the chromatin was significantly delayed.

SIGNOR-271470

P02649

Q99523

0

binding

up-regulates quantity

0.427

Here, we identified the pro-neurotrophin receptor sortilin as major endocytic pathway for clearance of APOE/Aβ complexes in neurons. Sortilin binds APOE with high affinity. Lack of receptor expression in mice results in accumulation of APOE and of Aβ in the brain and in aggravated plaque burden. Sortilin interacts with all human APOE isoforms.

SIGNOR-273721

P98177

Q13043

0

phosphorylation

up-regulates

0.427

The other major signaling modules that directly regulate the activity of the foxo factors include the stress-activated jun-n-terminal kinase (jnk), the mammalian ortholog of the ste20-like protein kinase (mst1), and the deacetylase sirt1

SIGNOR-178193

P61006

Q92834

0

guanine nucleotide exchange factor

up-regulates activity

0.427

PGR interacts with the small GTPase RAB8A, which participates in cilia biogenesis and maintenance. We show that RPGR primarily associates with the GDP-bound form of RAB8A and stimulates GDP/GTP nucleotide exchange. RPGR functions as a GEF for RAB8A and RPGR–RAB8A association may facilitate ciliary trafficking.

SIGNOR-253030

Q13547

P20749

0

binding

up-regulates

0.427

We show that bcl-3 is a substrate for the protein kinase gsk3 and that gsk3-mediated bcl-3 phosphorylation, which is inhibited by akt activation, targets its degradation through the proteasome pathway. This phosphorylation modulates its association with hdac1, -3, and -6

SIGNOR-129801

Q12965

O43426

0

binding

up-regulates activity

0.427

We describe binding of two PRD-containing endocytic proteins, dynamin and synaptojanin-1, to the SH3 domain of Myo1E. This interaction was detected both in vitro, using pull-downs of purified proteins, and in vivo, using immunoprecipitation of protein complexes from synapse-enriched brain extract and immunolocalization of Myo1E and dynamin. Our observation of the interaction between human Myo1E and endocytic proteins suggests that this longtailed myosin may play a role in clathrin-dependent endocytosis.Interaction between Myo1E SH3 domain and PRD-containing endocytic proteins may promote recruitment of Myo1E to clathrin-coated structures since an inactivating mutation in the SH3 domain reduced Myo1E localization to clathrin-containing puncta.

SIGNOR-265423

P01116

Q8N9B8

0

guanine nucleotide exchange factor

up-regulates

0.427

Gefs catalyse the transition from gdp-bound, inactive ras to gtp-bound, active ras.

SIGNOR-183826

P56524

Q5H9F3

0

binding

up-regulates activity

0.427

BCoR-L1 interacts with Class II HDACs, HDAC4, HDAC5, and HDAC7, suggesting that they are involved in its function as transcriptional corepressor.

SIGNOR-259112

P61586

P85298

0

gtpase-activating protein

down-regulates activity

0.427

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

SIGNOR-260463

Q8IVP5

P68400

0

phosphorylation

down-regulates activity

0.427

Here, we identify that the mitochondrially localized PGAM5 phosphatase interacts with and dephosphorylates FUNDC1 at serine 13 (Ser-13) upon hypoxia or carbonylcyanide p-trifluoromethoxyphenylhydrazone (FCCP) treatment. Dephosphorylation of FUNDC1 catalyzed by PGAM5 enhances its interaction with LC3, which is abrogated following knockdown of PGAM5 or the introduction of a cell-permeable unphosphorylated peptide encompassing the Ser-13 and LIR of FUNDC1. We further observed that CK2 phosphorylates FUNDC1 to reverse the effect of PGAM5 in mitophagy activation.

SIGNOR-273622

P03372

Q99728

0

ubiquitination

down-regulates quantity

0.427

As shown in xref , both FOXK2 and BARD1 enhanced the ubiquitination of ER\u03b1, with the extent of ubiquitination being enhanced when both FOXK2 and BARD1 were overexpressed.|These findings suggested that FOXK2 might act as a negative regulator of Estrogen receptor\u03b1, and its association with both Estrogen receptor\u03b1 and BRCA1/BARD1 could lead to the down-regulation of Estrogen receptor\u03b1 transcriptional activity, effectively regulating the function of Estrogen receptor\u03b1.

SIGNOR-278803

O75460

P07237

0

binding

down-regulates activity

0.427

The secretory pathway kinase Fam20C phosphorylates Ser357 of PDI and responds rapidly to various ER stressors. Phosphorylation of Ser357 induces an open conformation of PDI and turns it from a "foldase" into a "holdase", which is critical for preventing protein misfolding in the ER. Phosphorylated PDI also binds to the lumenal domain of IRE1α, a major UPR signal transducer, and attenuates excessive IRE1α activity.

SIGNOR-275573

Q8NBP7

P36956

0

transcriptional regulation

up-regulates quantity by expression

0.427

Expression of nuclear forms of sterol-regulatory element binding protein-1 (SREBP-1) and SREBP-2 dramatically increased the promoter activity of PCSK9.

SIGNOR-255222

Q9UJU2

P23760

0

binding

up-regulates activity

0.427

Pax3 binds to lef1 pax3 activity may directly effect the expression of factors regulated by signal transduction pathways dependent on lef1.

SIGNOR-162100

P31749

Q07912

0

phosphorylation

up-regulates activity

0.427

Ack1 (also known as ACK or TNK2), which directly phosphorylates AKT at an evolutionarily conserved tyrosine 176 in the kinase domain. Tyr176-phosphorylated AKT localizes to the plasma membrane and promotes Thr308/Ser473-phosphorylation leading to AKT activation.

SIGNOR-252446

P31749

P45983

0

phosphorylation

up-regulates activity

0.427

We report that JNKs are necessary for the reactivation of Akt after ischemic injury. We identified Thr450 of Akt as a residue that is phosphorylated by JNKs, and the phosphorylation status of Thr450 regulates reactivation of Akt after hypoxia, apparently by priming Akt for subsequent phosphorylation by 3-phosphoinositide-dependent protein kinase.

SIGNOR-252426

P23396

P67775

0

dephosphorylation

down-regulates

0.427

We identified that pp2a interacts with wild-type rps3, but not with mutants (s6a/t221a) (fig. 8), and that it associates with the n-terminal region of rps3 (fig. 2). From our results presented here, we conclude that pp2a is involved in the dephosphorylation of phosphorylated rps3 by pkc, and that serine 6 on the n-terminal region of rps3 appears to mediate the pp2a recruitment.

SIGNOR-137963

P31749

P62136

0

dephosphorylation

down-regulates activity

0.426

Here, we identify PP1 as a serine/threonine phosphatase that associates with and dephosphorylates AKT in breast cancer cells|The heat shock protein 90 inhibitor geldanamycin and the ErbB inhibitor ZD1839 promote rapid PP1 phosphatase-dependent inactivation of AKT in ErbB2 overexpressing breast cancer cells

SIGNOR-252603

Q09472

O60885

0

binding

up-regulates activity

0.426

In this study, we explored the role of Brd4 and its interaction with the p300 acetyltransferase in the regulation of Nox4 and the in vivo efficacy of a BET inhibitor to reverse established age-associated lung fibrosis. |Together, these studies suggest that Brd4 enhances p300-mediated histone acetylation.

SIGNOR-262064

Q9UBN7

P27361

0

phosphorylation

up-regulates

0.426

Histone deacetylase 6 (hdac6) is well known for its ability to promote cell migrationextracellular signal-regulated kinase (erk) phosphorylates histone deacetylase 6 (hdac6) at serine 1035 to stimulate cell migrationwe have identified two novel erk-mediated phosphorylation sites: threonine 1031 and serine 1035 in hdac6. Both sites were phosphorylated by erk1

SIGNOR-202702

P35558

Q8IXJ6

0

deacetylation

up-regulates quantity by stabilization

0.426

Conversely, SIRT2 deacetylates and stabilizes PEPCK1.|Furthermore, coexpression of P300 increased acetylation levels of wild-type PEPCK1, but not PEPCK13K/R, indicating that P300 acts on these lysine residues of PEPCK1

SIGNOR-267599

Q14118

Q9ULB1

0

binding

up-regulates activity

0.426

The DGC is potentially recruited to the postsynaptic membrane though a direct neurexin–dystroglycan interaction and an indirect interaction with NL2 via the synaptic scaffolding protein S-SCAM.

SIGNOR-265458

Q14118

P58400

0

binding

up-regulates activity

0.426

The DGC is potentially recruited to the postsynaptic membrane though a direct neurexin–dystroglycan interaction and an indirect interaction with NL2 via the synaptic scaffolding protein S-SCAM.

SIGNOR-265459

P29374

P24941

0

phosphorylation

down-regulates

0.426

In the present study we identified rbp1 as a novel cdk substrate. Rbp1 is phosphorylated by cdk2 on serines 864 and 1007, which are n- and c-terminal to the lxcxe motif, respectively. Cdk2-mediated phosphorylation of rbp1 or prb destabilizes their interaction in vitro, with concurrent phosphorylation of both proteins leading to their dissociation

SIGNOR-170455

P30679

P47900

0

binding

up-regulates activity

0.426

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-257339

P15336

P31751

0

phosphorylation

up-regulates activity

0.426

Taken together, these data suggest that AMPK regulates EC migration through phosphorylation of AKT2, which promotes ATF2 transactivation of MMP-2 during EC migration.|Within this subgroup, we chose AKT2 for analysis because AKT2 phosphorylates activating transcription factor 2 (ATF2) [ xref , xref ].

SIGNOR-280178

P24385

Q16539

0

phosphorylation

up-regulates

0.426

A large number of cytosolic proteins can be phosphorylated by p38 mapks, including phospholipase a2, the microtubule-associated protein tau, nhe-1, cyclin d1, cdk inhibitors, bcl2 family proteins, growth factor receptors or keratins

SIGNOR-166594

P04040

Q16236

0

transcriptional regulation

up-regulates quantity by expression

0.426

BTG2 was found to up-regulate expression of antioxidant enzymes known to be regulated by NFE2L2, including catalase, SOD1, and SOD2

SIGNOR-254651

Q5VWQ8

Q13546

0

phosphorylation

up-regulates activity

0.426

We further show that RIP1 (the Ser/Thr protein kinase receptor-interacting protein) associates with the GAP domain of AIP1 and mediates TNF-induced AIP1 phosphorylation at Ser-604 and JNK/p38 activation as demonstrated by both overexpression and small interfering RNA knockdown of RIP1 in EC.

SIGNOR-259976

P15923

P46531

0

binding

down-regulates

0.426

We provide evidence that notch and deltex may act on e47 by inhibiting signaling through ras because (i) full e47 activity was found to be dependent on ras and (ii) both notch and deltex inhibited gal4-jun, a hybrid transcription factor whose activity is dependent on signaling from ras to sapk/jnk.

SIGNOR-56150

P07949

P10586

0

dephosphorylation

down-regulates

0.426

Lar expression significantly reduced tyrosine-1062 phosphorylation in ret-men2a but not in ret-men2b

SIGNOR-85170

P13688

P12931

0

phosphorylation

up-regulates activity

0.426

Recent reports have also suggested that Bgp1 behaves as a signal transduction molecule. Several physiological events promote the Tyr phosphorylation of Bgp1 on one or two Tyr residues within its cytoplasmic domain (Tyr-488 and Tyr-515). BGP becomes Tyr-phosphorylated by Src-like Tyr kinases in activated neutrophils (24) and in human colon carcinoma cellsWe have recently shown that Tyr phosphorylation of the mouse Bgp1 cytoplasmic domain in CT51 mouse colonic carcinoma cells led to its binding to the protein-Tyr phosphatase SHP-1 and that this event required the presence of both Tyr-488 and Tyr-515

SIGNOR-246471

P30679

P30411

0

binding

up-regulates activity

0.426

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-257281

Q99988

P18847

0

transcriptional regulation

up-regulates quantity by expression

0.426

In addition, DIM increased the expression of NAG-1 as well as activating transcription factor 3 (ATF3), and the induction of ATF3 was earlier than that of NAG-1. The DIM treatment increased luciferase activity of NAG-1 in HCT-116 cells transfected with NAG-1 promoter construct. The results suggest that I3C represses cell proliferation through up-regulation of NAG-1 and that ATF3 may play a pivotal role in DIM-induced NAG-1 expression in human colorectal cancer cells.

SIGNOR-253725

Q9NQS7

O14578

0

phosphorylation

up-regulates activity

0.426

Figure 5.CIT-K phosphorylates INCENP. (a) Schematic diagram of INCENP structure illustrating the phosphorylated sites identified by MS.

SIGNOR-280232

Q13765

Q13418

0

phosphorylation

up-regulates

0.426

Ilk phosphorylated alpha-nac on residue ser-43. Ilk-dependent phosphorylation of alpha-nac induced the nuclear accumulation of the coactivator and that phosphorylation of alpha-nac by ilk is required for the potentiation of c-jun-mediated responses by the kinase.

SIGNOR-127694

E9PAV3

Q13418

0

phosphorylation

up-regulates

0.426

The inactivation of gsk3? In response to adhesion and ilk activation (6) would then result in a thr-159-hypophosphorylated ?-Nac that would become unavailable for proteasome degradation but would become a substrate for the ilk kinase activity on residue ser-43. The ser-43-phosphorylated ?-Nac would preferentially interact with c-jun (30), translocate to the nucleus, and potentiate transcription

SIGNOR-127631

O15455

P00533

0

phosphorylation

up-regulates activity

0.426

Although both the ErbB1 and the ErbB2 isoforms of EGFR can bind to activated TLR3, functionally, only ErbB1 can trigger TLR3 signaling.|There is a high degree of specificity of the targets of the two PTKs, EGFR and Src

SIGNOR-278932

P00533

P06493

0

phosphorylation

down-regulates

0.426

Using a synthetic peptide corresponding to the sequence surrounding ser-1002, p34cdc2 was identified as a kinase capable of phosphorylating this serine residue. phosphorylation of the egf receptor by p34cdc2 was associated with a decrease in its tyrosine protein kinase activity.

SIGNOR-38313

Q8NHV4

Q8TD19

0

phosphorylation

up-regulates activity

0.426

Nek9 phosphorylates NEDD1 on Ser377 driving its recruitment and thereby that of γ-tubulin to the centrosome in mitotic cells.

SIGNOR-263016

Q13873

O95476

0

binding

down-regulates

0.426

We show that dullard promotes the ubiquitin-mediated proteosomal degradation of bmp receptors

SIGNOR-151001

Q53EL6

Q9Y297

0

ubiquitination

down-regulates

0.425

Both akt and p70(s6k) phosphorylate pdcd4, allowing for binding of the e3-ubiquitin ligase beta-trcp and consequently ubiquitylation.

SIGNOR-160985

P46937

P06493

0

phosphorylation

up-regulates activity

0.425

Our evidence suggested that these YAP sites (Ser138, Thr143, and Ser367) were CDK1 phosphorylation sites.|These data demonstrate that the YAP phosphorylation sites Ser138, Thr143, and Ser367 are important for proper mitosis and cytokinesis.

SIGNOR-276587

P06241

Q99835

0

phosphorylation

up-regulates

0.425

Instead, shh rapidly and locally stimulated phosphorylation of the src family kinase (sfk) members src and fyn in a smo-dependent fashion.

SIGNOR-199156

Q86TI0

Q13131

0

phosphorylation

down-regulates

0.425

In rat l6 myotubes, endogenous tbc1d1 is strongly phosphorylated on ser237 and binds to 14-3-3s in response to the ampk activators aicar

SIGNOR-159048

P06748

P53350

0

phosphorylation

up-regulates

0.425

Phosphorylated at ser-4 by plk1 and plk2. Phosphorylation at ser-4 by plk2 in s phase is required for centriole duplication and is sufficient to trigger centriole replication. Phosphorylation at ser-4 by plk1 takes place during mitosis.

SIGNOR-125666

P20916

P06241

0

phosphorylation

up-regulates activity

0.425

Fyn constitutively binds to MAG in a latent form. Ligand stimulation of L-MAG would result in activation of Fyn kinase and phosphorylation of Tyr-620. Binding and activation of PLC y through this phosphotyrosine residue would contribute to the signaling pathway involved in the regulation of myelination.

SIGNOR-251178

P08754

Q99500

0

binding

up-regulates activity

0.425

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-257175

Q00653

P04637

0

binding

up-regulates

0.425

P52 cooperates with p53 to regulate other known p53 target genes.

SIGNOR-149811

Q9UHF1

Q86V15

0

transcriptional regulation

up-regulates quantity

0.425

We have recently demonstrated that a novel transcriptional pathway involving activation of the Epidermal Growth Factor-like Domain 7 (Egfl7) gene by the transcription factor CASTOR (CASZ1) is required for blood vessel assembly and lumen morphogenesis.

SIGNOR-266858

P36956

Q5VTR2

0

ubiquitination

down-regulates activity

0.425

Here, we reveal that RNF20-induced SREBP1c ubiquitination down-regulates hepatic lipogenic activity upon PKA activation.|Overexpression of RNF20 represses SREBP1c activity, leading to a decrease in the expression of lipogenic genes.

SIGNOR-278643

P14921

O75444

0

binding

down-regulates

0.425

Full-length c-maf binds to the c-myb and ets-1. / c-maf inhibits c-myb and ets-1 transcriptional activity.

SIGNOR-56808

P38405

P07550

0

binding

up-regulates activity

0.425

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-256952

Q14457

Q16644

0

phosphorylation

up-regulates activity

0.425

Taken together, these data indicate that MK2 and MK3 directly phosphorylate Beclin 1 S90 in vitro, and that MK2 like kinase activity also mediates starvation induced Beclin 1 S90 phosphorylation in cultured cells.

SIGNOR-279342

Q969H0

Q13315

0

phosphorylation

up-regulates activity

0.425

In response to ionizing radiation, ATM phosphorylates FBXW7 at serine 26 to recruit it to DNA double-strand break (DSB) sites, whereas activated DNA-PKcs phosphorylates XRCC4 at serines 325/326, which promotes binding of XRCC4 to FBXW7

SIGNOR-259942

P0DMV8

Q9HC98

0

phosphorylation

up-regulates activity

0.425

Mitotic phosphorylation of Hsp72 by the kinase NEK6 at Thr66 located in the NBD promotes the localization of Hsp72 to the mitotic spindle and is required for efficient spindle assembly and chromosome congression and segregation.

SIGNOR-273885

P51955

Q15154

0

relocalization

up-regulates

0.425

Recruitment of nek2 and c-nap1 to the centrosome is dependent on pcm-1

SIGNOR-133337

Q9C026

P62837

0

binding

up-regulates activity

0.425

Collectively, these results indicated that TRIM9 is an E3 ligase for its self-ubiquitination and that the ubiquitination of TRIM9 likely serves as a signal for proteasomal degradation. As shown in Fig. 1A, TRIM9 was ubiquitinated by itself when incubated with UbcH5b. In contrast, ubiquitination was observed when incubated with other E2 enzymes. These results suggest that TRIM9 cooperates with UbcH5b for its self-ubiquitination. N

SIGNOR-271420

P55211

Q9Y2G2

0

binding

down-regulates

0.425

Tucan is a recently identified card-containing protein that can complex with caspase-9 and prevent cytochrome c-induced caspase activation.

SIGNOR-146663

P21796

P00441

0

binding

down-regulates activity

0.425

Misfolded Mutant SOD1 Directly Inhibits VDAC1 Conductance in a Mouse Model of Inherited ALS|With conformation-specific antibodies, we now demonstrate that misfolded mutant SOD1 binds directly to the voltage-dependent anion channel (VDAC1), an integral membrane protein imbedded in the outer mitochondrial membrane.

SIGNOR-262798

P84022

O15194

0

dephosphorylation

up-regulates activity

0.424

Dephosphorylation of Smad2/3 Linkers by SCP2 and SCP3|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity

SIGNOR-248306

O75874

P36888

0

phosphorylation

up-regulates activity

0.424

Moreover, in an in vitro kinase assay, purified recombinant FLT3 (rFLT3) phosphorylated recombinant IDH2 R140Q mutant but did not alter its catalytic activity (Figure 1C), whereas rFLT3 phosphorylated mIDH1 protein and enhanced its catalytic activity

SIGNOR-267630

P21796

Q96PY6

0

phosphorylation

down-regulates

0.424

Nek1 phosphorylates vdac1 on ser193. Wild-type vdac1 assumes an open configuration, but closes and prevents cytochrome c efflux when phosphorylated by nek1. A vdac1-ser193ala mutant, which cannot be phosphorylated by nek1 under identical conditions, remains open and constitutively allows cytochrome c efflux.

SIGNOR-164222

Q9UPY5

Q16236

0

transcriptional regulation

up-regulates quantity by expression

0.424

NFE2L2 is stabilized and translocates to the nucleus, where it dimerizes with sMAF proteins. This complex binds to AREs to mediate the transcription of genes involved in iron metabolism, GSH metabolism, and ROS detoxification. NFE2L2 directly binds to the promoter region of SLC7A11, leading to increased expression of this transporter, which in turn contributes to the resistance to ferroptosis and to radiotherapy

SIGNOR-279867

Q9Y6B2

Q00987

0

polyubiquitination

down-regulates quantity by destabilization

0.424

Degradation of EID-1 occurs via ubiquitin-dependent proteolysis and correlates with MDM2 binding. These results are consistent with a model wherein destruction of EID-1 is linked to its ability to interact with MDM2 via either p300 or pRB.

SIGNOR-272582

P36956

P23443

0

phosphorylation

up-regulates activity

0.424

Besides promoting protein synthesis, S6K1 also phosphorylates and activates sterol regulatory element binding protein 1 and 2 (SREBP and SREBP2), which promotes de novo lipid synthesis that is critical for cell growth and proliferation.|Besides promoting protein synthesis, S6K1 also phosphorylates and activates sterol regulatory element-binding protein 1 and 2 (SREBP and SREBP2), which promotes de novo lipid synthesis that is critical for cell growth and proliferation ( xref ).

SIGNOR-280120

Q9UNN4

P68400

0

phosphorylation

up-regulates activity

0.424

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-250873

Q13526

P53350

0

phosphorylation

up-regulates

0.424

Here we demonstrate that ser-65 in pin1 is the major site for plk1-specific phosphorylation, and the polo-box domain of plk1 is required for this phosphorylation. Interestingly, the phosphorylation of pin1 by plk1 does not affect its isomerase activity but rather is linked to its protein stability. pin1 is ubiquitinated in hela s3 cells, and substitution of glu for ser-65 reduces the ubiquitination of pin1.

SIGNOR-139919

Q9BX66

P00519

0

phosphorylation

up-regulates activity

0.424

We have here identified Tyr360 in CAP as a major phosphorylation site by c-Abl, although Tyr 632 also might contribute since its substitution in combination with the Y360F mutation reduced the phosphorylation of CAP to a very low level. Y360 in CAP is the major phosphorylation site of c-Abl. Since Tyr326 was not a major c-Abl phosphorylation site, we sought to identify a putative other kinase that might be involved in the phosphorylation of Y326 in CAP.

SIGNOR-278153

P78352

Q9HBW1

0

binding

up-regulates activity

0.424

A possible function for the NGL–PSD-95 interaction is to couple trans-synaptic adhesion events to the recruitment of PSD-95 and other PSD-95-associated postsynaptic proteins. PSD-95 and liprin-α may be key synaptic scaffolding proteins that couple trans-synaptic adhesions to the assembly of synaptic proteins/vesicles

SIGNOR-264051

P84022

O14595

0

dephosphorylation

up-regulates activity

0.424

Dephosphorylation of Smad2/3 Linkers by SCP2 and SCP3|MAPK-mediated linker phosphorylation appears to have a dual role in Smad2/3 regulation. Mitogens and hyperactive Ras result in extracellular signal-regulated kinase (ERK)-mediated phosphorylation of Smad3 at Ser-204, Ser-208, and Thr-179 and of Smad2 at Ser-245/250/255 and Thr-220. Mutation of these sites increases the ability of Smad3 to activate target genes, suggesting that MAPK phosphorylation of Smad3 is inhibitory (11, 12). However, in contrast, ERK-dependent phosphorylation of Smad2 at Thr-8 enhances its transcriptional activity

SIGNOR-248293