GleghornLab/Signor_3class · Datasets at Hugging Face

IdA stringlengths 6 21	IdB stringlengths 6 21	labels int64 0 2	mechanism stringclasses 40 values	effect stringclasses 10 values	score float64 0.1 0.99 ⌀	sentence stringlengths 10 1.63k ⌀	signor_id stringlengths 12 14
Q92888	P61586	1	guanine nucleotide exchange factor	up-regulates activity	0.831	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-260528
P42574	Q9H3R0	1	cleavage	down-regulates activity	0.2	JMJD2C as a novel substrate for caspase-3 (cysteine-aspartic acid protease-3), and cleavage of JMJD2C by caspase-3 led to inactivation of JMJD2C demethylase activity and elevation of H3K9 methylation levels.	SIGNOR-263870
P50461	P15173	2	binding	up-regulates activity	0.519	we found that nuclear MLP functions through a physical interaction with the muscle basic helix-loop-helix (bHLH) transcription factors MyoD, MRF4, and myogenin. we propose that it serves as a cofactor for the myogenic bHLH proteins by increasing their interaction with specific DNA regulatory elements.	SIGNOR-241113
Q92633	P63096	2	binding	up-regulates activity	0.555	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-256696
Q92917	P17612	0	phosphorylation	up-regulates activity	0.307	PKA phosphorylates GPKOW at S27 and T316 in vitro. GPKOWs ability to bind RNA is sensitive to mutations of its PKA phosphorylation sites.	SIGNOR-266309
P13674	Q16665	0	transcriptional regulation	up-regulates quantity by expression	0.314	Hypoxia upregulates P4HA1 expression in PDAC PDOs through HIF1α. Our results show that the treatment of PDO4 and PDO11 cells with 10 μmol/L of PX-478 for 24 hours reduced the levels of P4HA1 in hypoxia (Fig. 2F), suggesting P4HA1 expression in hypoxia is regulated by HIF1α expression.	SIGNOR-279840
P40763	P45983	0	phosphorylation	up-regulates activity	0.567	Transfection of the cells with sirna specific for jnk1 revealed that jnk silencing reduced serine727 phosphorylation of stat3,	SIGNOR-235704
P49674	Q9UD71	1	phosphorylation	up-regulates activity	0.322	CKIepsilon phosphorylates and activates DARPP-32, a key molecule in various complex signaling pathways, including dopamine and glutamine signaling, which have both been demonstrated to be main pathways in substance dependence.	SIGNOR-279701
Q92949	O14645	1	transcriptional regulation	up-regulates quantity by expression	0.394	FOXJ1 expression in basal cells induced the expression of a panel of cilia-associated genes, including centrin 2 (CETN2); dynein, axonemal, heavy chain 11 (DNAH11); dynein, axonemal, intermediate chain 1 (DNAI1); dynein, axonemal, light intermediate chain 1 (DNALI1); EF-hand domain, C-terminal, containing 1 (EFHC1); sperm associated antigen 6 (SPAG6); tektin 1 (TEKT1), TEKT2 and tubulin, alpha 1a (TUBA1A; Figure 3C and Additional file 2: Table S1).	SIGNOR-266933
Q9H4E7	P06239	0	phosphorylation	up-regulates activity	0.5	In vitro kinase assays indeed demonstrated that Lck can phosphorylate wild-type IBP but not the Y210F mutant. IBP Binds PI(3,4,5)P3 upon Phosphorylation by Lck	SIGNOR-251372
P23458	O14543	2	binding	down-regulates activity	0.732	SOCS3 binds specific receptor-JAK complexes to control cytokine signaling by direct kinase inhibition	SIGNOR-253051
P27361	P25098	1	phosphorylation	down-regulates	0.2	Erk1 phosphorylates grk2 at ser(670). Inhibition of erk activity in hek293 cells potentiates grk2 activity, whereas, conversely, erk activation inhibits grk2 activity.	SIGNOR-72582
Q9HCE7	O15198	1	ubiquitination	down-regulates	0.669	Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degra-dation of smads and receptors for tgf-beta and bmps	SIGNOR-195669
P19438	O95429	2	binding	down-regulates activity	0.647	It was suggested that the silencer of death domains (SODD) protein constitutively associates intracellularly with TNFR1 and inhibits the recruitment of cytoplasmic signaling proteins to TNFR1 to prevent spontaneous aggregation of the cytoplasmic death domains of TNFR1 molecules that are juxtaposed in the absence of ligand stimulation	SIGNOR-245022
Q13158	O14763	2	binding	up-regulates	0.849	Fadd binds to ligated trailr1 or trail-r2	SIGNOR-98565
P25098	P16671	1	phosphorylation	down-regulates quantity by destabilization	0.2	We, therefore, propose a pathway by which inhibition of GRK2 in the failing heart prevents CD36 phosphorylation, ubiquitination, and, in turn, induces its proteasomal degradation.\|Our data reveal direct phosphorylation of CD36 by GRK2.	SIGNOR-279524
Q86Y97	P62805	1	methylation	down-regulates activity	0.2	SUV420H1 and SUV420H2 are two highly homologous enzymes that methylate lysine 20 of histone H4 (H4K20), a mark that has been implicated in transcriptional regulation.	SIGNOR-266650
P58753	Q15109	2	binding	up-regulates activity	0.41	These results indicate that TIRAP functions as an essential adaptor protein for RAGE, binding to ligand-activated phosphorylated RAGE and transducing a signal from it.	SIGNOR-280459
Q16539	P49918	1	phosphorylation	up-regulates	0.262	G1-s control by p38/hog1 sapks upon osmostress. Upon osmostress, activated p38 and hog1 sapks phosphorylate the s/cdk inhibitor p57 or sic1 respectively at one single residue. In mammalian cells (left panel), p57 phosphorylation on thr143 leads to an increase of the affinity of p57 towards the cyclin a/cdk2 complex leading to a g1 arrest.	SIGNOR-198390
Q86VP1	O15111	0	phosphorylation	up-regulates activity	0.383	Here we demonstrate that tax1bp1 was inducibly phosphorylated on ser593 and ser624 in response to proinflammatory stimuli. The kinase ikkalpha, but not ikkbeta, was required for phosphorylation of tax1bp1 and directly phosphorylated tax1bp1 in response to stimulation with tumor necrosis factor (tnf) or interleukin 1 (il-1).	SIGNOR-175062
O75084	O00755	2	binding	up-regulates activity	0.678	Wnt7a-Fzd7 signaling stimulates symmetric stem cell divisions	SIGNOR-255646
Q01196	P10147	1	transcriptional regulation	up-regulates quantity by expression	0.2	We show that RUNX1 can specifically bind to both RUNX sites but that only the proximal RUNX site is essential for PMA/ PHA stimulation of the MIP-1a promoter in Jurkat T-cells. We also show that the endogenous MIP-1a promoter is constitutively bound by RUNX1.	SIGNOR-251738
P17252	Q96T49	1	phosphorylation	down-regulates activity	0.2	PKCα phosphorylated the full length recombinant TIMAP in in vitro kinase assay and Ser331 of TIMAP was shown to be phosphorylated by PKC. Phosphorylation of TIMAP upon PKC activation in endothelial cells results in enrichment of TIMAP in the membrane, but no such change can be observed in PKC depleted cells. Phosphorylation state of TIMAP, through affecting PP1 activity, has a remarkable effect on endothelial barrier function.	SIGNOR-273802
Q9UBY5	P50148	2	binding	up-regulates activity	0.483	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-257297
P17612	Q08289	1	phosphorylation	up-regulates activity	0.43	Voltage-dependent L-type calcium (Ca) channels are heteromultimeric proteins that are regulated through phosphorylation by cAMP-dependent protein kinase (PKA) Mutagenesis of a single residue at Ser459 resulted in the loss of one site of phosphorylation by PKA, and mutagenesis of two residues at Ser478/479 resulted in the loss of approximately two sites of PKA-mediated phosphorylation	SIGNOR-250341
O00755	O75084	2	binding	up-regulates activity	0.678	Wnt7a-Fzd7 signaling stimulates symmetric stem cell divisions	SIGNOR-255646
Q9Y4K4	P46108	2	binding	up-regulates activity	0.364	Two novel candidates for signalling partners of Crk family adapter proteins, the hematopoietic progenitor kinase 1 (HPK1) and the kinase homologous to SPS1/STE20 (KHS), were found to bind with great selectivity to the first SH3 domains of c-Crk and CRKL.\|These results make it likely that HPK1 and KHS participate in the signal transduction of Crk family adapter proteins in certain cell types.	SIGNOR-262830
Q13153	O95747	0	phosphorylation	down-regulates activity	0.382	OSR1 phosphorylated threonine 84 in the N-terminal regulatory domain of PAK1. phosphorylation of PAK1 by OSR1 desensitizes PAK1 to activation by small G proteins, providing a modulatory input to PAK1 activity.	SIGNOR-250210
P27361	P50616	1	phosphorylation	down-regulates	0.352	Biochemical analyses have then shown that erk mapk (erk2) and jnk/sapk (jnk2) bind to and phosphorylate tob in vitro. Erk catalyzes the phosphorylation more efficiently than jnk	SIGNOR-88728
P11362	P18669	1	phosphorylation	up-regulates activity	0.33	Nevertheless, these data suggest that FGFR1 dependent tyrosine phosphorylation " further " enhances PGAM1 activation.\|Phosphorylation of PGAM1 WT by FGFR1 resulted in a significant increase in the amount of bound 2,3-BPG analogue, whereas substitution of PGAM1 Y26 abolished enhanced binding of cofactor in the presence of rFGFR1 (XREF_FIG).	SIGNOR-279175
P28482	P53805	1	phosphorylation	up-regulates activity	0.27	Consensus phosphorylation sites for p42/44 MAPK and GSK-3 are present in the SP repeat of MCIP1 at serine 112 and serine 108, respectively \|Several endogenous proteins are capable of inhibiting the catalytic activity of calcineurin. Modulatory calcineurin interacting protein 1 (MCIP1) is unique among these proteins on the basis of its pattern of expression and its function in a negative feedback loop to regulate calcineurin activity. Here we show that MCIP1 can be phosphorylated by MAPK and glycogen synthase kinase-3 and that phosphorylated MCIP1 is a substrate for calcineurin.	SIGNOR-249198
P23467	P29474	1	dephosphorylation	down-regulates activity	0.267	VE-PTP interacts with eNOS and dephosphorylates Tyr81	SIGNOR-277521
P04049	Q05639	1	phosphorylation	down-regulates quantity by destabilization	0.2	Mass spectrometry identified in vitro S21 and T88 as phosphorylation sites mediated by B-Raf but not C-Raf on eEF1A1 whereas S21 was phosphorylated on eEF1A2 by both B- and C-Raf.	SIGNOR-276407
P30291	O14757	0	phosphorylation	up-regulates	0.611	Chk1 also phosphorylates and stabilizes wee1.	SIGNOR-163164
Q00535	Q9UQB3	1	phosphorylation	up-regulates activity	0.327	Cdk5 mediated delta-catenin phosphorylation regulates delta-catenin subcellular localization into two distinct pools : a cytoplasmic or intraneurite state as well as a pool that is localized to the membrane.\|Cdk5 phosphorylates delta-catenin on serines 300 and 357.	SIGNOR-279323
Q9HDB5	Q8N0W4	2	binding	up-regulates activity	0.767	Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.\|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c)	SIGNOR-264170
Q9Y6K1	P42658	1	transcriptional regulation	down-regulates quantity by repression	0.2	In the absence of Dnmt3b, Dnmt3a was associated with Dpp6 gene promoter and regulated its expression and methylation in P19 cells.	SIGNOR-268962
Q8TBB1	Q05586	1	ubiquitination	down-regulates quantity by destabilization	0.288	We used the Ligand of Numb protein X (LNX) family of E3s, a group of PDZ domain-containing RING-type E3 ubiquitin ligases, to demonstrate the feasibility of this strategy. Many potential substrates of LNX E3s were identified. Eight of the nine selected candidates were ubiquitinated in vitro, and two novel endogenous substrates, PDZ-binding kinase (PBK) and breakpoint cluster region protein (BCR), were confirmed in vivo.	SIGNOR-272901
Q9Y4C1	Q99814	0	transcriptional regulation	up-regulates quantity by expression	0.265	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-271583
P09619	P06241	1	phosphorylation	up-regulates activity	0.58	PDGF-induced phosphorylation of Tyr28 in the N-terminus of Fyn affects Fyn activation. We show here that Fyn, a member of the Src family, is phosphorylated on Tyr28 in the unique N-terminal part of the molecule after interaction with the intracellular domain of the PDGF beta-receptor. Activated Fyn furthermore undergoes autophosphorylation on Tyr30, Tyr39 and Tyr420. When Fyn mutants with Tyr28, Tyr30 or Tyr39 replaced with phenylalanine residues were transfected into NIH3T3 cells a decreased activation after PDGF stimulation was seen, suggesting a functional importance of the N-terminal tyrosine phosphorylation of Fyn.	SIGNOR-250253
O75030	Q9HAZ1	0	phosphorylation	down-regulates quantity by destabilization	0.2	Mechanistically, wild type CLK4 (WT-CLK4) but not kinase-dead CLK4-K189R mutant phosphorylated MITF at Y360. This modification promoted its interaction with E3 ligase COP1 and its K63-linked ubiquitination at K308/K372, leading to sequestosome 1 recognition and autophagic degradation.	SIGNOR-274116
Q96AX9	Q13546	1	ubiquitination	down-regulates quantity by destabilization	0.295	These data suggest that after binding, MIB2 inhibits RIPK1 through a mechanism that is dependent on the E3 ligase activity of MIB2.\|Whereas MIB2 readily ubiquitylated wild-type RIPK1, mutating K377 to R significantly reduced MIB2 mediated ubiquitylation of RIPK1 (XREF_SUPPLEMENTARY A).	SIGNOR-278633
Q15831	Q96L34	1	phosphorylation	up-regulates	0.535	Lkb1 is a master kinase that activates 13 kinases of the ampk subfamily, including mark/par-1we recently demonstrated that the lkb1 tumour suppressor kinase, in complex with the pseudokinase strad and the scaffolding protein mo25, phosphorylates and activates amp-activated protein kinase (ampk). A total of 12 human kinases (nuak1, nuak2, brsk1, brsk2, qik, qsk, sik, mark1, mark2, mark3, mark4 and melk) are related to ampk. Here we demonstrate that lkb1 can phosphorylate the t-loop of all the members of this subfamily, apart from melk, increasing their activity >50-fold	SIGNOR-122682
Q9Y5T5	P33981	0	phosphorylation	down-regulates quantity by destabilization	0.37	Usp16 is a TTK phosphorylation substrate.	SIGNOR-277351
P98161	P51817	0	phosphorylation	up-regulates	0.257	The possibility of functional interactions between pkd1-encoded polycystin-1 and prkx was suggested by the renal co-distribution of prkx and polycystin-1 and the binding and phosphorylation of the c-terminal of polycystin-1 by prkx at s4166 in vitro. Taken together these results suggest that prkx can reverse the abnormalities in epithelial adhesion, migration and morphogenesis associated with pkd1 inhibition and cyst formation in adpkd.	SIGNOR-158852
P51617	Q9H4G4	1	phosphorylation	up-regulates activity	0.325	We found that TIRAP-MyD88 dependent kinase IRAK1 phosphorylated GAPR-1 at Serine 58 site. The phosphorylation of GAPR-1 promoted its interaction with TRAM-TRIF dependent inhibitor TMED7, and impaired TMED7-mediated disruption of the TRAM-TRIF complex to trigger IFN-β and the IL10 secretion.	SIGNOR-262887
P56705	O75581	2	binding	up-regulates	0.648	Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation.	SIGNOR-131835
P20393	Q9Y5X4	2	binding	up-regulates	0.399	All four proteins, nr2e3, nr1d1, nrl and crx, could be co-immunoprecipitated from the bovine retinal nuclear extract, suggesting their existence in a multi-protein transcriptional regulatory complex in vivo.	SIGNOR-125661
O14965	P12931	0	phosphorylation	up-regulates activity	0.309	We report here that Src phosphorylates and activates AURA at T288, and AURA also activates focal adhesion kinase (FAK, also known as PTK2), leading to initiation of cell movement.	SIGNOR-279286
O75365	P15311	1	dephosphorylation	down-regulates activity	0.277	Here we report the identification of Ezrin as a specific and direct cellular substrate of PRL-3. In HCT116 colon cancer cell line, Ezrin was identified among the cellular proteins whose phosphorylation level decreased upon ectopic over-expression of wtPRL-3 but not of catalytically inactive PRL-3 mutants. Although PRL-3 over-expression in HCT116 cells appeared to affect Ezrin phosphorylation status at both tyrosine residues and Thr567, suppression of the endogenous protein by RNA interference pointed to Ezrin-Thr567 as the residue primarily affected by PRL-3 action.	SIGNOR-248342
Q16828	P41162	0	transcriptional regulation	down-regulates quantity by repression	0.2	ETV3 target genes including etv3, ddx20, and dusp6 provide negative feedback regulation of ETV3 production and activity. Negative feedback along with constitutive instability may serve to tightly regulate ETV3 abundance. Our date suggest that phosphorylation by ERK2 relieves repression by ETV3, allowing activation of cell cycle control genes including myc, components of the NF-κB pathway, and genes required form RNA processing and translation.	SIGNOR-262780
Q9BXW9	Q13315	0	phosphorylation	up-regulates	0.789	These results suggest that s222 and either s1401, s1404, or s1408 are sites of atm-dependent phosphorylation in vitro.Phosphorylation Of fancd2 is required for activation of an s phase checkpoint	SIGNOR-90117
Q13114	O43318	1	ubiquitination	up-regulates activity	0.457	Biological investigations demonstrated that TRAF3 activates TAK1 protein kinase activity via a direct binding to TAK1, then the RING finger of TRAF3 ubiquitinates TAK1, leading to TAK1 phosphorylation and activation.\|TRAF3 activates TAK1 through ubiquitination.	SIGNOR-278787
Q9HBA0	P06241	0	phosphorylation	up-regulates activity	0.35	ROS could be detected by Fyn, which is required to activate TRPV4 in a redox-sensitive manner.\|The Ca 2+ response to H 2 O 2 required the basal phosphorylation of TRPV4 by the Src kinase Fyn, which may serve as the redox sensor responsible for TRPV4 activation (Figure 2 ) [220] , and was able to increase barrier permeability [219] .	SIGNOR-279991
P24385	Q13309	2	binding	down-regulates quantity by destabilization	0.594	We show that SK-UT-1B cells express a novel splice variant of Skp2 that localizes to the cytoplasm and that cyclin D1 ubiquitination takes place in the nucleus. We propose that the translocation of Skp2 into the nucleus is required for the ubiquitination of cyclin D1 and that the absence of the SCF(Skp2) complex in the nucleus of SK-UT-1B cells is the mechanism underlying the ubiquitination defect observed in this cell line.	SIGNOR-272575
Q13315	Q8NHY2	1	phosphorylation	down-regulates	0.2	Atm engages autodegradation of the e3 ubiquitin ligase cop1 after dna damage. We observed that in response to dna damage, atm phosphorylated cop1 on ser(387) and stimulated a rapid autodegradation mechanism	SIGNOR-149082
P40763	O14522	0	dephosphorylation	down-regulates activity	0.516	Identification of STAT3 as a substrate of receptor protein tyrosine phosphatase T\|Phosphorylation of a tyrosine at amino acid Y705 is essential for the function of STAT3, and PTPRT specifically dephosphorylated STAT3 at this position.	SIGNOR-263981
Q13285	P60484	0	dephosphorylation	down-regulates activity	0.256	The fact that SF-1 and PIP3 is robustly dephosphorylated by PTEN, yet SF-1 and PIP2 is resistant to phosphorylation by p110 PI3-kinases, suggests that nuclear proteins like SF-1 can help decouple PTEN signaling in the nucleus from p110 signaling.\|We also showed that PTEN can dephosphorylate the SF-1 and PIP3 product of the IPMK reaction, and that PTEN inhibits SF-1 transcriptional activity.	SIGNOR-277117
P52564	Q9UL54	2	binding	up-regulates activity	0.649	Cotransfection experiments suggested that tao2 selectively activates mek3 and mek6 but not meks 1, 4, or 7.	SIGNOR-70950
Q86Y07	Q9UKT8	1	phosphorylation	down-regulates activity	0.296	Collectively, CK1 and VRK2, but not GRK2 kinase, appears to mediate FBXW2 phosphorylation at the beta-TrCP binding motif.\|We followed this lead, and inactivated VRK2 and GRK2 by siRNA silencing, or CK1 and VRK2 by small molecule inhibitor IC-261, and found that GRK2 knockdown had no effect, whereas CK1 and VRK2 inhibition or VRK2 silencing largely blocked the degradation of exogenously expressed FBXW2 (XREF_FIG and XREF_SUPPLEMENTARY).	SIGNOR-280161
P14859	Q13131	0	phosphorylation	down-regulates	0.2	Mitosis-specific phosphorylation site in the homeodomain of oct-1 was phosphorylated in vitro by protein kinase a. Pka-mediated phosphorylation event was identified in the cns-specific pou domain protein brn-2/n-oct-3/pou3f2 (nieto et al. 2007). In this case, the modification, at a position homologous to oct1 s385, was found to alter binding specificity for complex dimeric sites.	SIGNOR-53254
Q9UJ55	O15516	2	binding	down-regulates activity	0.2	Magel2 represses the activity of the Clock:Bmal1 heterodimer in a Per2-luciferase assay. Magel2 interacts with Bmal1 and with Per2 as measured by co-immunoprecipitation in co-transfected cells, and exhibits a subcellular distribution consistent with these interactions when visualized by immunofluorescence. As well, Magel2 induces the redistribution of the subcellular localization of Clock towards the cytoplasm, in contrast to the nucleus-directed effect of Bmal1 on Clock subcellular localization.	SIGNOR-253516
P00533	O15126	1	phosphorylation	up-regulates activity	0.335	In our efforts to identify cellular tyrosine kinases that phosphorylate SCAMPs, we are quite intrigued by the observation that among a number of kinases, only the EGFR exhibits activity toward SCAMPs. EGF catalyzes the progressive phosphorylation of the SCAMPs up to 1 h poststimulation and may enhance colocalization of the EGFR and SCAMP3 within the cell interior. EGF also induces SCAMP-EGFR association, as detected by coimmunoprecipitation, and phosphorylation of SCAMP3 is stimulated by the EGFR in vitro. These results suggest that phosphorylation of SCAMPs, either directly or indirectly, may be functionally linked to the internalization/down-regulation of the EGFR. we have observed that there are two tyrosines conserved in SCAMP1 and SCAMP3, which are not found in SCAMP2. Of these two tyrosines (Tyr37 and Tyr73 in SCAMP1; Tyr 41 and Tyr83 in SCAMP3), we consider Tyr37/41 to be a more likely site for tyrosine phosphorylation	SIGNOR-262857
P08912	P63096	2	binding	up-regulates activity	0.2	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-256730
Q13705	Q15796	1	phosphorylation	up-regulates activity	0.776	It has been suggested that binding of myostatin to the ActRIIB results in the phosphorylation of two serine residues of Smad2 or Smad3 at COOH domains	SIGNOR-254984
P06493	Q01167	1	phosphorylation	up-regulates	0.372	We have mapped two cdk phosphorylation sites, serines 368 and 423, which play a role in defining foxk2 function through regulating its stability and its activity as a transcriptional repressor protein. These two cdk sites appear vital for foxk2 function because expression of a mutant lacking these sites cannot be tolerated and causes apoptosis.	SIGNOR-167826
O94953	P68431	1	demethylation	down-regulates activity	0.2	The KDM4 family of Jumonj domain histone demethylases specifically target di- and tri-methylated lysine 9 on histone H3 (H3K9me3), removing a modification central to defining heterochromatin and gene repression. The majority of studies regarding its function describe it as an activator that removes repressive H3K9me3 and H3K9me2 at or near regulated promoters in order to facilitate expression of the indicated pathways.	SIGNOR-263734
Q96J02	Q15583	1	ubiquitination	up-regulates activity	0.2	Based on these observations, we suggest that a mechanism of protein stabilization might account for the accumulation of TGIF protein in response to TNF-alpha signaling.Next, we used three different approaches to investigate the possibility that Itch could contribute to the ability of TNF-alpha to promote TGIF stabilization.\|We also employed the experimental strategy combining the detection of monoubiquitinated and polyubiquitinated TGIF and found that mutation of K259 not only compromised monoubiquitination of TGIF by Itch but also enhanced its polyubiquitination.	SIGNOR-278817
O43597	Q13191	2	binding	down-regulates	0.486	One function of hspry2 in signaling processes downstream of rtks may be to modulate c-cbl physiological function such as that seen with receptor-mediated endocytosis.	SIGNOR-83507
O75925	Q13485	1	sumoylation	up-regulates	0.394	These data demonstrate that pias1 protein positively modulates tgf-beta responses as a sumo e3 ligase for smad4	SIGNOR-123462
Q9NPG1	Q9UBV4	2	binding	up-regulates	0.617	Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation.	SIGNOR-131674
P09327	P12931	0	phosphorylation	up-regulates activity	0.363	These data suggest that phosphorylation of villin by c-src is involved in the actin cytoskeleton remodeling necessary for cell migration.To further investigate the role of tyrosine phosphorylated villin in cell migration, we used phosphorylation site mutants (tyrosine to phenylalanine or tyrosine to glutamic acid) in HeLa cells. We determined that tyrosine phosphorylation at residues 60, 81, and 256 of human villin played an essential role in cell migration as well as in the reorganization of the actin cytoskeleton	SIGNOR-247441
P42261	Q13237	0	phosphorylation	up-regulates activity	0.44	In cultured hippocampal neurons, activation of cGKII induces an accumulation of GluR1 on the cellular plasma membrane at extrasynaptic sites, and blockage of cGKII activity prevents the surface increase of GluR1, and also the increase in mEPSC frequency and amplitude, that follows a chemical form of LTP (chemLTP).\|In this complex, cGKII phosphorylates GluR1 at serine 845 (S845), a site known to be phosphorylated also by PKA.	SIGNOR-278427
P06213	O14654	1	phosphorylation	up-regulates activity	0.518	The binding of insulin to the subunit of IR not only concentrates insulin at its site of action, but also induces conformational changes in the receptor, which in turn stimulates the tyrosine kinase activity intrinsic to the _ subunit of the IR and triggers the signaling cascades (Fig. 3). Insulin receptors trans phosphorylate several immediate substrates (on Tyr residues) including IRS1-4, Shc, and Gab 1, Cbl, APS, and P60dok.	SIGNOR-217897
P43005	Q03135	2	binding	down-regulates activity	0.2	EAAT3 has previously been shown to form complexes with caveolin-1, a major component of caveolae, which participate in the regulation of transport proteins. The present study explored the impact of caveolin-1 on electrogenic transport by excitatory amino acid transporter isoforms EAAT1-4. caveolin-1 is a powerful negative regulator of the excitatory glutamate transporters EAAT1, EAAT2, EAAT3, and EAAT4. Caveolin-1 has been shown to form complexes with the excitatory amino acid transporter EAAT3 (EAAC1) (Gonzalez et al. 2007) and may thus modify the EAAT isoforms by direct interaction with the carriers.	SIGNOR-264807
P50053	P60891	1	phosphorylation	up-regulates activity	0.348	Ketohexokinase-A (KHK-A; also known as fructokinase-A) phosphorylates PRPS1 T225 and activates PRPS1 by blocking the binding of ADP, AMP, and GDP, which is required for hepatocellular carcinoma development	SIGNOR-265735
Q8N726	Q14669	0	ubiquitination	down-regulates quantity by destabilization	0.582	ULF interacts with ARF both in vitro and in vivo and promotes the lysine-independent ubiquitylation and degradation of ARF.	SIGNOR-266781
Q9UQK1	O95278	0	dephosphorylation	up-regulates quantity by stabilization	0.749	We have recently described that the activity of R5/PTG is down-regulated by the laforin-malin complex, composed of a dual specificity phosphatase (laforin) and an E3-ubiquitin ligase (malin). We now demonstrate that phosphorylation of R5/PTG at Ser-8 by AMPK accelerates its laforin/malin-dependent ubiquitination and subsequent proteasomal degradation, which results in a decrease of its glycogenic activity.	SIGNOR-276239
O00321	P23769	2	binding	up-regulates activity	0.43	Transcriptional assays with the Spi1 promoter-reporter demonstrated that Gata2 cooperates with Etv2 and augments the transcriptional activity of Etv2.The protein-protein interaction between Etv2 and Gata2 is mediated by the Ets and Gata domains. Using the embryoid body differentiation system, we demonstrate that co-expression of Gata2 augments the activity of Etv2 in promoting endothelial and hematopoietic lineage differentiation.	SIGNOR-256008
O75385	Q9Y478	0	phosphorylation	up-regulates	0.537	Ampk and ulk1 interact and that the latter is phosphorylated by ampk. This phosphorylation leads to the direct activation of ulk1 by ampk bypassing mtor-inhibition	SIGNOR-173044
P35367	O95837	2	binding	up-regulates activity	0.457	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-257425
P16220	Q00535	0	phosphorylation	up-regulates activity	0.374	CDK5 Activates the Self-Renewal Regulator CREB1 in GSCs.\|Our data indicate that CDK5, which has previously been shown to activate CREB1 through cAMP and PKA in dopamine neurons present in the ventral tegmental area, can directly bind with and phosphorylate CREB1 in a PKA and cAMP independent manner, at least in GSCs.	SIGNOR-279682
O15530	Q9UBS0	1	phosphorylation	up-regulates activity	0.609	Mutational analysis revealed that the phosphorylation of Thr241 and Thr401 in p70beta1 was indispensable for the kinase activity. In contrast, a p70beta1 mutant in which Ser383 was substituted with Gly (S383G) still retained nearly the half maximal activity. Sequential phosphorylation of wild-type and S383G mutant of p70beta1 with mTOR and 3-phosphoinositide-dependent protein kinase 1 (PDK1) in vitro synergistically activated their kinase activities.	SIGNOR-250272
Q9BT67	Q9H0M0	0	ubiquitination	down-regulates quantity	0.381	Accordingly, the ubiquitination assays were performed and the results revealed that knockdown of WWP1 reduced the ubiquitination of NDFIP1 in HuCCT1 and vice versa in HCCC-9810 and RBE (Fig. 7E).\|In addition, we found that WWP1 could reduce the protein level of NDFIP1 via ubiquitination.	SIGNOR-278796
Q92934	P10415	1	relocalization	down-regulates activity	0.801	Apoptosis is initiated when Bcl-2 and its prosurvival relatives are engaged by proapoptotic BH3-only proteins via interaction of its BH3 domain with a groove on the Bcl-2-like proteins. These interactions have been considered promiscuous, but our analysis of the affinity of eight BH3 peptides for five Bcl-2-like proteins has revealed that the interactions vary over 10,000-fold in affinity, and accordingly, only certain protein pairs associate inside cells. Bim and Puma potently engaged all the prosurvival proteins comparably. Bad, however, bound tightly to Bcl-2, Bcl-xL, and Bcl-w but only weakly to A1 and not to Mcl-1.	SIGNOR-133756
Q9H4A6	P78527	0	phosphorylation	up-regulates activity	0.318	In response to DNA damage, DNA-PK phosphorylates GOLPH3, resulting in increased interaction with MYO18A, which applies a tensile force to the Golgi. Interference with the Golgi DNA damage response by depletion of DNA-PK, GOLPH3, or MYO18A reduces survival after DNA damage, whereas overexpression of GOLPH3, as is observed frequently in human cancers, confers resistance to killing by DNA-damaging agents	SIGNOR-253558
O43318	Q6P589	1	phosphorylation	down-regulates quantity by destabilization	0.2	TAK1 phosphorylated the Ser3 in the noncanonical degron motif of TIPE2 to trigger its interaction with β-TrCP for subsequent ubiquitination and degradation.	SIGNOR-273668
P16220	Q6SA08	0	phosphorylation	up-regulates	0.578	Tssk5, a novel member of the testis-specific serine/threonine kinase family, phosphorylates creb at ser-133, and stimulates the cre/creb responsive pathway.	SIGNOR-138289
P06239	Q9H4E7	1	phosphorylation	up-regulates activity	0.5	In vitro kinase assays indeed demonstrated that Lck can phosphorylate wild-type IBP but not the Y210F mutant. IBP Binds PI(3,4,5)P3 upon Phosphorylation by Lck	SIGNOR-251372
P04049	O60674	0	phosphorylation	up-regulates activity	0.617	JAK2 phosphorylated Raf-1. e sites at 340/341 are indeed phosphorylated by JAK2 and that this phosphorylation represents a major component of the activation process.	SIGNOR-251361
P53350	O95239	1	phosphorylation	down-regulates activity	0.467	Moreover, phosphorylation of KIF4 and condensin I by Aurora B and polo like kinase 1 (Plk1) is important for KIF4 and condensin I localization to the chromosome.\|These results suggest that Plk1 negatively regulates the loading of both KIF4 and condensin to the chromosome.	SIGNOR-280069
P41181	Q07002	0	phosphorylation	down-regulates quantity by destabilization	0.26	CDK18 controls AQP2 through phosphorylation at serine 261 and STUB1-mediated ubiquitination. \|We had previously observed that a decrease in the phosphorylation of AQP2 at S261 is associated with a decrease in its poly-ubiquitination and an increase in its abundance	SIGNOR-264562
Q92830	Q16695	1	acetylation	down-regulates activity	0.2	The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14.	SIGNOR-269604
P22681	Q9Y2R2	0	dephosphorylation	down-regulates	0.387	The tyrosine phosphatase lyp1 was found to be constitutively associated with the proto-oncogene c-cbl in thymocytes and t cells. Overexpression of lyp1 reduces cbl tyrosine phosphorylation. It is known that cbl is heavily tyrosine phosphorylated after tcr stimulation and can associate with the syk and zap tyrosine kinases, negatively regulating their activities. Tyrosine phosphatases keep cbl in a basally dephosphorylated state.	SIGNOR-65405
A8MYZ6	O75874	1	transcriptional regulation	up-regulates quantity by expression	0.2	We identify FOXOs as transcriptional activators of IDH1. FOXOs promote IDH1 expression and thereby maintain the cytosolic levels of α-ketoglutarate and NADPH.	SIGNOR-260092
Q96Q05	Q99558	2	binding	up-regulates activity	0.478	We demonstrated by immunohistochemistry that NIBP expression in the brain is localized to neurons. NIBP physically interacts with NIK, IKK(beta), but not IKK(alpha) or IKK(gamma). NIBP overexpression potentiates tumor necrosis factor-alpha-induced NF-kappaB activation through increased phosphorylation of the IKK complex and its downstream I(kappa)B(alpha) and p65 substrates.	SIGNOR-269672
Q8NFJ6	Q9HC23	2	binding	up-regulates	0.665	We have cloned two closely related receptors for pk1 and pk2. These receptors, named prokineticin receptor 1 and 2 (pkr1 and pkr2)	SIGNOR-87919
P11802	Q06830	1	phosphorylation	down-regulates	0.226	Peroxiredoxin (prx) i is a member of the peroxiredoxin family of peroxidases and contains a consensus site (thr(90)-pro-lys-lys) for phosphorylation by cyclin-dependent kinases (cdks). This protein has now been shown to be phosphorylated specifically on thr(90) by several cdks, including cdc2, in vitro. Phosphorylation of prx i on thr(90) reduced the peroxidase activity of this protein by 80%.Prx i was also phosphorylated, with an efficiency similar to that observed with cdc2, when incubated in vitro with cdk2, cdk4, or cdk6 that had been immunoprecipitated from hela cell lysates with specific antibodies (data not shown).	SIGNOR-87105
Q15672	P31749	0	phosphorylation	up-regulates	0.438	Moreover, phosphorylation of twist-1 at ser42 was shown in vivo in various human cancer tissues, suggesting that this post-translational modification ensures functional activation of twist-1 after promotion of survival during carcinogenesis.	SIGNOR-164884
P30679	P25116	2	binding	up-regulates activity	0.567	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. \| We defined positive coupling if any member of the subfamily scored LogRAi ≥ -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ≥ -1.0 for defining true couplings. \| The score associated to this interaction has a LogRAi ≥ -1.0.	SIGNOR-257353

Q92888

P61586

1

guanine nucleotide exchange factor

up-regulates activity

0.831

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-260528

P42574

Q9H3R0

1

cleavage

down-regulates activity

0.2

JMJD2C as a novel substrate for caspase-3 (cysteine-aspartic acid protease-3), and cleavage of JMJD2C by caspase-3 led to inactivation of JMJD2C demethylase activity and elevation of H3K9 methylation levels.

SIGNOR-263870

P50461

P15173

2

binding

up-regulates activity

0.519

we found that nuclear MLP functions through a physical interaction with the muscle basic helix-loop-helix (bHLH) transcription factors MyoD, MRF4, and myogenin. we propose that it serves as a cofactor for the myogenic bHLH proteins by increasing their interaction with specific DNA regulatory elements.

SIGNOR-241113

Q92633

P63096

2

binding

up-regulates activity

0.555

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-256696

Q92917

P17612

0

phosphorylation

up-regulates activity

0.307

PKA phosphorylates GPKOW at S27 and T316 in vitro. GPKOWs ability to bind RNA is sensitive to mutations of its PKA phosphorylation sites.

SIGNOR-266309

P13674

Q16665

0

transcriptional regulation

up-regulates quantity by expression

0.314

Hypoxia upregulates P4HA1 expression in PDAC PDOs through HIF1α. Our results show that the treatment of PDO4 and PDO11 cells with 10 μmol/L of PX-478 for 24 hours reduced the levels of P4HA1 in hypoxia (Fig. 2F), suggesting P4HA1 expression in hypoxia is regulated by HIF1α expression.

SIGNOR-279840

P40763

P45983

0

phosphorylation

up-regulates activity

0.567

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

SIGNOR-235704

P49674

Q9UD71

1

phosphorylation

up-regulates activity

0.322

CKIepsilon phosphorylates and activates DARPP-32, a key molecule in various complex signaling pathways, including dopamine and glutamine signaling, which have both been demonstrated to be main pathways in substance dependence.

SIGNOR-279701

Q92949

O14645

1

transcriptional regulation

up-regulates quantity by expression

0.394

FOXJ1 expression in basal cells induced the expression of a panel of cilia-associated genes, including centrin 2 (CETN2); dynein, axonemal, heavy chain 11 (DNAH11); dynein, axonemal, intermediate chain 1 (DNAI1); dynein, axonemal, light intermediate chain 1 (DNALI1); EF-hand domain, C-terminal, containing 1 (EFHC1); sperm associated antigen 6 (SPAG6); tektin 1 (TEKT1), TEKT2 and tubulin, alpha 1a (TUBA1A; Figure 3C and Additional file 2: Table S1).

SIGNOR-266933

Q9H4E7

P06239

0

phosphorylation

up-regulates activity

0.5

In vitro kinase assays indeed demonstrated that Lck can phosphorylate wild-type IBP but not the Y210F mutant. IBP Binds PI(3,4,5)P3 upon Phosphorylation by Lck

SIGNOR-251372

P23458

O14543

2

binding

down-regulates activity

0.732

SOCS3 binds specific receptor-JAK complexes to control cytokine signaling by direct kinase inhibition

SIGNOR-253051

P27361

P25098

1

phosphorylation

down-regulates

0.2

Erk1 phosphorylates grk2 at ser(670). Inhibition of erk activity in hek293 cells potentiates grk2 activity, whereas, conversely, erk activation inhibits grk2 activity.

SIGNOR-72582

Q9HCE7

O15198

1

ubiquitination

down-regulates

0.669

Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degra-dation of smads and receptors for tgf-beta and bmps

SIGNOR-195669

P19438

O95429

2

binding

down-regulates activity

0.647

It was suggested that the silencer of death domains (SODD) protein constitutively associates intracellularly with TNFR1 and inhibits the recruitment of cytoplasmic signaling proteins to TNFR1 to prevent spontaneous aggregation of the cytoplasmic death domains of TNFR1 molecules that are juxtaposed in the absence of ligand stimulation

SIGNOR-245022

Q13158

O14763

2

binding

up-regulates

0.849

Fadd binds to ligated trailr1 or trail-r2

SIGNOR-98565

P25098

P16671

1

phosphorylation

down-regulates quantity by destabilization

0.2

We, therefore, propose a pathway by which inhibition of GRK2 in the failing heart prevents CD36 phosphorylation, ubiquitination, and, in turn, induces its proteasomal degradation.|Our data reveal direct phosphorylation of CD36 by GRK2.

SIGNOR-279524

Q86Y97

P62805

1

methylation

down-regulates activity

0.2

SUV420H1 and SUV420H2 are two highly homologous enzymes that methylate lysine 20 of histone H4 (H4K20), a mark that has been implicated in transcriptional regulation.

SIGNOR-266650

P58753

Q15109

2

binding

up-regulates activity

0.41

These results indicate that TIRAP functions as an essential adaptor protein for RAGE, binding to ligand-activated phosphorylated RAGE and transducing a signal from it.

SIGNOR-280459

Q16539

P49918

1

phosphorylation

up-regulates

0.262

G1-s control by p38/hog1 sapks upon osmostress. Upon osmostress, activated p38 and hog1 sapks phosphorylate the s/cdk inhibitor p57 or sic1 respectively at one single residue. In mammalian cells (left panel), p57 phosphorylation on thr143 leads to an increase of the affinity of p57 towards the cyclin a/cdk2 complex leading to a g1 arrest.

SIGNOR-198390

Q86VP1

O15111

0

phosphorylation

up-regulates activity

0.383

Here we demonstrate that tax1bp1 was inducibly phosphorylated on ser593 and ser624 in response to proinflammatory stimuli. The kinase ikkalpha, but not ikkbeta, was required for phosphorylation of tax1bp1 and directly phosphorylated tax1bp1 in response to stimulation with tumor necrosis factor (tnf) or interleukin 1 (il-1).

SIGNOR-175062

O75084

O00755

2

binding

up-regulates activity

0.678

Wnt7a-Fzd7 signaling stimulates symmetric stem cell divisions

SIGNOR-255646

Q01196

P10147

1

transcriptional regulation

up-regulates quantity by expression

0.2

We show that RUNX1 can specifically bind to both RUNX sites but that only the proximal RUNX site is essential for PMA/ PHA stimulation of the MIP-1a promoter in Jurkat T-cells. We also show that the endogenous MIP-1a promoter is constitutively bound by RUNX1.

SIGNOR-251738

P17252

Q96T49

1

phosphorylation

down-regulates activity

0.2

PKCα phosphorylated the full length recombinant TIMAP in in vitro kinase assay and Ser331 of TIMAP was shown to be phosphorylated by PKC. Phosphorylation of TIMAP upon PKC activation in endothelial cells results in enrichment of TIMAP in the membrane, but no such change can be observed in PKC depleted cells. Phosphorylation state of TIMAP, through affecting PP1 activity, has a remarkable effect on endothelial barrier function.

SIGNOR-273802

Q9UBY5

P50148

2

binding

up-regulates activity

0.483

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-257297

P17612

Q08289

1

phosphorylation

up-regulates activity

0.43

Voltage-dependent L-type calcium (Ca) channels are heteromultimeric proteins that are regulated through phosphorylation by cAMP-dependent protein kinase (PKA) Mutagenesis of a single residue at Ser459 resulted in the loss of one site of phosphorylation by PKA, and mutagenesis of two residues at Ser478/479 resulted in the loss of approximately two sites of PKA-mediated phosphorylation

SIGNOR-250341

O00755

O75084

2

binding

up-regulates activity

0.678

Wnt7a-Fzd7 signaling stimulates symmetric stem cell divisions

SIGNOR-255646

Q9Y4K4

P46108

2

binding

up-regulates activity

0.364

Two novel candidates for signalling partners of Crk family adapter proteins, the hematopoietic progenitor kinase 1 (HPK1) and the kinase homologous to SPS1/STE20 (KHS), were found to bind with great selectivity to the first SH3 domains of c-Crk and CRKL.|These results make it likely that HPK1 and KHS participate in the signal transduction of Crk family adapter proteins in certain cell types.

SIGNOR-262830

Q13153

O95747

0

phosphorylation

down-regulates activity

0.382

OSR1 phosphorylated threonine 84 in the N-terminal regulatory domain of PAK1. phosphorylation of PAK1 by OSR1 desensitizes PAK1 to activation by small G proteins, providing a modulatory input to PAK1 activity.

SIGNOR-250210

P27361

P50616

1

phosphorylation

down-regulates

0.352

Biochemical analyses have then shown that erk mapk (erk2) and jnk/sapk (jnk2) bind to and phosphorylate tob in vitro. Erk catalyzes the phosphorylation more efficiently than jnk

SIGNOR-88728

P11362

P18669

1

phosphorylation

up-regulates activity

0.33

Nevertheless, these data suggest that FGFR1 dependent tyrosine phosphorylation " further " enhances PGAM1 activation.|Phosphorylation of PGAM1 WT by FGFR1 resulted in a significant increase in the amount of bound 2,3-BPG analogue, whereas substitution of PGAM1 Y26 abolished enhanced binding of cofactor in the presence of rFGFR1 (XREF_FIG).

SIGNOR-279175

P28482

P53805

1

phosphorylation

up-regulates activity

0.27

Consensus phosphorylation sites for p42/44 MAPK and GSK-3 are present in the SP repeat of MCIP1 at serine 112 and serine 108, respectively |Several endogenous proteins are capable of inhibiting the catalytic activity of calcineurin. Modulatory calcineurin interacting protein 1 (MCIP1) is unique among these proteins on the basis of its pattern of expression and its function in a negative feedback loop to regulate calcineurin activity. Here we show that MCIP1 can be phosphorylated by MAPK and glycogen synthase kinase-3 and that phosphorylated MCIP1 is a substrate for calcineurin.

SIGNOR-249198

P23467

P29474

1

dephosphorylation

down-regulates activity

0.267

VE-PTP interacts with eNOS and dephosphorylates Tyr81

SIGNOR-277521

P04049

Q05639

1

phosphorylation

down-regulates quantity by destabilization

0.2

Mass spectrometry identified in vitro S21 and T88 as phosphorylation sites mediated by B-Raf but not C-Raf on eEF1A1 whereas S21 was phosphorylated on eEF1A2 by both B- and C-Raf.

SIGNOR-276407

P30291

O14757

0

phosphorylation

up-regulates

0.611

Chk1 also phosphorylates and stabilizes wee1.

SIGNOR-163164

Q00535

Q9UQB3

1

phosphorylation

up-regulates activity

0.327

Cdk5 mediated delta-catenin phosphorylation regulates delta-catenin subcellular localization into two distinct pools : a cytoplasmic or intraneurite state as well as a pool that is localized to the membrane.|Cdk5 phosphorylates delta-catenin on serines 300 and 357.

SIGNOR-279323

Q9HDB5

Q8N0W4

2

binding

up-regulates activity

0.767

Pre- and postsynaptic plasma membranes are always precisely aligned, and are separated by a synaptic cleft of ~20 nm. The cleft contains an undefined proteinaceous material in the middle, and is presumably bridged by synaptic cell-adhesion molecules such as Nrxns and Nlgns that align the pre- and postsynaptic elements and mediate trans-synaptic signaling.|Nlgns bind to both alpha- and beta-Nrxns with nanomolar affinities; binding involves the sixth LNS-domain of alpha-Nrxns which corresponds to the only LNS-domain of beta-Nrxns52. The binding affinities differ characteristically between various pairs of Nlgns and Nrxns, and are controlled by alternative splicing of both Nrxns and Nlgns (Figure 1c)

SIGNOR-264170

Q9Y6K1

P42658

1

transcriptional regulation

down-regulates quantity by repression

0.2

In the absence of Dnmt3b, Dnmt3a was associated with Dpp6 gene promoter and regulated its expression and methylation in P19 cells.

SIGNOR-268962

Q8TBB1

Q05586

1

ubiquitination

down-regulates quantity by destabilization

0.288

We used the Ligand of Numb protein X (LNX) family of E3s, a group of PDZ domain-containing RING-type E3 ubiquitin ligases, to demonstrate the feasibility of this strategy. Many potential substrates of LNX E3s were identified. Eight of the nine selected candidates were ubiquitinated in vitro, and two novel endogenous substrates, PDZ-binding kinase (PBK) and breakpoint cluster region protein (BCR), were confirmed in vivo.

SIGNOR-272901

Q9Y4C1

Q99814

0

transcriptional regulation

up-regulates quantity by expression

0.265

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-271583

P09619

P06241

1

phosphorylation

up-regulates activity

0.58

PDGF-induced phosphorylation of Tyr28 in the N-terminus of Fyn affects Fyn activation. We show here that Fyn, a member of the Src family, is phosphorylated on Tyr28 in the unique N-terminal part of the molecule after interaction with the intracellular domain of the PDGF beta-receptor. Activated Fyn furthermore undergoes autophosphorylation on Tyr30, Tyr39 and Tyr420. When Fyn mutants with Tyr28, Tyr30 or Tyr39 replaced with phenylalanine residues were transfected into NIH3T3 cells a decreased activation after PDGF stimulation was seen, suggesting a functional importance of the N-terminal tyrosine phosphorylation of Fyn.

SIGNOR-250253

O75030

Q9HAZ1

0

phosphorylation

down-regulates quantity by destabilization

0.2

Mechanistically, wild type CLK4 (WT-CLK4) but not kinase-dead CLK4-K189R mutant phosphorylated MITF at Y360. This modification promoted its interaction with E3 ligase COP1 and its K63-linked ubiquitination at K308/K372, leading to sequestosome 1 recognition and autophagic degradation.

SIGNOR-274116

Q96AX9

Q13546

1

ubiquitination

down-regulates quantity by destabilization

0.295

These data suggest that after binding, MIB2 inhibits RIPK1 through a mechanism that is dependent on the E3 ligase activity of MIB2.|Whereas MIB2 readily ubiquitylated wild-type RIPK1, mutating K377 to R significantly reduced MIB2 mediated ubiquitylation of RIPK1 (XREF_SUPPLEMENTARY A).

SIGNOR-278633

Q15831

Q96L34

1

phosphorylation

up-regulates

0.535

Lkb1 is a master kinase that activates 13 kinases of the ampk subfamily, including mark/par-1we recently demonstrated that the lkb1 tumour suppressor kinase, in complex with the pseudokinase strad and the scaffolding protein mo25, phosphorylates and activates amp-activated protein kinase (ampk). A total of 12 human kinases (nuak1, nuak2, brsk1, brsk2, qik, qsk, sik, mark1, mark2, mark3, mark4 and melk) are related to ampk. Here we demonstrate that lkb1 can phosphorylate the t-loop of all the members of this subfamily, apart from melk, increasing their activity >50-fold

SIGNOR-122682

Q9Y5T5

P33981

0

phosphorylation

down-regulates quantity by destabilization

0.37

Usp16 is a TTK phosphorylation substrate.

SIGNOR-277351

P98161

P51817

0

phosphorylation

up-regulates

0.257

The possibility of functional interactions between pkd1-encoded polycystin-1 and prkx was suggested by the renal co-distribution of prkx and polycystin-1 and the binding and phosphorylation of the c-terminal of polycystin-1 by prkx at s4166 in vitro. Taken together these results suggest that prkx can reverse the abnormalities in epithelial adhesion, migration and morphogenesis associated with pkd1 inhibition and cyst formation in adpkd.

SIGNOR-158852

P51617

Q9H4G4

1

phosphorylation

up-regulates activity

0.325

We found that TIRAP-MyD88 dependent kinase IRAK1 phosphorylated GAPR-1 at Serine 58 site. The phosphorylation of GAPR-1 promoted its interaction with TRAM-TRIF dependent inhibitor TMED7, and impaired TMED7-mediated disruption of the TRAM-TRIF complex to trigger IFN-β and the IL10 secretion.

SIGNOR-262887

P56705

O75581

2

binding

up-regulates

0.648

Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation.

SIGNOR-131835

P20393

Q9Y5X4

2

binding

up-regulates

0.399

All four proteins, nr2e3, nr1d1, nrl and crx, could be co-immunoprecipitated from the bovine retinal nuclear extract, suggesting their existence in a multi-protein transcriptional regulatory complex in vivo.

SIGNOR-125661

O14965

P12931

0

phosphorylation

up-regulates activity

0.309

We report here that Src phosphorylates and activates AURA at T288, and AURA also activates focal adhesion kinase (FAK, also known as PTK2), leading to initiation of cell movement.

SIGNOR-279286

O75365

P15311

1

dephosphorylation

down-regulates activity

0.277

Here we report the identification of Ezrin as a specific and direct cellular substrate of PRL-3. In HCT116 colon cancer cell line, Ezrin was identified among the cellular proteins whose phosphorylation level decreased upon ectopic over-expression of wtPRL-3 but not of catalytically inactive PRL-3 mutants. Although PRL-3 over-expression in HCT116 cells appeared to affect Ezrin phosphorylation status at both tyrosine residues and Thr567, suppression of the endogenous protein by RNA interference pointed to Ezrin-Thr567 as the residue primarily affected by PRL-3 action.

SIGNOR-248342

Q16828

P41162

0

transcriptional regulation

down-regulates quantity by repression

0.2

ETV3 target genes including etv3, ddx20, and dusp6 provide negative feedback regulation of ETV3 production and activity. Negative feedback along with constitutive instability may serve to tightly regulate ETV3 abundance. Our date suggest that phosphorylation by ERK2 relieves repression by ETV3, allowing activation of cell cycle control genes including myc, components of the NF-κB pathway, and genes required form RNA processing and translation.

SIGNOR-262780

Q9BXW9

Q13315

0

phosphorylation

up-regulates

0.789

These results suggest that s222 and either s1401, s1404, or s1408 are sites of atm-dependent phosphorylation in vitro.Phosphorylation Of fancd2 is required for activation of an s phase checkpoint

SIGNOR-90117

Q13114

O43318

1

ubiquitination

up-regulates activity

0.457

Biological investigations demonstrated that TRAF3 activates TAK1 protein kinase activity via a direct binding to TAK1, then the RING finger of TRAF3 ubiquitinates TAK1, leading to TAK1 phosphorylation and activation.|TRAF3 activates TAK1 through ubiquitination.

SIGNOR-278787

Q9HBA0

P06241

0

phosphorylation

up-regulates activity

0.35

ROS could be detected by Fyn, which is required to activate TRPV4 in a redox-sensitive manner.|The Ca 2+ response to H 2 O 2 required the basal phosphorylation of TRPV4 by the Src kinase Fyn, which may serve as the redox sensor responsible for TRPV4 activation (Figure 2 ) [220] , and was able to increase barrier permeability [219] .

SIGNOR-279991

P24385

Q13309

2

binding

down-regulates quantity by destabilization

0.594

We show that SK-UT-1B cells express a novel splice variant of Skp2 that localizes to the cytoplasm and that cyclin D1 ubiquitination takes place in the nucleus. We propose that the translocation of Skp2 into the nucleus is required for the ubiquitination of cyclin D1 and that the absence of the SCF(Skp2) complex in the nucleus of SK-UT-1B cells is the mechanism underlying the ubiquitination defect observed in this cell line.

SIGNOR-272575

Q13315

Q8NHY2

1

phosphorylation

down-regulates

0.2

Atm engages autodegradation of the e3 ubiquitin ligase cop1 after dna damage. We observed that in response to dna damage, atm phosphorylated cop1 on ser(387) and stimulated a rapid autodegradation mechanism

SIGNOR-149082

P40763

O14522

0

dephosphorylation

down-regulates activity

0.516

Identification of STAT3 as a substrate of receptor protein tyrosine phosphatase T|Phosphorylation of a tyrosine at amino acid Y705 is essential for the function of STAT3, and PTPRT specifically dephosphorylated STAT3 at this position.

SIGNOR-263981

Q13285

P60484

0

dephosphorylation

down-regulates activity

0.256

The fact that SF-1 and PIP3 is robustly dephosphorylated by PTEN, yet SF-1 and PIP2 is resistant to phosphorylation by p110 PI3-kinases, suggests that nuclear proteins like SF-1 can help decouple PTEN signaling in the nucleus from p110 signaling.|We also showed that PTEN can dephosphorylate the SF-1 and PIP3 product of the IPMK reaction, and that PTEN inhibits SF-1 transcriptional activity.

SIGNOR-277117

P52564

Q9UL54

2

binding

up-regulates activity

0.649

Cotransfection experiments suggested that tao2 selectively activates mek3 and mek6 but not meks 1, 4, or 7.

SIGNOR-70950

Q86Y07

Q9UKT8

1

phosphorylation

down-regulates activity

0.296

Collectively, CK1 and VRK2, but not GRK2 kinase, appears to mediate FBXW2 phosphorylation at the beta-TrCP binding motif.|We followed this lead, and inactivated VRK2 and GRK2 by siRNA silencing, or CK1 and VRK2 by small molecule inhibitor IC-261, and found that GRK2 knockdown had no effect, whereas CK1 and VRK2 inhibition or VRK2 silencing largely blocked the degradation of exogenously expressed FBXW2 (XREF_FIG and XREF_SUPPLEMENTARY).

SIGNOR-280161

P14859

Q13131

0

phosphorylation

down-regulates

0.2

Mitosis-specific phosphorylation site in the homeodomain of oct-1 was phosphorylated in vitro by protein kinase a. Pka-mediated phosphorylation event was identified in the cns-specific pou domain protein brn-2/n-oct-3/pou3f2 (nieto et al. 2007). In this case, the modification, at a position homologous to oct1 s385, was found to alter binding specificity for complex dimeric sites.

SIGNOR-53254

Q9UJ55

O15516

2

binding

down-regulates activity

0.2

Magel2 represses the activity of the Clock:Bmal1 heterodimer in a Per2-luciferase assay. Magel2 interacts with Bmal1 and with Per2 as measured by co-immunoprecipitation in co-transfected cells, and exhibits a subcellular distribution consistent with these interactions when visualized by immunofluorescence. As well, Magel2 induces the redistribution of the subcellular localization of Clock towards the cytoplasm, in contrast to the nucleus-directed effect of Bmal1 on Clock subcellular localization.

SIGNOR-253516

P00533

O15126

1

phosphorylation

up-regulates activity

0.335

In our efforts to identify cellular tyrosine kinases that phosphorylate SCAMPs, we are quite intrigued by the observation that among a number of kinases, only the EGFR exhibits activity toward SCAMPs. EGF catalyzes the progressive phosphorylation of the SCAMPs up to 1 h poststimulation and may enhance colocalization of the EGFR and SCAMP3 within the cell interior. EGF also induces SCAMP-EGFR association, as detected by coimmunoprecipitation, and phosphorylation of SCAMP3 is stimulated by the EGFR in vitro. These results suggest that phosphorylation of SCAMPs, either directly or indirectly, may be functionally linked to the internalization/down-regulation of the EGFR. we have observed that there are two tyrosines conserved in SCAMP1 and SCAMP3, which are not found in SCAMP2. Of these two tyrosines (Tyr37 and Tyr73 in SCAMP1; Tyr 41 and Tyr83 in SCAMP3), we consider Tyr37/41 to be a more likely site for tyrosine phosphorylation

SIGNOR-262857

P08912

P63096

2

binding

up-regulates activity

0.2

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-256730

Q13705

Q15796

1

phosphorylation

up-regulates activity

0.776

It has been suggested that binding of myostatin to the ActRIIB results in the phosphorylation of two serine residues of Smad2 or Smad3 at COOH domains

SIGNOR-254984

P06493

Q01167

1

phosphorylation

up-regulates

0.372

We have mapped two cdk phosphorylation sites, serines 368 and 423, which play a role in defining foxk2 function through regulating its stability and its activity as a transcriptional repressor protein. These two cdk sites appear vital for foxk2 function because expression of a mutant lacking these sites cannot be tolerated and causes apoptosis.

SIGNOR-167826

O94953

P68431

1

demethylation

down-regulates activity

0.2

The KDM4 family of Jumonj domain histone demethylases specifically target di- and tri-methylated lysine 9 on histone H3 (H3K9me3), removing a modification central to defining heterochromatin and gene repression. The majority of studies regarding its function describe it as an activator that removes repressive H3K9me3 and H3K9me2 at or near regulated promoters in order to facilitate expression of the indicated pathways.

SIGNOR-263734

Q96J02

Q15583

1

ubiquitination

up-regulates activity

0.2

Based on these observations, we suggest that a mechanism of protein stabilization might account for the accumulation of TGIF protein in response to TNF-alpha signaling.Next, we used three different approaches to investigate the possibility that Itch could contribute to the ability of TNF-alpha to promote TGIF stabilization.|We also employed the experimental strategy combining the detection of monoubiquitinated and polyubiquitinated TGIF and found that mutation of K259 not only compromised monoubiquitination of TGIF by Itch but also enhanced its polyubiquitination.

SIGNOR-278817

O43597

Q13191

2

binding

down-regulates

0.486

One function of hspry2 in signaling processes downstream of rtks may be to modulate c-cbl physiological function such as that seen with receptor-mediated endocytosis.

SIGNOR-83507

O75925

Q13485

1

sumoylation

up-regulates

0.394

These data demonstrate that pias1 protein positively modulates tgf-beta responses as a sumo e3 ligase for smad4

SIGNOR-123462

Q9NPG1

Q9UBV4

2

binding

up-regulates

0.617

Wnt proteins bind to the frizzled receptors and lrp5/6 co-receptors, and through stabilizing the critical mediator betBeta-catenin, initiate a complex signaling cascade that plays an important role in regulating cell proliferation and differentiation.

SIGNOR-131674

P09327

P12931

0

phosphorylation

up-regulates activity

0.363

These data suggest that phosphorylation of villin by c-src is involved in the actin cytoskeleton remodeling necessary for cell migration.To further investigate the role of tyrosine phosphorylated villin in cell migration, we used phosphorylation site mutants (tyrosine to phenylalanine or tyrosine to glutamic acid) in HeLa cells. We determined that tyrosine phosphorylation at residues 60, 81, and 256 of human villin played an essential role in cell migration as well as in the reorganization of the actin cytoskeleton

SIGNOR-247441

P42261

Q13237

0

phosphorylation

up-regulates activity

0.44

In cultured hippocampal neurons, activation of cGKII induces an accumulation of GluR1 on the cellular plasma membrane at extrasynaptic sites, and blockage of cGKII activity prevents the surface increase of GluR1, and also the increase in mEPSC frequency and amplitude, that follows a chemical form of LTP (chemLTP).|In this complex, cGKII phosphorylates GluR1 at serine 845 (S845), a site known to be phosphorylated also by PKA.

SIGNOR-278427

P06213

O14654

1

phosphorylation

up-regulates activity

0.518

The binding of insulin to the subunit of IR not only concentrates insulin at its site of action, but also induces conformational changes in the receptor, which in turn stimulates the tyrosine kinase activity intrinsic to the _ subunit of the IR and triggers the signaling cascades (Fig. 3). Insulin receptors trans phosphorylate several immediate substrates (on Tyr residues) including IRS1-4, Shc, and Gab 1, Cbl, APS, and P60dok.

SIGNOR-217897

P43005

Q03135

2

binding

down-regulates activity

0.2

EAAT3 has previously been shown to form complexes with caveolin-1, a major component of caveolae, which participate in the regulation of transport proteins. The present study explored the impact of caveolin-1 on electrogenic transport by excitatory amino acid transporter isoforms EAAT1-4. caveolin-1 is a powerful negative regulator of the excitatory glutamate transporters EAAT1, EAAT2, EAAT3, and EAAT4. Caveolin-1 has been shown to form complexes with the excitatory amino acid transporter EAAT3 (EAAC1) (Gonzalez et al. 2007) and may thus modify the EAAT isoforms by direct interaction with the carriers.

SIGNOR-264807

P50053

P60891

1

phosphorylation

up-regulates activity

0.348

Ketohexokinase-A (KHK-A; also known as fructokinase-A) phosphorylates PRPS1 T225 and activates PRPS1 by blocking the binding of ADP, AMP, and GDP, which is required for hepatocellular carcinoma development

SIGNOR-265735

Q8N726

Q14669

0

ubiquitination

down-regulates quantity by destabilization

0.582

ULF interacts with ARF both in vitro and in vivo and promotes the lysine-independent ubiquitylation and degradation of ARF.

SIGNOR-266781

Q9UQK1

O95278

0

dephosphorylation

up-regulates quantity by stabilization

0.749

We have recently described that the activity of R5/PTG is down-regulated by the laforin-malin complex, composed of a dual specificity phosphatase (laforin) and an E3-ubiquitin ligase (malin). We now demonstrate that phosphorylation of R5/PTG at Ser-8 by AMPK accelerates its laforin/malin-dependent ubiquitination and subsequent proteasomal degradation, which results in a decrease of its glycogenic activity.

SIGNOR-276239

O00321

P23769

2

binding

up-regulates activity

0.43

Transcriptional assays with the Spi1 promoter-reporter demonstrated that Gata2 cooperates with Etv2 and augments the transcriptional activity of Etv2.The protein-protein interaction between Etv2 and Gata2 is mediated by the Ets and Gata domains. Using the embryoid body differentiation system, we demonstrate that co-expression of Gata2 augments the activity of Etv2 in promoting endothelial and hematopoietic lineage differentiation.

SIGNOR-256008

O75385

Q9Y478

0

phosphorylation

up-regulates

0.537

Ampk and ulk1 interact and that the latter is phosphorylated by ampk. This phosphorylation leads to the direct activation of ulk1 by ampk bypassing mtor-inhibition

SIGNOR-173044

P35367

O95837

2

binding

up-regulates activity

0.457

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-257425

P16220

Q00535

0

phosphorylation

up-regulates activity

0.374

CDK5 Activates the Self-Renewal Regulator CREB1 in GSCs.|Our data indicate that CDK5, which has previously been shown to activate CREB1 through cAMP and PKA in dopamine neurons present in the ventral tegmental area, can directly bind with and phosphorylate CREB1 in a PKA and cAMP independent manner, at least in GSCs.

SIGNOR-279682

O15530

Q9UBS0

1

phosphorylation

up-regulates activity

0.609

Mutational analysis revealed that the phosphorylation of Thr241 and Thr401 in p70beta1 was indispensable for the kinase activity. In contrast, a p70beta1 mutant in which Ser383 was substituted with Gly (S383G) still retained nearly the half maximal activity. Sequential phosphorylation of wild-type and S383G mutant of p70beta1 with mTOR and 3-phosphoinositide-dependent protein kinase 1 (PDK1) in vitro synergistically activated their kinase activities.

SIGNOR-250272

Q9BT67

Q9H0M0

0

ubiquitination

down-regulates quantity

0.381

Accordingly, the ubiquitination assays were performed and the results revealed that knockdown of WWP1 reduced the ubiquitination of NDFIP1 in HuCCT1 and vice versa in HCCC-9810 and RBE (Fig. 7E).|In addition, we found that WWP1 could reduce the protein level of NDFIP1 via ubiquitination.

SIGNOR-278796

Q92934

P10415

1

relocalization

down-regulates activity

0.801

Apoptosis is initiated when Bcl-2 and its prosurvival relatives are engaged by proapoptotic BH3-only proteins via interaction of its BH3 domain with a groove on the Bcl-2-like proteins. These interactions have been considered promiscuous, but our analysis of the affinity of eight BH3 peptides for five Bcl-2-like proteins has revealed that the interactions vary over 10,000-fold in affinity, and accordingly, only certain protein pairs associate inside cells. Bim and Puma potently engaged all the prosurvival proteins comparably. Bad, however, bound tightly to Bcl-2, Bcl-xL, and Bcl-w but only weakly to A1 and not to Mcl-1.

SIGNOR-133756

Q9H4A6

P78527

0

phosphorylation

up-regulates activity

0.318

In response to DNA damage, DNA-PK phosphorylates GOLPH3, resulting in increased interaction with MYO18A, which applies a tensile force to the Golgi. Interference with the Golgi DNA damage response by depletion of DNA-PK, GOLPH3, or MYO18A reduces survival after DNA damage, whereas overexpression of GOLPH3, as is observed frequently in human cancers, confers resistance to killing by DNA-damaging agents

SIGNOR-253558

O43318

Q6P589

1

phosphorylation

down-regulates quantity by destabilization

0.2

TAK1 phosphorylated the Ser3 in the noncanonical degron motif of TIPE2 to trigger its interaction with β-TrCP for subsequent ubiquitination and degradation.

SIGNOR-273668

P16220

Q6SA08

0

phosphorylation

up-regulates

0.578

Tssk5, a novel member of the testis-specific serine/threonine kinase family, phosphorylates creb at ser-133, and stimulates the cre/creb responsive pathway.

SIGNOR-138289

P06239

Q9H4E7

1

phosphorylation

up-regulates activity

0.5

In vitro kinase assays indeed demonstrated that Lck can phosphorylate wild-type IBP but not the Y210F mutant. IBP Binds PI(3,4,5)P3 upon Phosphorylation by Lck

SIGNOR-251372

P04049

O60674

0

phosphorylation

up-regulates activity

0.617

JAK2 phosphorylated Raf-1. e sites at 340/341 are indeed phosphorylated by JAK2 and that this phosphorylation represents a major component of the activation process.

SIGNOR-251361

P53350

O95239

1

phosphorylation

down-regulates activity

0.467

Moreover, phosphorylation of KIF4 and condensin I by Aurora B and polo like kinase 1 (Plk1) is important for KIF4 and condensin I localization to the chromosome.|These results suggest that Plk1 negatively regulates the loading of both KIF4 and condensin to the chromosome.

SIGNOR-280069

P41181

Q07002

0

phosphorylation

down-regulates quantity by destabilization

0.26

CDK18 controls AQP2 through phosphorylation at serine 261 and STUB1-mediated ubiquitination. |We had previously observed that a decrease in the phosphorylation of AQP2 at S261 is associated with a decrease in its poly-ubiquitination and an increase in its abundance

SIGNOR-264562

Q92830

Q16695

1

acetylation

down-regulates activity

0.2

The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14.

SIGNOR-269604

P22681

Q9Y2R2

0

dephosphorylation

down-regulates

0.387

The tyrosine phosphatase lyp1 was found to be constitutively associated with the proto-oncogene c-cbl in thymocytes and t cells. Overexpression of lyp1 reduces cbl tyrosine phosphorylation. It is known that cbl is heavily tyrosine phosphorylated after tcr stimulation and can associate with the syk and zap tyrosine kinases, negatively regulating their activities. Tyrosine phosphatases keep cbl in a basally dephosphorylated state.

SIGNOR-65405

A8MYZ6

O75874

1

transcriptional regulation

up-regulates quantity by expression

0.2

We identify FOXOs as transcriptional activators of IDH1. FOXOs promote IDH1 expression and thereby maintain the cytosolic levels of α-ketoglutarate and NADPH.

SIGNOR-260092

Q96Q05

Q99558

2

binding

up-regulates activity

0.478

We demonstrated by immunohistochemistry that NIBP expression in the brain is localized to neurons. NIBP physically interacts with NIK, IKK(beta), but not IKK(alpha) or IKK(gamma). NIBP overexpression potentiates tumor necrosis factor-alpha-induced NF-kappaB activation through increased phosphorylation of the IKK complex and its downstream I(kappa)B(alpha) and p65 substrates.

SIGNOR-269672

Q8NFJ6

Q9HC23

2

binding

up-regulates

0.665

We have cloned two closely related receptors for pk1 and pk2. These receptors, named prokineticin receptor 1 and 2 (pkr1 and pkr2)

SIGNOR-87919

P11802

Q06830

1

phosphorylation

down-regulates

0.226

Peroxiredoxin (prx) i is a member of the peroxiredoxin family of peroxidases and contains a consensus site (thr(90)-pro-lys-lys) for phosphorylation by cyclin-dependent kinases (cdks). This protein has now been shown to be phosphorylated specifically on thr(90) by several cdks, including cdc2, in vitro. Phosphorylation of prx i on thr(90) reduced the peroxidase activity of this protein by 80%.Prx i was also phosphorylated, with an efficiency similar to that observed with cdc2, when incubated in vitro with cdk2, cdk4, or cdk6 that had been immunoprecipitated from hela cell lysates with specific antibodies (data not shown).

SIGNOR-87105

Q15672

P31749

0

phosphorylation

up-regulates

0.438

Moreover, phosphorylation of twist-1 at ser42 was shown in vivo in various human cancer tissues, suggesting that this post-translational modification ensures functional activation of twist-1 after promotion of survival during carcinogenesis.

SIGNOR-164884

P30679

P25116

2

binding

up-regulates activity

0.567

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

SIGNOR-257353