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
Q8WXG6	Q8TDJ6	binding	up-regulates quantity	0.448	We isolated here a novel protein that was co-immunoprecipitated with Rab3 GEP and GAP by their respective antibodies from the crude synaptic vesicle fraction of rat brain. The protein, named rabconnectin-3, bound both Rab3 GEP and GAP. These results indicate that rabconnectin-3 serves as a scaffold molecule for both Rab3 GEP and GAP on synaptic vesicles.	SIGNOR-265581
P52630	Q5T197	ubiquitination	down-regulates activity	0.448	DCST1 promotes ubiquitination of STAT2.\|The ability of DCST1 to degrade STAT2 levels was visible both in the presence and absence of IFNbetastimulation.\|In our study, DCST1 was found to interact with and promote ubiquitination of STAT2, leading to reduced STAT2 expression and attenuated activation of the ISG induction pathway.	SIGNOR-278747
O75113	P46934	monoubiquitination	up-regulates activity	0.448	This observation, together with the monoubiquitination of Nedd4-BP1 by the ubiquitin ligase Nedd4 suggests that the NYN domain proteins of eukaryotes are regulated by monoubiquitination. Given the localization of Nedd4-BP1 to punctuate nuclear bodies, it is likely that they are parts of nuclear RNA-processing complexes that are dependent on monoubiquitination for their assembly.	SIGNOR-272626
P11387	P78527	phosphorylation	down-regulates quantity by destabilization	0.448	Here, we show that the Ku70/Ku80 heterodimer binds with topoI, and that the DNA-dependent protein kinase (DNA-PKcs) phosphorylates topoI on serine 10 (topoI-pS10), which is subsequently ubiquitinated by BRCA1.	SIGNOR-277352
P24928	O60885	phosphorylation	up-regulates	0.448	We report that brd4 is an atypical kinase that binds to the carboxyl-terminal domain (ctd) of rna polymerase ii and directly phosphorylates its serine 2 (ser2) sites both in vitro and in vivo under conditions where other ctd kinases are inactive. our findings may provide a mechanistic basis for several functional studies that showed that loss of brd4 causes transcription termination and embryonic lethality	SIGNOR-197012
Q9Y566	Q15398	relocalization	up-regulates activity	0.448	SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3).	SIGNOR-264598
P38405	P13945	binding	up-regulates activity	0.448	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-256896
P27986	P37173	binding	up-regulates	0.448	These studies revealed that PI 3-kinase is associated in vivo with both TGF-_ receptor subtypes and that TGF-_1 stimulation enhances PI 3-kinase activity associated with type I TGF-_ receptor in hASM cells.	SIGNOR-227521
P15514	P78536	cleavage	up-regulates activity	0.448	ADAM17 is involved in the release and activation of several growth factors and cytokine receptor ligands. Among the growth factors activated by ADAM17 are TGF-alpha, amphiregulin, epiregulin and HB-EGF	SIGNOR-259842
P61073	P54578	deubiquitination	up-regulates quantity by stabilization	0.448	The physical interaction of CXCR4 and USP14 is paralleled by USP14-catalyzed deubiquitination of the receptor\|We also observed that ubiquitination of CXCR4 facilitated receptor degradation, whereas overexpression of USP14 or RNAi-induced knockdown of USP14 blocked CXCL12-mediated CXCR4 degradation	SIGNOR-265057
Q9BYX4	Q6PJ69	ubiquitination	up-regulates activity	0.448	These results indicate that TRIM65 promotes MDA5 ubiquitination at lysine 743, which is important for MDA5 activation.	SIGNOR-278535
Q99638	Q9UKI8	phosphorylation	up-regulates	0.448	Tlk1b phosphorylates hrad9 at s328 after the induction of dsb, occupancy of rad9 adjacent to the break increased during repair while that of asf1 decreased, and the effect was more pronounced in tlk1b-overexpressing cells. We propose that following genotoxic stress, tlk1/1b is first recruited to the dsb in a complex with rad9. It then exchanges with asf1 to promote nucleosomes eviction at the dsb and access of the repair machinery to unencumbered dna.	SIGNOR-181748
Q99717	P12757	binding	down-regulates	0.448	Ski also represses bmp signaling through interactions with smad4 and bmp-specific r-smads, smad1 or smad8.	SIGNOR-95474
Q8WUP2	Q9BQL6	binding	up-regulates activity	0.448	Kindlin binds migfilin tandem LIM domains and regulates migfilin focal adhesion localization and recruitment dynamics. Two integrin-binding proteins present in FAs, kindlin-1 and kindlin-2, are important for integrin activation, FA formation, and signaling. By binding filamin, migfilin provides a link between kindlin and the actin cytoskeleton.	SIGNOR-266103
P63096	P28566	binding	up-regulates activity	0.448	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-256705
P08754	P30559	binding	up-regulates activity	0.448	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-257178
P15941	P43403	phosphorylation	up-regulates activity	0.448	Indeed, the present results demonstrate that ZAP-70 phosphorylates MUC1-CD and that the MUC1-CD Y-20 site functions, at least in part, as a ZAP-70 substrate (Fig. 4C). In this regard, the in vivo phosphorylation data indicate that ZAP-70 may also contribute to phosphorylation of MUC1-CD Y-46.The results further show that ZAP-70 phosphorylation of MUC1-CD stimulates the interaction of MUC1 andBeta-catenin.	SIGNOR-247039
P11021	Q99941	transcriptional regulation	up-regulates quantity by expression	0.448	Accordingly, N-terminal fragments of each ATF6 isoform (N-ATF6α and N-ATF6β) were overexpressed in HeLa cells and the effects on GRP78 induction were assessed. When expressed at similar levels, N-ATF6α conferred ∼200-fold greater GRP78 promoter activation than N-ATF6β.	SIGNOR-261566
P08754	P28566	binding	up-regulates activity	0.448	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-256848
Q9UKL3	Q14790	binding	up-regulates	0.448	The caspase-8-binding protein flice-associated huge protein (flash) would form a molecular complex with caspase-8, thereby presumably activating the mitochondrial apoptosis pathway by regulating caspase-8 activity.	SIGNOR-152473
P09471	P08908	binding	up-regulates activity	0.447	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-256972
P14598	Q05655	phosphorylation	up-regulates	0.447	Pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation. The use of p47phox mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc?, ???, And ?.	SIGNOR-89229
O00548	Q8NES3	binding	up-regulates	0.447	The modification of notch by fringe would influence binding between the notch receptor and its ligand. It was reported previously that mfng and lfng inhibited notch1-mediated signaling triggered by jagged1 and enhanced that triggered by delta1, and either jagged1- or delta1-triggered notch2 signaling was enhanced by lfng	SIGNOR-107699
Q96AY2	P53350	phosphorylation	up-regulates activity	0.447	In human cells, EME1 is phosphorylated by both cyclin-dependent kinases (CDKs) and PLK1, and this modification is directly correlated with increased MUS81 cleavage activity in\u00a0vitro.	SIGNOR-280068
O75602	Q92949	transcriptional regulation	up-regulates quantity by expression	0.447	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-266935
P00533	O75159	binding	down-regulates quantity	0.447	SOCS5 Can Physically Associate with the EGFR. The complex recruited by SOCS proteins is composed of ElonginBC, Cullin, and Roc1 (15, 16). Together, this complex has E3 ubiquitin ligase activity. We suspect that the role of the SB domain is to mediate coupling of EGFR with the Elongin-Cullin-Roc E3 ubiquitin ligase complex, resulting in enhanced EGFR degradation.	SIGNOR-271516
P49918	P31749	phosphorylation	down-regulates	0.447	Cdk inhibitor p57 (kip2) is downregulated by akt during her2-mediated tumorigenicityakt phosphorylates p57 on ser 282 or thr310. Akt activity results in destabilization of p57 by accelerating turnover rate of p57 and enhancing p57 ubiquitination	SIGNOR-252535
Q14207	P24941	phosphorylation	up-regulates	0.447	Importantly, mutation of cdk2 phosphorylation sites to alanine abrogates the ability of p220 to activate the histone h2b promoter.	SIGNOR-82141
P20963	Q9Y2R2	dephosphorylation	down-regulates activity	0.447	In vitro experiments with purified recombinant proteins demonstrated that PTPN22-D195A/C227S interacted directly with activated Lck, Zap70, and TCRzeta, confirming the initial substrate trap results. Native PTPN22 dephosphorylated Lck and Zap70 at their activating tyrosine residues Tyr-394 and Tyr-493, respectively, but not at the regulatory tyrosines Tyr-505 (Lck) or Tyr-319 (Zap70). Native PTPN22 also dephosphorylated TCRzeta in vitro and in cells, and its substrate trap variant co-immunoprecipitated with TCRzeta when both were coexpressed in 293T cells, establishing TCRzeta as a direct substrate of PTPN22.	SIGNOR-248837
P14416	P43250	phosphorylation	down-regulates activity	0.447	GRK6 is located predominantly in dopaminergic neurons [ xref ] and functionally phosphorylates DRD2.	SIGNOR-279046
Q9UBK2	P31749	phosphorylation	down-regulates activity	0.447	Here we describe a mechanism by which insulin, through the intermediary protein kinase akt2/protein kinase b (pkb)-beta, elicits the phosphorylation and inhibition of the transcriptional coactivator peroxisome proliferator-activated receptor-coactivator 1alpha (pgc-1alpha), a global regulator of hepatic metabolism during fasting / phosphorylation of pgc-1alpha At ser570 Is required for akt to inhibit recruitment of pgc-1alpha To chromatin.	SIGNOR-252502
P42858	Q00535	phosphorylation	up-regulates	0.447	Huntingtin is an antiapoptotic proteinwe show here that huntingtin is phosphorylated by the cyclin-dependent kinase 5 (cdk5) at serines 1181 and 1201. Phosphorylation can be induced by dna damage in vitro and in vivo. The state of huntingtin phosphorylation is a crucial regulator of neuronal cell death. Absence of phosphorylation of huntingtin at serines 1181 and 1201 confers toxic properties to wild-type huntingtin in a p53-dependent manner in striatal neurons and accelerates neuronal death induced by dna damage.	SIGNOR-156840
P15311	P43405	phosphorylation	up-regulates activity	0.447	Phospho-SYK has also been shown to specifically activate ezrin upon CD81 engagement.\|We found that the activated SYK led to a time dependent phosphorylation of ezrin (pY354 and pThr567) and radixin (pThr564) (XREF_FIG).	SIGNOR-279129
P51991	Q9UHD9	binding	up-regulates quantity by stabilization	0.447	We screened a yeast two-hybrid library using the central domain of ubiquilin-2 hoping to identify proteins whose binding is affected by the UBQLN2 mutations.\|\|Additionally, our evidence that ubiquilin-2 is in- volved in stabilizing hnRNPA1 protein	SIGNOR-262272
P24863	Q92585	relocalization	up-regulates	0.447	Cycc:cdk8 and cyct1:cdk9/p-tefb are recruited with notch and associated coactivators (mam, skip) to the hes1 promoter in signaling cells.	SIGNOR-130709
Q86T82	P24941	phosphorylation	up-regulates activity	0.447	There is positive reinforcement of this signaling mechanism because phosphorylation of Ser628 by CDK2/cyclin E and CDK2/cyclin A complexes produces maximal USP37 activity	SIGNOR-265045
P23528	Q96GD0	dephosphorylation	down-regulates activity	0.447	Chronophin, a novel HAD-type serine protein phosphatase, regulates cofilin-dependent actin dynamics\|Cofilin is a key regulator of actin cytoskeletal dynamics whose activity is controlled by phosphorylation of a single serine residue. We report the biochemical isolation of chronophin (CIN), a unique cofilin-activating phosphatase of the haloacid dehalogenase (HAD) superfamily.	SIGNOR-248764
P60953	Q9P2F6	gtpase-activating protein	down-regulates activity	0.447	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-260474
Q06187	O60674	phosphorylation	up-regulates activity	0.447	Jak2 and Lyn coimmunoprecipitated with Btk and phosphorylated Btk on tyrosine (XREF_FIG C).	SIGNOR-279196
P56270	P68400	phosphorylation	up-regulates	0.447	Site-specific mutagenesis of maz revealed that the serine residue at position 480 was the major site of phosphorylation by ckii both in vitro and in vivo. Phosphorylation of maz by ckii at this serine residue was required for maximum binding of maz to the pyrimidine-rich dna of the nuclease-hypersensitive element (nhe) in the 5'-end promoter region of the c-myc gene. Mutation of serine at position 480 to alanine eliminated the dna-binding activity of maz to this element.	SIGNOR-70082
O60566	O14757	phosphorylation	up-regulates activity	0.447	Nonetheless, in our experimental system a Chk1-dependent BubR1 phosphorylation was also observed after Noc treatment.\|Possible requirement of Chk1 in U2OS cells to activate the mitotic spindle checkpoint proteins Mad2 and BubR1.	SIGNOR-280223
P63092	P37288	binding	up-regulates activity	0.447	Here we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique G alpha subunit C-termini. For each receptor, we probed chimeric G alpha subunit activation via a transforming growth factor-alpha (TGF alpha) shedding response in HEK293 cells lacking endogenous Gq/11- and G12/13- signaling. \| We defined positive coupling if any member of the subfamily scored LogRAi ‚â• -1 and negative coupling if all of the members scored LogRAi < -1 (Figure 3A-B). ROC analysis gives AUC = 0.78 (Figure S4A) when considering high-confidence known coupling data and suggested a threshold of LogRAi ‚â• -1.0 for defining true couplings. \| The score associated to this interaction has a LogRAi ‚â• -1.0.	SIGNOR-256805
P12830	Q9UQB3	binding	up-regulates quantity by stabilization	0.447	To clarify the role of p120 in mammalian cells, we have knocked down p120 with siRNA in cells expressing epithelial (E-), placental (P-), neuronal (N-), and vascular endothelial (VE-) cadherins. We report that each of these cadherins, as well as α- and β-catenins, were rapidly degraded in the absence of p120, resulting in loss of cell–cell adhesion. The effect was clearly dose dependent, indicating that p120 expression levels may directly determine cadherin levels. Degradation of p120-uncoupled cadherin occurred after its arrival at the surface, indicating that p120 regulates cadherin turnover at the level of internalization or recycling. p120 homologues ARVCF and δ-catenin could substitute for p120, so at least one family member is likely required to maintain adhesion. Thus, cadherin complexes are rapidly turned over and degraded in mammalian cells in the absence of direct interaction with p120 or a p120 family member.	SIGNOR-252134
Q96ST3	Q13118	binding	up-regulates activity	0.447	detailed biochemical and functional analyses have demonstrated that the TIEG2 _-HRM domain interacts specifically with the PAH2 domain of mSin3A to repress transcription. our data suggest the presence of a conserved _-helical repression motif (_-HRM) in the TIEG and BTEB subfamilies of Sp1-like proteins that mediates transcriptional repression activity through interaction with the corepressor mSin3A.	SIGNOR-222394
P19544	Q6N021	binding	up-regulates activity	0.447	In this study, we demonstrate that WT1 binds directly to TET2 and recruits TET2 to specific genomic sites to regulate the expression of WT1 target genes.	SIGNOR-255703
Q8WV24	O14965	phosphorylation	down-regulates quantity by destabilization	0.447	Aurora A directly phosphorylates PHLDA1 leading to its degradation. Aurora A phosphorylates PHLDA1 at Ser 98.	SIGNOR-273545
P61586	Q8N103	gtpase-activating protein	down-regulates activity	0.447	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-260523
Q13322	P12931	phosphorylation	down-regulates	0.447	Grb10 tyrosine phosphorylation was stimulated by expression of constitutively active src or fyn in cells and by incubation with purified src or fyn in vitro. The insulin stimulated or src/fyn-mediated tyrosine phosphorylation in vivo was significantly reduced when grb10 tyrosine 67 was changed to glycine. This mutant form of grb10 bound with higher affinity to the ir in cells than that of the wild-type protein, suggesting that tyrosine phosphorylation of grb10 may normally negatively regulate its binding to the ir.	SIGNOR-78706
P32019	P20339	binding	up-regulates activity	0.447	We report that Rab5 acts at the plasma membrane, downstream of ruffling, to promote macropinosome sealing and scission. Rab5 is recruited to plasmalemmal circular ruffles before macropinosome closure. Rab5 effectors Inpp5b, OCRL and APPL1 localize to macropinocytic cups and vesicles, and are required for macropinosome sealing. The mammalian 5-phosphatases Inpp5b and OCRL, which can degrade PtdIns(4,5)P2, are both Rab5-associating effectors implicated in endocytosis and macropinocytosis	SIGNOR-277770
P19086	P25116	binding	up-regulates activity	0.447	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-257127
P53350	Q53GT1	binding	down-regulates activity	0.446	Here, we identify PLK1 as a target of the cullin 3 (CUL3)-based E3 ubiquitin ligase, containing the BTB adaptor KLHL22, which regulates chromosome alignment and PLK1 kinetochore localization but not PLK1 stability. In the absence of KLHL22, PLK1 accumulates on kinetochores, resulting in activation of the spindle assembly checkpoint (SAC). CUL3-KLHL22 ubiquitylates Lys 492, located within the PBD, leading to PLK1 dissociation from kinetochore phosphoreceptors.	SIGNOR-272108
P00367	Q9Y572	binding	up-regulates	0.446	Rip3 directly interacts with glycogen phosphorylase (pygl), glutamate ammonia ligase (glul), and glutamate dehydrogenase 1 (glud1). Rip kinase activity is required to enhance the activities of all three enzymes both in vivo and in vitro.	SIGNOR-187314
P15172	P53778	phosphorylation	up-regulates activity	0.446	We determined that p38-gamma directly phosphorylated MyoD on Ser199 and Ser200, which results in enhanced occupancy of MyoD on the promoter of myogenin together with markedly decreased transcriptional activity. Phosphorylation of MyoD by p38-γ directs the assembly of a repressive transcriptional complex at the Myogenin promoter.	SIGNOR-276273
P05771-2	P67775	dephosphorylation	down-regulates activity	0.446	Inhibition of PP2A increased phosphorylation at Ser660 that determines calcium sensitivity and activity of PKCbetaII isoform	SIGNOR-248621
Q9UEW8	Q9H4A3	phosphorylation	up-regulates	0.446	Activation of wnk1 coincides with the phosphorylation and activation of two wnk1 substrates, namely, the protein kinases ste20/sps1-related proline alanine-rich kinase (spak) and oxidative stress response kinase-1 (osr1).	SIGNOR-151671
P29353	P36888	phosphorylation	up-regulates activity	0.446	Intracellular FLT3 signaling involves tyrosine phosphorylation of several cytoplasmic proteins including SHC. We have found that upon FLT3 activation SHC phosphorylation occurs at tyrosine 239/240 and 313.	SIGNOR-251147
P28482	P62136	dephosphorylation	down-regulates	0.446	P-erk1/2 proteins were efficiently dephosphorylated in vitro by protein phosphatases 1 and 2a (pp1/2a) and mapk phosphatase 3 (mkp3)	SIGNOR-103152
P10997	P29120	cleavage	up-regulates activity	0.446	The processing of proinsulin to insulin occurs in the secretory granules at the C-terminal end of pairs of basic amino acids, Arg31-Arg32 and Lys64-Arg65 [9,10]. Following cleavage, by the prohormone convertases, PC3 (also known as PC1) and PC2, the pair of basic amino acids are removed rapidly by carboxypeptidase E (CPE) to produce the mature insulin molecule	SIGNOR-261782
Q69YH5	Q96GD4	phosphorylation	down-regulates activity	0.446	This result demonstrates that the three sites of Repo-Man (Ser-543, Ser-977, and Ser-981) are phosphorylated by Aurora B in early mitosis. We uncover that PP1γ is recruited to mitotic chromosomes by its regulatory subunit Repo-Man in the absence of Aurora B activity and that Aurora B regulates dissociation of PP1γ by phosphorylating and disrupting PP1γ-Repo-Man interactions on chromatin.	SIGNOR-274001
P69891	Q9H165	transcriptional regulation	down-regulates quantity by repression	0.446	Our findings reveal that direct γ-globin gene promoter repression by BCL11A underlies hemoglobin switching.	SIGNOR-269067
Q12778	Q13131	phosphorylation	up-regulates	0.446	The energy sensor amp-activated protein kinase (ampk) has been shown to directly phosphorylate foxo factors at six regulatory sites that are distinct from the akt.	SIGNOR-157941
P23409	P50461	binding	up-regulates activity	0.446	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-241096
Q9BR76	Q8WYL5	dephosphorylation	up-regulates	0.446	Coronin 1b inhibits filament nucleation by arp2/3 complex and this inhibition is attenuated by phosphorylation of coronin 1b at serine 2, a site targeted by ssh1l.	SIGNOR-153604
P03372	P00519	phosphorylation	up-regulates	0.446	Eralpha can be phosphorylated on two sites, tyrosine 52 (y-52) and tyrosine 219 (y-219). Eralpha phosphorylation by c-abl stabilizes eralpha, resulting in enhanced eralpha transcriptional activity and increased expression of endogenous eralpha target genes.	SIGNOR-163562
Q9H204	P06241	phosphorylation	up-regulates	0.446	To unravel the cellular functions of magicin, we used a yeast two-hybrid system and identified fyn tyrosine kinase as a specific binding partner for magicin. Fyn phosphorylates magicin in vitro.	SIGNOR-148700
P63104	Q05655	phosphorylation	down-regulates activity	0.446	We confirmed that MAPKAPK2 interacted with and phosphorylated 14-3-3zeta in vitro and in HEK293 cells. \| Experimentally, S58D mutation significantly impaired both 14-3-3zeta dimerization and binding to Raf-1.	SIGNOR-249222
P69892	Q9H165	transcriptional regulation	down-regulates quantity by repression	0.446	Our findings reveal that direct γ-globin gene promoter repression by BCL11A underlies hemoglobin switching.	SIGNOR-269066
Q15759	O60271	binding	up-regulates	0.446	Cdo, jlp, and p38alpha/beta form complexes in differentiating myoblasts, and cdo and jlp cooperate to enhance levels of active p38alpha/beta in transfectants.	SIGNOR-150147
P05771	P67775	dephosphorylation	down-regulates activity	0.446	Specifically, the threonine at position 500 (T500) on the activation loop, and T641 and S660 on the carboxyl terminus of protein kinase C beta II are phosphorylated in vivo. T500 and S660 are selectively dephosphorylated in vitro by protein phosphatase 2A to yield an enzyme that is still capable of lipid-dependent activation, whereas all three residues are dephosphorylated by protein phosphatase 1 to yield an inactive enzyme.	SIGNOR-248620
O75379	P68400	phosphorylation	up-regulates	0.446	The r-snare vamp4, which contains a dileucine motif, binds to the ap-1 or the ggas. Serine 20 and leucines 25,26 are essential for this binding. Ap-1 association with vamp4 is enhanced when serine 30 is phosphorylated by casein kinase 2. This phosphorylation-dependent modulation of ap-1 binding is mediated by pacs-1 (phosphofurin acidic cluster sorting protein). Ablation of both the dileucine motif and serine 30 results in a dramatic mislocalization of vamp4 in the regulated secretory pathway.	SIGNOR-119090
P39748	P06493	phosphorylation	down-regulates activity	0.446	Phosphorylation of human fen1 by cyclin-dependent kinase modulates its role in replication fork regulation.As a functional consequence of phosphorylation by cdk1-cyclin a in vitro, endo- and exonuclease activities of fen1 are reduced whereas its dna binding is not affected.	SIGNOR-103535
Q13950	P31749	phosphorylation	down-regulates activity	0.446	Here we show that Akt kinase directly phosphorylates Runx2 to regulate invasive properties of breast cancer cells.	SIGNOR-280176
Q8IZP0	P28482	phosphorylation	up-regulates	0.445	Our mass spectrometry also identified abi1 s183 and s225 on abi1 (numbering corresponds to abi1 isoform 1) as sites phosphorylated on endogenous protein and in the wildtype erk-dependent in vitro phosphorylated sample. these data indicate erk phosphorylation of abi1 is required for basal and egf-induced wrc interaction with the wrp2/3 complex.	SIGNOR-172873
P38936	Q16539	phosphorylation	up-regulates quantity by stabilization	0.445	The stress-activated protein kinases p38 alpha and jnk1 stabilize p21(cip1) by phosphorylation.\|p38 alpha and JNK1 phosphorylated p21 in vivo, and both p38 alpha and JNK1 phosphorylated p21 at Ser(130) in vitro.	SIGNOR-89436
Q8NDV7	Q6PJ69	polyubiquitination	down-regulates quantity by destabilization	0.445	Ubiquitination assays demonstrate that TRIM65 is an ubiquitin E3 ligase for TNRC6 proteins. The combination of overexpression and knockdown studies establishes that TRIM65 relieves miRNA-driven suppression of mRNA expression through ubiquitination and subsequent degradation of TNRC6.	SIGNOR-272174
P55075	P10071	transcriptional regulation	down-regulates quantity	0.445	Whereas Fgf8 expression was almost absent in Shh-/- mutants, it was up-regulated in Gli3-/-;Shh-/- double mutants, suggesting that SHH is not required for Fgf8 induction, and that GLI3 normally represses Fgf8 independently of SHH	SIGNOR-268949
Q15796	O14595	dephosphorylation	down-regulates activity	0.445	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-248299
P24864	P49841	phosphorylation	down-regulates	0.445	Our experiments suggest that gsk3 is the kinase primarily responsible for phosphorylation of cyclin e on t380	SIGNOR-118563
P40763	P00519	phosphorylation	up-regulates activity	0.445	Previously, we showed that c-Abl and Arg promote phosphorylation of the STAT3 transcription factor (Y705) in a variety of cancer cell lines , .\|Since c-Abl and Arg activate STAT3, we investigated whether c-Abl and Arg regulate NF-kappaB signaling.	SIGNOR-279675
Q9H161	Q9UJU2	binding	up-regulates quantity by expression	0.445	Alx4 Stably Interacts with LEF-1. LEF-1 enhances Alx4 binding to DNA, suggesting that both interaction with LEF-1 and DNA binding are required to mediate its effects on the N-CAM promoter.	SIGNOR-254547
Q9UBK2	Q6NUN9	transcriptional regulation	up-regulates quantity by expression	0.445	PARIS represses the expression of the transcriptional coactivator, PGC-1α and the PGC-1α target gene, NRF-1 by binding to insulin response sequences in the PGC-1α promoter.	SIGNOR-277627
P02458	P03956	cleavage	down-regulates quantity by destabilization	0.445	MMP-1 cleaves type II collagen at the peptide bond Gly906-Leu907 Proteolysis of triple-helical collagen is an important step in the progression toward irreversible tissue damage in osteoarthritis. Earlier work on the expression of enzymes in cartilage suggested that collagenase-1 (MMP-1) contributes to the process.	SIGNOR-256341
P52789	P31749	phosphorylation	up-regulates activity	0.445	K63-linked ubiquitination enhances the interaction between Akt and HK2 and eventually increases HK2 phosphorylation on Thr473 and mitochondrial localization	SIGNOR-259984
P42224	P45983	phosphorylation	up-regulates activity	0.445	SP600125 prevented phosphorylation of STAT1 at Tyr701 site [..] Western blot analysis confirmed that blocking p-JNK using SP600125 markedly reduced STAT3 localization in the nucleus and STAT1 phosphorylation	SIGNOR-251101
O95644	P53779	phosphorylation	down-regulates	0.445	We show that jnk, erk, and p38 physically associate with the nfatc n-terminal regulatory domain and can directly phosphorylate functionally important residues involved in regulating nfatc subcellular localization, namely ser(172) and the conserved nfatc ser-pro repeats.	SIGNOR-74556
P49757	O43347	binding	down-regulates	0.445	The study confirmed p21(cip1) and numb proteins as targets of musashi1, suggesting additionally p27(kip1) in cell-cycle regulation and jagged-1 in notch .	SIGNOR-165617
Q9BPZ3	O95071	polyubiquitination	down-regulates quantity by destabilization	0.445	We demonstrate a mechanism for this co-regulation that involves an E3 ubiquitin ligase, EDD, which targets Paip2 for degradation. PABP depletion by RNA interference (RNAi) causes co-depletion of Paip2 protein without affecting Paip2 mRNA levels. Upon PABP knockdown, Paip2 interacts with EDD, which leads to Paip2 ubiquitination.	SIGNOR-272648
P62140	Q9UD71	binding	down-regulates activity	0.445	DARPP-32 (dopamine and cyclic AMP-regulated phospho-protein, relative molecular mass 32,000) is converted into an inhibitor of protein phosphatase 1 when it is phosphorylated by protein kinase A (PKA) at threonine 34.â€šÂ	SIGNOR-264959
Q96ST3	Q13886	binding	up-regulates activity	0.445	detailed biochemical and functional analyses have demonstrated that the TIEG2 _-HRM domain interacts specifically with the PAH2 domain of mSin3A to repress transcription. our data suggest the presence of a conserved _-helical repression motif (_-HRM) in the TIEG and BTEB subfamilies of Sp1-like proteins that mediates transcriptional repression activity through interaction with the corepressor mSin3A.	SIGNOR-222434
Q6YBV0	Q6IQ22	relocalization	down-regulates quantity by destabilization	0.445	We also found that Rab12 promotes constitutive degradation of PAT4 (proton‐coupled amino‐acid transporter 4\|Rab12 regulates lysosomal localization or degradation of amino‐acid transporters.	SIGNOR-264763
Q9NS56	P53350	phosphorylation	up-regulates activity	0.445	Plk1-mediated phosphorylation of topors regulates p53 stabilityherein, we have identified topoisomerase i-binding protein (topors), a p53-binding protein, as a plk1 target. We show that plk1 phosphorylates topors on ser(718) in vivo. Significantly, expression of a plk1-unphosphorylatable topors mutant (s718a) leads to a dramatic accumulation of p53 through inhibition of p53 degradation. Topors is an ubiquitin and small ubiquitin-like modifier ubiquitin-protein isopeptide ligase (sumo e3) ligase. Plk1-mediated phosphorylation of topors inhibits topors-mediated sumoylation of p53, whereas p53 ubiquitination is enhanced, leading to p53 degradation.	SIGNOR-185838
P04049	P05771	phosphorylation	up-regulates	0.445	Pkc can effectively phosphorylate raf-1, this is a direct effect of activated pkc and not the result of raf-1 autophosphorylation. the sites of pkc-mediated raf-1 phosphorylation are deduced to be ser497 and ser619.	SIGNOR-37474
P16410	O60674	phosphorylation	up-regulates quantity by stabilization	0.445	Janus Kinase 2 (Jak2) was directly associated with a box 1-like motif in the cytoplasmic tail of CTLA-4 molecule. Jak2 phosphorylated Y-165 residue in the cytoplasmic region of CTLA-4. It has been reported that phosphorylation and dephosphorylation of tyrosine residue Y-165 in the cytoplasmic region of CTLA-4 play an important role in its negative signaling and cell surface expression. Some signaling molecules such as Src homology 2 protein tyrosine phosphatase 2 (SHP-2) and the p85 subunit of phosphatidylinositol 3 kinase (PI3 kinase) associate with phosphorylated tyrosine residue Y-165, through Src homology 2 (SH2) domains. On the other hand, the adapter complex proteins, AP-2 and AP-50 interact with the same tyrosine residue when unphosphorylated, resulting in clathrin-mediated endocytosis of CTLA-4 molecules.	SIGNOR-251346
P45985	Q02779	phosphorylation	up-regulates activity	0.445	MST/MLK2, a member of the mixed lineage kinase family, directly phosphorylates and activates SEK1, an activator of c-Jun N-terminal kinase/stress-activated protein kinase.	SIGNOR-278954
P12931	P23467	dephosphorylation	down-regulates activity	0.445	Collectively, these results suggest that PTPRB inhibits Src activation and down -- regulation of PTPRB activates Src signalling pathway required for cell invasion in A549 cells.\|Knockdown of PTPRB increased Src phosphorylation and cell invasion, which was reversed by Src inhibitor PP2.	SIGNOR-277132
Q13547	P04150	binding	up-regulates	0.445	The GR directly interferes with Hes1 promoter activity, triggering the recruitment of histone deacetylase (HDAC) activities to the Hes1 gene	SIGNOR-253057
Q96PU5	Q96BR1	phosphorylation	down-regulates activity	0.445	Moreover, S422DSGK1, SGK1, and SGK3 also phosphorylated Nedd4-2 and thereby inhibited Nedd4-2 binding to its target.	SIGNOR-280125
P19367	P31749	binding	up-regulates	0.445	The glucose dependence of the antiapoptotic effects of growth factors and akt plus a strong correlation between akt-regulated mitochondrial hexokinase association and apoptotic susceptibility suggest a major role for hexokinases in these effects.	SIGNOR-252495
P63000	Q9P107	gtpase-activating protein	down-regulates activity	0.445	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-260506
Q99836	P12931	phosphorylation	up-regulates activity	0.445	Because MyD88 was phosphorylated at the tyrosine 58 residue in hemi-ITAM by LPS ( xref ), whether Src phosphorylates MyD88 at the tyrosine 58 residue was examined further, and MyD88 was phosphorylated by Src at Y58 ( xref ).\|Src activates MyD88 by phosphorylation at Y58 via the Src kinase domain.	SIGNOR-279655

Q8WXG6

Q8TDJ6

0

binding

up-regulates quantity

0.448

We isolated here a novel protein that was co-immunoprecipitated with Rab3 GEP and GAP by their respective antibodies from the crude synaptic vesicle fraction of rat brain. The protein, named rabconnectin-3, bound both Rab3 GEP and GAP. These results indicate that rabconnectin-3 serves as a scaffold molecule for both Rab3 GEP and GAP on synaptic vesicles.

SIGNOR-265581

P52630

Q5T197

0

ubiquitination

down-regulates activity

0.448

DCST1 promotes ubiquitination of STAT2.|The ability of DCST1 to degrade STAT2 levels was visible both in the presence and absence of IFNbetastimulation.|In our study, DCST1 was found to interact with and promote ubiquitination of STAT2, leading to reduced STAT2 expression and attenuated activation of the ISG induction pathway.

SIGNOR-278747

O75113

P46934

0

monoubiquitination

up-regulates activity

0.448

This observation, together with the monoubiquitination of Nedd4-BP1 by the ubiquitin ligase Nedd4 suggests that the NYN domain proteins of eukaryotes are regulated by monoubiquitination. Given the localization of Nedd4-BP1 to punctuate nuclear bodies, it is likely that they are parts of nuclear RNA-processing complexes that are dependent on monoubiquitination for their assembly.

SIGNOR-272626

P11387

P78527

0

phosphorylation

down-regulates quantity by destabilization

0.448

Here, we show that the Ku70/Ku80 heterodimer binds with topoI, and that the DNA-dependent protein kinase (DNA-PKcs) phosphorylates topoI on serine 10 (topoI-pS10), which is subsequently ubiquitinated by BRCA1.

SIGNOR-277352

P24928

O60885

0

phosphorylation

up-regulates

0.448

We report that brd4 is an atypical kinase that binds to the carboxyl-terminal domain (ctd) of rna polymerase ii and directly phosphorylates its serine 2 (ser2) sites both in vitro and in vivo under conditions where other ctd kinases are inactive. our findings may provide a mechanistic basis for several functional studies that showed that loss of brd4 causes transcription termination and embryonic lethality

SIGNOR-197012

Q9Y566

Q15398

0

relocalization

up-regulates activity

0.448

SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3).

SIGNOR-264598

P38405

P13945

0

binding

up-regulates activity

0.448

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-256896

P27986

P37173

0

binding

up-regulates

0.448

These studies revealed that PI 3-kinase is associated in vivo with both TGF-_ receptor subtypes and that TGF-_1 stimulation enhances PI 3-kinase activity associated with type I TGF-_ receptor in hASM cells.

SIGNOR-227521

P15514

P78536

0

cleavage

up-regulates activity

0.448

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

SIGNOR-259842

P61073

P54578

0

deubiquitination

up-regulates quantity by stabilization

0.448

The physical interaction of CXCR4 and USP14 is paralleled by USP14-catalyzed deubiquitination of the receptor|We also observed that ubiquitination of CXCR4 facilitated receptor degradation, whereas overexpression of USP14 or RNAi-induced knockdown of USP14 blocked CXCL12-mediated CXCR4 degradation

SIGNOR-265057

Q9BYX4

Q6PJ69

0

ubiquitination

up-regulates activity

0.448

These results indicate that TRIM65 promotes MDA5 ubiquitination at lysine 743, which is important for MDA5 activation.

SIGNOR-278535

Q99638

Q9UKI8

0

phosphorylation

up-regulates

0.448

Tlk1b phosphorylates hrad9 at s328 after the induction of dsb, occupancy of rad9 adjacent to the break increased during repair while that of asf1 decreased, and the effect was more pronounced in tlk1b-overexpressing cells. We propose that following genotoxic stress, tlk1/1b is first recruited to the dsb in a complex with rad9. It then exchanges with asf1 to promote nucleosomes eviction at the dsb and access of the repair machinery to unencumbered dna.

SIGNOR-181748

Q99717

P12757

0

binding

down-regulates

0.448

Ski also represses bmp signaling through interactions with smad4 and bmp-specific r-smads, smad1 or smad8.

SIGNOR-95474

Q8WUP2

Q9BQL6

0

binding

up-regulates activity

0.448

Kindlin binds migfilin tandem LIM domains and regulates migfilin focal adhesion localization and recruitment dynamics. Two integrin-binding proteins present in FAs, kindlin-1 and kindlin-2, are important for integrin activation, FA formation, and signaling. By binding filamin, migfilin provides a link between kindlin and the actin cytoskeleton.

SIGNOR-266103

P63096

P28566

0

binding

up-regulates activity

0.448

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-256705

P08754

P30559

0

binding

up-regulates activity

0.448

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-257178

P15941

P43403

0

phosphorylation

up-regulates activity

0.448

Indeed, the present results demonstrate that ZAP-70 phosphorylates MUC1-CD and that the MUC1-CD Y-20 site functions, at least in part, as a ZAP-70 substrate (Fig. 4C). In this regard, the in vivo phosphorylation data indicate that ZAP-70 may also contribute to phosphorylation of MUC1-CD Y-46.The results further show that ZAP-70 phosphorylation of MUC1-CD stimulates the interaction of MUC1 andBeta-catenin.

SIGNOR-247039

P11021

Q99941

0

transcriptional regulation

up-regulates quantity by expression

0.448

Accordingly, N-terminal fragments of each ATF6 isoform (N-ATF6α and N-ATF6β) were overexpressed in HeLa cells and the effects on GRP78 induction were assessed. When expressed at similar levels, N-ATF6α conferred ∼200-fold greater GRP78 promoter activation than N-ATF6β.

SIGNOR-261566

P08754

P28566

0

binding

up-regulates activity

0.448

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-256848

Q9UKL3

Q14790

0

binding

up-regulates

0.448

The caspase-8-binding protein flice-associated huge protein (flash) would form a molecular complex with caspase-8, thereby presumably activating the mitochondrial apoptosis pathway by regulating caspase-8 activity.

SIGNOR-152473

P09471

P08908

0

binding

up-regulates activity

0.447

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-256972

P14598

Q05655

0

phosphorylation

up-regulates

0.447

Pkc alpha, beta ii, delta, and zeta expressed in human neutrophils can individually phosphorylate p47(phox) and induce both its translocation and nadph oxidase activation. The use of p47phox mutants identified serines 303, 304, 315, 320, 328, 359, 370, and 379 as targets of pkc?, ???, And ?.

SIGNOR-89229

O00548

Q8NES3

0

binding

up-regulates

0.447

The modification of notch by fringe would influence binding between the notch receptor and its ligand. It was reported previously that mfng and lfng inhibited notch1-mediated signaling triggered by jagged1 and enhanced that triggered by delta1, and either jagged1- or delta1-triggered notch2 signaling was enhanced by lfng

SIGNOR-107699

Q96AY2

P53350

0

phosphorylation

up-regulates activity

0.447

In human cells, EME1 is phosphorylated by both cyclin-dependent kinases (CDKs) and PLK1, and this modification is directly correlated with increased MUS81 cleavage activity in\u00a0vitro.

SIGNOR-280068

O75602

Q92949

0

transcriptional regulation

up-regulates quantity by expression

0.447

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-266935

P00533

O75159

0

binding

down-regulates quantity

0.447

SOCS5 Can Physically Associate with the EGFR. The complex recruited by SOCS proteins is composed of ElonginBC, Cullin, and Roc1 (15, 16). Together, this complex has E3 ubiquitin ligase activity. We suspect that the role of the SB domain is to mediate coupling of EGFR with the Elongin-Cullin-Roc E3 ubiquitin ligase complex, resulting in enhanced EGFR degradation.

SIGNOR-271516

P49918

P31749

0

phosphorylation

down-regulates

0.447

Cdk inhibitor p57 (kip2) is downregulated by akt during her2-mediated tumorigenicityakt phosphorylates p57 on ser 282 or thr310. Akt activity results in destabilization of p57 by accelerating turnover rate of p57 and enhancing p57 ubiquitination

SIGNOR-252535

Q14207

P24941

0

phosphorylation

up-regulates

0.447

Importantly, mutation of cdk2 phosphorylation sites to alanine abrogates the ability of p220 to activate the histone h2b promoter.

SIGNOR-82141

P20963

Q9Y2R2

0

dephosphorylation

down-regulates activity

0.447

In vitro experiments with purified recombinant proteins demonstrated that PTPN22-D195A/C227S interacted directly with activated Lck, Zap70, and TCRzeta, confirming the initial substrate trap results. Native PTPN22 dephosphorylated Lck and Zap70 at their activating tyrosine residues Tyr-394 and Tyr-493, respectively, but not at the regulatory tyrosines Tyr-505 (Lck) or Tyr-319 (Zap70). Native PTPN22 also dephosphorylated TCRzeta in vitro and in cells, and its substrate trap variant co-immunoprecipitated with TCRzeta when both were coexpressed in 293T cells, establishing TCRzeta as a direct substrate of PTPN22.

SIGNOR-248837

P14416

P43250

0

phosphorylation

down-regulates activity

0.447

GRK6 is located predominantly in dopaminergic neurons [ xref ] and functionally phosphorylates DRD2.

SIGNOR-279046

Q9UBK2

P31749

0

phosphorylation

down-regulates activity

0.447

Here we describe a mechanism by which insulin, through the intermediary protein kinase akt2/protein kinase b (pkb)-beta, elicits the phosphorylation and inhibition of the transcriptional coactivator peroxisome proliferator-activated receptor-coactivator 1alpha (pgc-1alpha), a global regulator of hepatic metabolism during fasting / phosphorylation of pgc-1alpha At ser570 Is required for akt to inhibit recruitment of pgc-1alpha To chromatin.

SIGNOR-252502

P42858

Q00535

0

phosphorylation

up-regulates

0.447

Huntingtin is an antiapoptotic proteinwe show here that huntingtin is phosphorylated by the cyclin-dependent kinase 5 (cdk5) at serines 1181 and 1201. Phosphorylation can be induced by dna damage in vitro and in vivo. The state of huntingtin phosphorylation is a crucial regulator of neuronal cell death. Absence of phosphorylation of huntingtin at serines 1181 and 1201 confers toxic properties to wild-type huntingtin in a p53-dependent manner in striatal neurons and accelerates neuronal death induced by dna damage.

SIGNOR-156840

P15311

P43405

0

phosphorylation

up-regulates activity

0.447

Phospho-SYK has also been shown to specifically activate ezrin upon CD81 engagement.|We found that the activated SYK led to a time dependent phosphorylation of ezrin (pY354 and pThr567) and radixin (pThr564) (XREF_FIG).

SIGNOR-279129

P51991

Q9UHD9

0

binding

up-regulates quantity by stabilization

0.447

We screened a yeast two-hybrid library using the central domain of ubiquilin-2 hoping to identify proteins whose binding is affected by the UBQLN2 mutations.||Additionally, our evidence that ubiquilin-2 is in- volved in stabilizing hnRNPA1 protein

SIGNOR-262272

P24863

Q92585

0

relocalization

up-regulates

0.447

Cycc:cdk8 and cyct1:cdk9/p-tefb are recruited with notch and associated coactivators (mam, skip) to the hes1 promoter in signaling cells.

SIGNOR-130709

Q86T82

P24941

0

phosphorylation

up-regulates activity

0.447

There is positive reinforcement of this signaling mechanism because phosphorylation of Ser628 by CDK2/cyclin E and CDK2/cyclin A complexes produces maximal USP37 activity

SIGNOR-265045

P23528

Q96GD0

0

dephosphorylation

down-regulates activity

0.447

Chronophin, a novel HAD-type serine protein phosphatase, regulates cofilin-dependent actin dynamics|Cofilin is a key regulator of actin cytoskeletal dynamics whose activity is controlled by phosphorylation of a single serine residue. We report the biochemical isolation of chronophin (CIN), a unique cofilin-activating phosphatase of the haloacid dehalogenase (HAD) superfamily.

SIGNOR-248764

P60953

Q9P2F6

0

gtpase-activating protein

down-regulates activity

0.447

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-260474

Q06187

O60674

0

phosphorylation

up-regulates activity

0.447

Jak2 and Lyn coimmunoprecipitated with Btk and phosphorylated Btk on tyrosine (XREF_FIG C).

SIGNOR-279196

P56270

P68400

0

phosphorylation

up-regulates

0.447

Site-specific mutagenesis of maz revealed that the serine residue at position 480 was the major site of phosphorylation by ckii both in vitro and in vivo. Phosphorylation of maz by ckii at this serine residue was required for maximum binding of maz to the pyrimidine-rich dna of the nuclease-hypersensitive element (nhe) in the 5'-end promoter region of the c-myc gene. Mutation of serine at position 480 to alanine eliminated the dna-binding activity of maz to this element.

SIGNOR-70082

O60566

O14757

0

phosphorylation

up-regulates activity

0.447

Nonetheless, in our experimental system a Chk1-dependent BubR1 phosphorylation was also observed after Noc treatment.|Possible requirement of Chk1 in U2OS cells to activate the mitotic spindle checkpoint proteins Mad2 and BubR1.

SIGNOR-280223

P63092

P37288

0

binding

up-regulates activity

0.447

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

SIGNOR-256805

P12830

Q9UQB3

0

binding

up-regulates quantity by stabilization

0.447

To clarify the role of p120 in mammalian cells, we have knocked down p120 with siRNA in cells expressing epithelial (E-), placental (P-), neuronal (N-), and vascular endothelial (VE-) cadherins. We report that each of these cadherins, as well as α- and β-catenins, were rapidly degraded in the absence of p120, resulting in loss of cell–cell adhesion. The effect was clearly dose dependent, indicating that p120 expression levels may directly determine cadherin levels. Degradation of p120-uncoupled cadherin occurred after its arrival at the surface, indicating that p120 regulates cadherin turnover at the level of internalization or recycling. p120 homologues ARVCF and δ-catenin could substitute for p120, so at least one family member is likely required to maintain adhesion. Thus, cadherin complexes are rapidly turned over and degraded in mammalian cells in the absence of direct interaction with p120 or a p120 family member.

SIGNOR-252134

Q96ST3

Q13118

0

binding

up-regulates activity

0.447

detailed biochemical and functional analyses have demonstrated that the TIEG2 _-HRM domain interacts specifically with the PAH2 domain of mSin3A to repress transcription. our data suggest the presence of a conserved _-helical repression motif (_-HRM) in the TIEG and BTEB subfamilies of Sp1-like proteins that mediates transcriptional repression activity through interaction with the corepressor mSin3A.

SIGNOR-222394

P19544

Q6N021

0

binding

up-regulates activity

0.447

In this study, we demonstrate that WT1 binds directly to TET2 and recruits TET2 to specific genomic sites to regulate the expression of WT1 target genes.

SIGNOR-255703

Q8WV24

O14965

0

phosphorylation

down-regulates quantity by destabilization

0.447

Aurora A directly phosphorylates PHLDA1 leading to its degradation. Aurora A phosphorylates PHLDA1 at Ser 98.

SIGNOR-273545

P61586

Q8N103

0

gtpase-activating protein

down-regulates activity

0.447

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-260523

Q13322

P12931

0

phosphorylation

down-regulates

0.447

Grb10 tyrosine phosphorylation was stimulated by expression of constitutively active src or fyn in cells and by incubation with purified src or fyn in vitro. The insulin stimulated or src/fyn-mediated tyrosine phosphorylation in vivo was significantly reduced when grb10 tyrosine 67 was changed to glycine. This mutant form of grb10 bound with higher affinity to the ir in cells than that of the wild-type protein, suggesting that tyrosine phosphorylation of grb10 may normally negatively regulate its binding to the ir.

SIGNOR-78706

P32019

P20339

0

binding

up-regulates activity

0.447

We report that Rab5 acts at the plasma membrane, downstream of ruffling, to promote macropinosome sealing and scission. Rab5 is recruited to plasmalemmal circular ruffles before macropinosome closure. Rab5 effectors Inpp5b, OCRL and APPL1 localize to macropinocytic cups and vesicles, and are required for macropinosome sealing. The mammalian 5-phosphatases Inpp5b and OCRL, which can degrade PtdIns(4,5)P2, are both Rab5-associating effectors implicated in endocytosis and macropinocytosis

SIGNOR-277770

P19086

P25116

0

binding

up-regulates activity

0.447

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-257127

P53350

Q53GT1

0

binding

down-regulates activity

0.446

Here, we identify PLK1 as a target of the cullin 3 (CUL3)-based E3 ubiquitin ligase, containing the BTB adaptor KLHL22, which regulates chromosome alignment and PLK1 kinetochore localization but not PLK1 stability. In the absence of KLHL22, PLK1 accumulates on kinetochores, resulting in activation of the spindle assembly checkpoint (SAC). CUL3-KLHL22 ubiquitylates Lys 492, located within the PBD, leading to PLK1 dissociation from kinetochore phosphoreceptors.

SIGNOR-272108

P00367

Q9Y572

0

binding

up-regulates

0.446

Rip3 directly interacts with glycogen phosphorylase (pygl), glutamate ammonia ligase (glul), and glutamate dehydrogenase 1 (glud1). Rip kinase activity is required to enhance the activities of all three enzymes both in vivo and in vitro.

SIGNOR-187314

P15172

P53778

0

phosphorylation

up-regulates activity

0.446

We determined that p38-gamma directly phosphorylated MyoD on Ser199 and Ser200, which results in enhanced occupancy of MyoD on the promoter of myogenin together with markedly decreased transcriptional activity. Phosphorylation of MyoD by p38-γ directs the assembly of a repressive transcriptional complex at the Myogenin promoter.

SIGNOR-276273

P05771-2

P67775

0

dephosphorylation

down-regulates activity

0.446

Inhibition of PP2A increased phosphorylation at Ser660 that determines calcium sensitivity and activity of PKCbetaII isoform

SIGNOR-248621

Q9UEW8

Q9H4A3

0

phosphorylation

up-regulates

0.446

Activation of wnk1 coincides with the phosphorylation and activation of two wnk1 substrates, namely, the protein kinases ste20/sps1-related proline alanine-rich kinase (spak) and oxidative stress response kinase-1 (osr1).

SIGNOR-151671

P29353

P36888

0

phosphorylation

up-regulates activity

0.446

Intracellular FLT3 signaling involves tyrosine phosphorylation of several cytoplasmic proteins including SHC. We have found that upon FLT3 activation SHC phosphorylation occurs at tyrosine 239/240 and 313.

SIGNOR-251147

P28482

P62136

0

dephosphorylation

down-regulates

0.446

P-erk1/2 proteins were efficiently dephosphorylated in vitro by protein phosphatases 1 and 2a (pp1/2a) and mapk phosphatase 3 (mkp3)

SIGNOR-103152

P10997

P29120

0

cleavage

up-regulates activity

0.446

The processing of proinsulin to insulin occurs in the secretory granules at the C-terminal end of pairs of basic amino acids, Arg31-Arg32 and Lys64-Arg65 [9,10]. Following cleavage, by the prohormone convertases, PC3 (also known as PC1) and PC2, the pair of basic amino acids are removed rapidly by carboxypeptidase E (CPE) to produce the mature insulin molecule

SIGNOR-261782

Q69YH5

Q96GD4

0

phosphorylation

down-regulates activity

0.446

This result demonstrates that the three sites of Repo-Man (Ser-543, Ser-977, and Ser-981) are phosphorylated by Aurora B in early mitosis. We uncover that PP1γ is recruited to mitotic chromosomes by its regulatory subunit Repo-Man in the absence of Aurora B activity and that Aurora B regulates dissociation of PP1γ by phosphorylating and disrupting PP1γ-Repo-Man interactions on chromatin.

SIGNOR-274001

P69891

Q9H165

0

transcriptional regulation

down-regulates quantity by repression

0.446

Our findings reveal that direct γ-globin gene promoter repression by BCL11A underlies hemoglobin switching.

SIGNOR-269067

Q12778

Q13131

0

phosphorylation

up-regulates

0.446

The energy sensor amp-activated protein kinase (ampk) has been shown to directly phosphorylate foxo factors at six regulatory sites that are distinct from the akt.

SIGNOR-157941

P23409

P50461

0

binding

up-regulates activity

0.446

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-241096

Q9BR76

Q8WYL5

0

dephosphorylation

up-regulates

0.446

Coronin 1b inhibits filament nucleation by arp2/3 complex and this inhibition is attenuated by phosphorylation of coronin 1b at serine 2, a site targeted by ssh1l.

SIGNOR-153604

P03372

P00519

0

phosphorylation

up-regulates

0.446

Eralpha can be phosphorylated on two sites, tyrosine 52 (y-52) and tyrosine 219 (y-219). Eralpha phosphorylation by c-abl stabilizes eralpha, resulting in enhanced eralpha transcriptional activity and increased expression of endogenous eralpha target genes.

SIGNOR-163562

Q9H204

P06241

0

phosphorylation

up-regulates

0.446

To unravel the cellular functions of magicin, we used a yeast two-hybrid system and identified fyn tyrosine kinase as a specific binding partner for magicin. Fyn phosphorylates magicin in vitro.

SIGNOR-148700

P63104

Q05655

0

phosphorylation

down-regulates activity

0.446

We confirmed that MAPKAPK2 interacted with and phosphorylated 14-3-3zeta in vitro and in HEK293 cells. | Experimentally, S58D mutation significantly impaired both 14-3-3zeta dimerization and binding to Raf-1.

SIGNOR-249222

P69892

Q9H165

0

transcriptional regulation

down-regulates quantity by repression

0.446

Our findings reveal that direct γ-globin gene promoter repression by BCL11A underlies hemoglobin switching.

SIGNOR-269066

Q15759

O60271

0

binding

up-regulates

0.446

Cdo, jlp, and p38alpha/beta form complexes in differentiating myoblasts, and cdo and jlp cooperate to enhance levels of active p38alpha/beta in transfectants.

SIGNOR-150147

P05771

P67775

0

dephosphorylation

down-regulates activity

0.446

Specifically, the threonine at position 500 (T500) on the activation loop, and T641 and S660 on the carboxyl terminus of protein kinase C beta II are phosphorylated in vivo. T500 and S660 are selectively dephosphorylated in vitro by protein phosphatase 2A to yield an enzyme that is still capable of lipid-dependent activation, whereas all three residues are dephosphorylated by protein phosphatase 1 to yield an inactive enzyme.

SIGNOR-248620

O75379

P68400

0

phosphorylation

up-regulates

0.446

The r-snare vamp4, which contains a dileucine motif, binds to the ap-1 or the ggas. Serine 20 and leucines 25,26 are essential for this binding. Ap-1 association with vamp4 is enhanced when serine 30 is phosphorylated by casein kinase 2. This phosphorylation-dependent modulation of ap-1 binding is mediated by pacs-1 (phosphofurin acidic cluster sorting protein). Ablation of both the dileucine motif and serine 30 results in a dramatic mislocalization of vamp4 in the regulated secretory pathway.

SIGNOR-119090

P39748

P06493

0

phosphorylation

down-regulates activity

0.446

Phosphorylation of human fen1 by cyclin-dependent kinase modulates its role in replication fork regulation.As a functional consequence of phosphorylation by cdk1-cyclin a in vitro, endo- and exonuclease activities of fen1 are reduced whereas its dna binding is not affected.

SIGNOR-103535

Q13950

P31749

0

phosphorylation

down-regulates activity

0.446

Here we show that Akt kinase directly phosphorylates Runx2 to regulate invasive properties of breast cancer cells.

SIGNOR-280176

Q8IZP0

P28482

0

phosphorylation

up-regulates

0.445

Our mass spectrometry also identified abi1 s183 and s225 on abi1 (numbering corresponds to abi1 isoform 1) as sites phosphorylated on endogenous protein and in the wildtype erk-dependent in vitro phosphorylated sample. these data indicate erk phosphorylation of abi1 is required for basal and egf-induced wrc interaction with the wrp2/3 complex.

SIGNOR-172873

P38936

Q16539

0

phosphorylation

up-regulates quantity by stabilization

0.445

The stress-activated protein kinases p38 alpha and jnk1 stabilize p21(cip1) by phosphorylation.|p38 alpha and JNK1 phosphorylated p21 in vivo, and both p38 alpha and JNK1 phosphorylated p21 at Ser(130) in vitro.

SIGNOR-89436

Q8NDV7

Q6PJ69

0

polyubiquitination

down-regulates quantity by destabilization

0.445

Ubiquitination assays demonstrate that TRIM65 is an ubiquitin E3 ligase for TNRC6 proteins. The combination of overexpression and knockdown studies establishes that TRIM65 relieves miRNA-driven suppression of mRNA expression through ubiquitination and subsequent degradation of TNRC6.

SIGNOR-272174

P55075

P10071

0

transcriptional regulation

down-regulates quantity

0.445

Whereas Fgf8 expression was almost absent in Shh-/- mutants, it was up-regulated in Gli3-/-;Shh-/- double mutants, suggesting that SHH is not required for Fgf8 induction, and that GLI3 normally represses Fgf8 independently of SHH

SIGNOR-268949

Q15796

O14595

0

dephosphorylation

down-regulates activity

0.445

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-248299

P24864

P49841

0

phosphorylation

down-regulates

0.445

Our experiments suggest that gsk3 is the kinase primarily responsible for phosphorylation of cyclin e on t380

SIGNOR-118563

P40763

P00519

0

phosphorylation

up-regulates activity

0.445

Previously, we showed that c-Abl and Arg promote phosphorylation of the STAT3 transcription factor (Y705) in a variety of cancer cell lines , .|Since c-Abl and Arg activate STAT3, we investigated whether c-Abl and Arg regulate NF-kappaB signaling.

SIGNOR-279675

Q9H161

Q9UJU2

0

binding

up-regulates quantity by expression

0.445

Alx4 Stably Interacts with LEF-1. LEF-1 enhances Alx4 binding to DNA, suggesting that both interaction with LEF-1 and DNA binding are required to mediate its effects on the N-CAM promoter.

SIGNOR-254547

Q9UBK2

Q6NUN9

0

transcriptional regulation

up-regulates quantity by expression

0.445

PARIS represses the expression of the transcriptional coactivator, PGC-1α and the PGC-1α target gene, NRF-1 by binding to insulin response sequences in the PGC-1α promoter.

SIGNOR-277627

P02458

P03956

0

cleavage

down-regulates quantity by destabilization

0.445

MMP-1 cleaves type II collagen at the peptide bond Gly906-Leu907 Proteolysis of triple-helical collagen is an important step in the progression toward irreversible tissue damage in osteoarthritis. Earlier work on the expression of enzymes in cartilage suggested that collagenase-1 (MMP-1) contributes to the process.

SIGNOR-256341

P52789

P31749

0

phosphorylation

up-regulates activity

0.445

K63-linked ubiquitination enhances the interaction between Akt and HK2 and eventually increases HK2 phosphorylation on Thr473 and mitochondrial localization

SIGNOR-259984

P42224

P45983

0

phosphorylation

up-regulates activity

0.445

SP600125 prevented phosphorylation of STAT1 at Tyr701 site [..] Western blot analysis confirmed that blocking p-JNK using SP600125 markedly reduced STAT3 localization in the nucleus and STAT1 phosphorylation

SIGNOR-251101

O95644

P53779

0

phosphorylation

down-regulates

0.445

We show that jnk, erk, and p38 physically associate with the nfatc n-terminal regulatory domain and can directly phosphorylate functionally important residues involved in regulating nfatc subcellular localization, namely ser(172) and the conserved nfatc ser-pro repeats.

SIGNOR-74556

P49757

O43347

0

binding

down-regulates

0.445

The study confirmed p21(cip1) and numb proteins as targets of musashi1, suggesting additionally p27(kip1) in cell-cycle regulation and jagged-1 in notch .

SIGNOR-165617

Q9BPZ3

O95071

0

polyubiquitination

down-regulates quantity by destabilization

0.445

We demonstrate a mechanism for this co-regulation that involves an E3 ubiquitin ligase, EDD, which targets Paip2 for degradation. PABP depletion by RNA interference (RNAi) causes co-depletion of Paip2 protein without affecting Paip2 mRNA levels. Upon PABP knockdown, Paip2 interacts with EDD, which leads to Paip2 ubiquitination.

SIGNOR-272648

P62140

Q9UD71

0

binding

down-regulates activity

0.445

DARPP-32 (dopamine and cyclic AMP-regulated phospho-protein, relative molecular mass 32,000) is converted into an inhibitor of protein phosphatase 1 when it is phosphorylated by protein kinase A (PKA) at threonine 34.â€šÂ

SIGNOR-264959

Q96ST3

Q13886

0

binding

up-regulates activity

0.445

detailed biochemical and functional analyses have demonstrated that the TIEG2 _-HRM domain interacts specifically with the PAH2 domain of mSin3A to repress transcription. our data suggest the presence of a conserved _-helical repression motif (_-HRM) in the TIEG and BTEB subfamilies of Sp1-like proteins that mediates transcriptional repression activity through interaction with the corepressor mSin3A.

SIGNOR-222434

Q6YBV0

Q6IQ22

0

relocalization

down-regulates quantity by destabilization

0.445

We also found that Rab12 promotes constitutive degradation of PAT4 (proton‐coupled amino‐acid transporter 4|Rab12 regulates lysosomal localization or degradation of amino‐acid transporters.

SIGNOR-264763

Q9NS56

P53350

0

phosphorylation

up-regulates activity

0.445

Plk1-mediated phosphorylation of topors regulates p53 stabilityherein, we have identified topoisomerase i-binding protein (topors), a p53-binding protein, as a plk1 target. We show that plk1 phosphorylates topors on ser(718) in vivo. Significantly, expression of a plk1-unphosphorylatable topors mutant (s718a) leads to a dramatic accumulation of p53 through inhibition of p53 degradation. Topors is an ubiquitin and small ubiquitin-like modifier ubiquitin-protein isopeptide ligase (sumo e3) ligase. Plk1-mediated phosphorylation of topors inhibits topors-mediated sumoylation of p53, whereas p53 ubiquitination is enhanced, leading to p53 degradation.

SIGNOR-185838

P04049

P05771

0

phosphorylation

up-regulates

0.445

Pkc can effectively phosphorylate raf-1, this is a direct effect of activated pkc and not the result of raf-1 autophosphorylation. the sites of pkc-mediated raf-1 phosphorylation are deduced to be ser497 and ser619.

SIGNOR-37474

P16410

O60674

0

phosphorylation

up-regulates quantity by stabilization

0.445

Janus Kinase 2 (Jak2) was directly associated with a box 1-like motif in the cytoplasmic tail of CTLA-4 molecule. Jak2 phosphorylated Y-165 residue in the cytoplasmic region of CTLA-4. It has been reported that phosphorylation and dephosphorylation of tyrosine residue Y-165 in the cytoplasmic region of CTLA-4 play an important role in its negative signaling and cell surface expression. Some signaling molecules such as Src homology 2 protein tyrosine phosphatase 2 (SHP-2) and the p85 subunit of phosphatidylinositol 3 kinase (PI3 kinase) associate with phosphorylated tyrosine residue Y-165, through Src homology 2 (SH2) domains. On the other hand, the adapter complex proteins, AP-2 and AP-50 interact with the same tyrosine residue when unphosphorylated, resulting in clathrin-mediated endocytosis of CTLA-4 molecules.

SIGNOR-251346

P45985

Q02779

0

phosphorylation

up-regulates activity

0.445

MST/MLK2, a member of the mixed lineage kinase family, directly phosphorylates and activates SEK1, an activator of c-Jun N-terminal kinase/stress-activated protein kinase.

SIGNOR-278954

P12931

P23467

0

dephosphorylation

down-regulates activity

0.445

Collectively, these results suggest that PTPRB inhibits Src activation and down -- regulation of PTPRB activates Src signalling pathway required for cell invasion in A549 cells.|Knockdown of PTPRB increased Src phosphorylation and cell invasion, which was reversed by Src inhibitor PP2.

SIGNOR-277132

Q13547

P04150

0

binding

up-regulates

0.445

The GR directly interferes with Hes1 promoter activity, triggering the recruitment of histone deacetylase (HDAC) activities to the Hes1 gene

SIGNOR-253057

Q96PU5

Q96BR1

0

phosphorylation

down-regulates activity

0.445

Moreover, S422DSGK1, SGK1, and SGK3 also phosphorylated Nedd4-2 and thereby inhibited Nedd4-2 binding to its target.

SIGNOR-280125

P19367

P31749

0

binding

up-regulates

0.445

The glucose dependence of the antiapoptotic effects of growth factors and akt plus a strong correlation between akt-regulated mitochondrial hexokinase association and apoptotic susceptibility suggest a major role for hexokinases in these effects.

SIGNOR-252495

P63000

Q9P107

0

gtpase-activating protein

down-regulates activity

0.445

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-260506

Q99836

P12931

0

phosphorylation

up-regulates activity

0.445

Because MyD88 was phosphorylated at the tyrosine 58 residue in hemi-ITAM by LPS ( xref ), whether Src phosphorylates MyD88 at the tyrosine 58 residue was examined further, and MyD88 was phosphorylated by Src at Y58 ( xref ).|Src activates MyD88 by phosphorylation at Y58 via the Src kinase domain.

SIGNOR-279655