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
Q06187	P42336	phosphorylation	up-regulates activity	0.514	Activation of Btk occurs by transphosphorylation of tyrosine 551 in the catalytic domain, resulting in a dramatic increase in the catalytic activity of the kinase (11, 12, 13). This allows for autophosphorylation at tyrosine 223 in the SH3 domain (14). Both Lyn and Syk have been demonstrated to be involved in BCR-mediated Btk activation (11), but processes that drive colocalization of these kinases are ill-defined. Recently, it was suggested that phosphatidylinositol 3-kinase (PI3-K) is also involved in Btk activation	SIGNOR-249610
Q9BUB5	P67775	dephosphorylation	down-regulates	0.514	Moreover, a dephosphorylation assay revealed that pp2a could directly dephosphorylate mnk1 and eif4e.	SIGNOR-168314
P28069	Q969G2	transcriptional regulation	up-regulates quantity by expression	0.514	We show that normal LHX4 binds to a human-specific element and subsequently activates transcription from the proximal upstream regulatory sequence of POUIF1, a gene encoding a POU homeodomain transcription factor known as the main regulator of GH expression.	SIGNOR-266056
P61586	Q8WZ64	gtpase-activating protein	down-regulates activity	0.514	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-260453
P15976	P31749	phosphorylation	up-regulates	0.514	We found that akt directly phosphorylates the transcription factor gata-1 at serine 310 and that this site-specific phosphorylation is required for the transcriptional activation of the timp-1 promoter.	SIGNOR-139782
P08754	P35372	binding	up-regulates activity	0.513	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-256854
P37231	P00533	phosphorylation	down-regulates quantity by destabilization	0.513	Here, we found that nuclear EGFR induced phosphorylation of PPARγ at Tyr-74 leading to PPARγ ubiquitination and degradation by mouse double minute 2 (MDM2) ubiquitin ligase.	SIGNOR-277190
Q96GX5	P06493	phosphorylation	up-regulates activity	0.513	We propose a model in which the initiating event for Gwl activation is phosphorylation by MPF of the proline-directed sites T193 and T206 in the presumptive activation loop	SIGNOR-249653
P35916	P12931	phosphorylation	up-regulates	0.513	Vegfr-3 is a direct c-src target and mass spectrometry analysis identified the sites phosphorylated by c-src as tyrosine 830, 833, 853, 1063, 1333, and 1337 vegfr-3 phosphorylation activates the recruitment to the receptor of the adaptor proteins crki/ii and shc inducing activation of jnk.	SIGNOR-165035
O60674	P28482	phosphorylation	down-regulates	0.513	We hypothesize that phosphorylation of ser523 in jak2 by erks 1 and/or 2 or other as-yet-unidentified kinases acts in a negative feedback manner	SIGNOR-236331
P55211	P00519	phosphorylation	up-regulates	0.513	C-abl phosphorylates casp9 on tyr-153 in vitro and in vivo in response to dna damage.The Present results demonstrate that c-abl binds directly to casp9.	SIGNOR-133260
P00519	P78527	phosphorylation	up-regulates activity	0.513	We show that DNA-PK phosphorylates and activates c-Abl in vitro.	SIGNOR-279268
O00418	Q15418	phosphorylation	down-regulates activity	0.513	We show that two such kinases, p70 s6 kinase (regulated via mtor) and p90(rsk1) (activated by erk), phosphorylate eef2k at a conserved serine and inhibit its activity	SIGNOR-109708
Q86YS7	P31751	phosphorylation	up-regulates activity	0.513	MS analysis of an HA-CDP138 sample from the in vitro kinase assay revealed that active Akt2 induces CDP138 phosphorylation at serine (Ser)197, which lies within a consensus Akt substrate motif RQRLIS 197 ( xref ).	SIGNOR-279585
Q00613	Q9UQM7	phosphorylation	up-regulates activity	0.513	Ser230 is located in the regulatory domain of HSF1, and promotes the magnitude of the inducible transcriptional activity. Ser230 lies within a consensus site for calcium/calmodulin-dependent protein kinase II (CaMKII), and CaMKII overexpression enhances both the level of in vivo Ser230 phosphorylation and transactivation of HSF1. The importance of Ser230 was further established by the S230A HSF1 mutant showing markedly reduced activity relative to wild-type HSF1 when expressed in hsf1(-/-) cells.	SIGNOR-250631
P63279	P06493	phosphorylation	up-regulates activity	0.512	Overall, these results suggest that Cdk1 and cyclin B mediates the phosphorylation of Ubc9 at serine 71.	SIGNOR-278174
P35240	Q13177	phosphorylation	down-regulates	0.512	Merlin contains a c-terminal serine 518, which is phosphorylated both by p21-activated kinase (pak) and protein kinase a (pka) (shaw et al., 2001;kissil et al., 2002;xiao et al., 2002;alfthan et al., 2004). Phosphorylation at this site is predicted to result in a more open conformation incapable of inhibiting cell growth,	SIGNOR-159768
P60953	Q9P107	gtpase-activating protein	down-regulates activity	0.512	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-260507
P35568	Q8WWQ0	binding	up-regulates activity	0.512	We have recently reported the isolation of a PH domain-interacting protein, PHIP, which selectively binds to the IRS-1 PH domain and is stably associated with IRS-1 in mammalian cells. Here we demonstrate that overexpression of PHIP in fibroblasts enhances insulin-induced transcriptional responses in a mitogen-activated protein kinase-dependent manner.	SIGNOR-266962
Q9NPA3	Q92748	binding	down-regulates activity	0.512	In the current study, we have determined the crystal structure of mouse S14 to 2.65-Å resolution. The structure of S14 reveals a helical protein arranged as a symmetric dimer. Cultured cell experiments indicate that S14 can form heterodimers with MIG12, suggesting a mechanism through which S14 could modulate ACC activity and subsequently rates of fatty acid synthesis via heterodimer formation with MIG12.In the current study, we have shown that regulating the levels of S14∶MIG12 heterodimers regulates the ability of MIG12 to activate ACC. Increasing S14∶MIG12 heterodimers by the overexpression of S14 resulted in decreased ACC activity and polymerization, whereas decreasing S14∶MIG12 heterodimers by knockdown of S14 increased ACC activity and polymerization.	SIGNOR-267113
Q969P5	P15173	binding	down-regulates activity	0.512	Myogenin had a MAFbx-recognition motif and interacted with MAFbx. MAFbx activated polyubiquitination of myogenin. The results of this study suggest that MAFbx functions as an F-box protein for ubiquitination of myogenin.	SIGNOR-237854
P63092	P47871	binding	up-regulates activity	0.512	Glucagon signals through its receptor on the cell surface (Fig.1). The binding of glucagon to the extracellular loops of the glucagon receptor results in conformational changes of the latter, leading to subsequent activation of the coupled G proteins. At least two classes of G proteins are known to be associated with and involved in the signal transduction of the glucagon receptor, namely Gsα and Gq. The activation of Gsα leads to activation of adenylate cyclase, increase in intracellular cAMP levels, and subsequent activation of protein kinase A (PKA).	SIGNOR-267715
Q13541	Q13315	phosphorylation	down-regulates	0.512	Here we report that atm... phosphorylates 4e-bp1 at ser 111cells lacking atm kinase activity exhibit a significant decrease in the insulin-induced dissociation of 4e-bp1 from eif-4e.	SIGNOR-85619
Q7LG56	Q13315	phosphorylation	up-regulates	0.512	Atm-mediated serine 72 phosphorylation stabilizes ribonucleotide reductase small subunit p53r2 protein against mdm2 to dna damage	SIGNOR-182423
P29992	P30556	binding	up-regulates activity	0.512	The angiotensin II type 1 receptor (AT1 R) is a G q/11-coupled G protein-coupled receptor that is widely expressed in multiple tissues, including vascular smooth muscle cells, brain, and kidney.	SIGNOR-278125
Q15642	Q99996	binding	up-regulates activity	0.512	Mechanistically, AKAP-9 interacted with cdc42 interacting protein 4 (CIP4) and regulated its expression. CIP4 levels were interrelated to the AKAP-9 level in CRC cells. Functionally, AKAP-9 was essential for TGF-β1-induced epithelial-mesenchymal transition of CRC cells, and CIP4 played a critical role in mediating the function of AKAP-9. Importantly, CIP4 expression was significantly up-regulated in human CRC tissues.\|Co-immunoprecipitation assay revealed that AKAP-9 and CIP4 physically interacted with each other in Lovo and HT29 cells (Fig. 4B and C).	SIGNOR-260303
P18846	Q14012	phosphorylation	up-regulates activity	0.512	Phosphopeptide mapping analysis and Western blotting studies demonstrated that in vitro, CaMK II phosphorylates only Ser63 (corresponding to Ser133 of CREB), which is essential for the activation, and not Ser72 (corresponding to Ser142 of CREB), which is a negative regulation site.	SIGNOR-250611
P05412	Q99986	phosphorylation	up-regulates	0.512	Vrk1 phosphorylates c-jun in ser63 and ser73 in vitro...VRK1 Activates c-jun dependent transcription	SIGNOR-127073
O14965	P17612	phosphorylation	up-regulates activity	0.512	Aurora2 is regulated by phosphorylation. phosphorylation occurs on a conserved residue, Threonine 288, within the activation loop of the catalytic domain of the kinase and results in a significant increase in the enzymatic activity. Threonine 288 resides within a consensus motif for the cAMP dependent kinase and can be phosphorylated by PKA in vitro.	SIGNOR-250337
P20749	Q9NQC7	deubiquitination	down-regulates	0.512	Cyld binds and deubiquitinates bcl-3in cyld+/+ keratinocytes, tpa or uv light triggers the translocation of cyld from the cytoplasm to the perinuclear region, where cyld binds and deubiquitinates bcl-3, thereby preventing nuclear accumulation of bcl-3 and p50/bcl-3- or p52/bcl-3-dependent proliferation.	SIGNOR-146774
P19419	P45983	phosphorylation	up-regulates activity	0.512	However, both of these stimuli strongly activate two other mapks, jnk1 and jnk2, and stimulate elk-1 transcriptional activity and phosphorylation jnk phosphorylation sites include ser383 and ser389, the major residues whose phosphorylation is responsible for enhancement of elk-1 trascriptional activity.	SIGNOR-236432
O94875	P22681	ubiquitination	down-regulates	0.512	Cbl-argbp2 complex mediates ubiquitination and degradation of c-abl	SIGNOR-96325
P50221	P15863	binding	up-regulates activity	0.512	We show that Mox1 and Mox2 proteins are capable of interacting with Pax1 and Pax3. We propose that the Mox family of homeodomain proteins participates in the molecular signaling network regulating the diverse events of somite development through the physical interaction with the Pax1 and Pax3 members of the Pax family.	SIGNOR-222193
P32927	Q06124	dephosphorylation	up-regulates	0.511	Shp2 is thought to act as a positive mediator of growth factor signals.. Hp2 could act as an adaptor between the activated c and grb2, thus leading to activation of the ras/mitogen-activated protein kinase pathway, known to be activated by il-3	SIGNOR-48557
P04150	Q16539	phosphorylation	up-regulates	0.511	We found serine 211 of the human gr to be a substrate for p38 mapk both in vitro and intracellularly. Mutation of this site to alanine greatly diminished gr-driven gene transcription and apoptosis.	SIGNOR-135198
P23025	Q96EB6	deacetylation	up-regulates activity	0.511	SIRT1 deacetylates XPA at residues K63, K67, and K215 to promote interactions with ATR	SIGNOR-262294
P42345	O15111	phosphorylation	up-regulates activity	0.511	In those studies, we found that IKKalpha interacts with and phosphorylates mTOR in the mTORC1 complex to activate mTORC1, and that Akt signaling drives the IKKalpha-mTORC1 interaction.\|We then studied whether IKKalpha promotes Akt and mTOR activity in other mammalian cancer cell lines.	SIGNOR-279607
O14950	O43293	phosphorylation	up-regulates	0.511	Hzipk phosphorylated the regulatory light chain of myosin ii (mrlc) at both ser19 and thr18 in vitro. Phosphorylation of mrlc is required to generate the driving force in the migration of the cells but not necessary for localization of myosin ii at the leading edge.	SIGNOR-16043
O43306	P08754	binding	down-regulates activity	0.511	Types V and VI adenylyl cyclase are most sensitive to inhibition by Gnai1, Gnai2, and Gnai3	SIGNOR-278079
P78317	Q9HBE1	binding	down-regulates	0.511	In vitro and in vivo interaction between rnf4 and patz was demonstrated / patz acted as a transcriptional repressor, whereas its partner rnf4 behaved as a transcriptional activator./ the association of patz with rnf4 switches activation to repression	SIGNOR-75775
Q13485	P28482	phosphorylation	up-regulates	0.511	Phosphorylation of thr276 is shown to be important for tgf-?-Induced nuclear accumulation and, as a consequence, transcriptional activity of smad4. these results suggest that smad4 can be phosphorylated by erk2 at thr276.	SIGNOR-101660
Q12778	P06493	phosphorylation	down-regulates	0.511	Overexpression of cdk1 inhibits the transcriptional activity of foxo1 in pca cells through s249 phosphorylation on foxo1.	SIGNOR-178202
Q96LB1	O00230	binding	up-regulates	0.511	The mrgx2 receptor has been shown to be activated by the peptides cortistatin and proadrenomedullin n-terminal peptides (pamp)	SIGNOR-139855
P63096	P08172	binding	up-regulates activity	0.511	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-256685
Q96R06	O14965	phosphorylation	up-regulates activity	0.511	We report here that Astrin acts as a mitotic phosphoprotein, and Aurora-A phosphorylates Astrin at Ser(115). The phosphorylation-deficient mutant Astrin S115A abnormally activates spindle assembly checkpoint and delays mitosis progression, decreases spindle stability, and induces chromosome misalignment. Mechanistic analyses reveal that Astrin phosphorylation mimicking mutant S115D, instead of S115A, binds and induces ubiquitination and degradation of securin, which sequentially activates Separase, an enzyme required for the separation of sister chromatids.	SIGNOR-276648
P41968	P42127	binding	down-regulates activity	0.511	The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and alpha, beta, and gamma melanocyte-stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins	SIGNOR-268703
Q14247	Q8WZ74	binding	up-regulates activity	0.511	Fluorescence recovery after photobleaching further suggested that CTTNBP2 modulates the mobility of cortactin in neurons. CTTNBP2 may thus help to immobilize cortactin in dendritic spines and control the density of dendritic spines.	SIGNOR-269703
P60953	Q92502	gtpase-activating protein	down-regulates activity	0.511	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-260520
P15172	P11802	binding	down-regulates	0.511	In contrast to cdk2, cyclin d/cdk4 blocks myod activity through an as yet unclear mechanism that may involve direct binding. Cyclin d/cdk4 can also block the activity of myogenin and all mef2 isoforms.	SIGNOR-176527
P16298	P0DP24	binding	up-regulates	0.511	Calcium-bound calmodulin associates with calcineurin (cn), releasing the phosphatase from the repressive effects on an autoinhibitory domain.	SIGNOR-266322
P24385	Q8N3Y1	binding	down-regulates quantity by destabilization	0.511	We next investigated whether in vitro ubiquitination of cyclin D1 through the SCF-like (SCFL) complex FBXW8 (SKP1-CUL7-FBXW8-RBX1/SCFLFBXW8) requires phosphorylation of cyclin D1 at Thr286 (Fig. 3F). Polyubiquitination through SCFLFBXW8 was dramatically reduced by the depletion of ERK2 (lane 2). Furthermore, cyclin D1 polyubiquitination was largely prevented by the alanine-for-Thr286 substitution (T286A, lane 3), suggesting that phosphorylation of cyclin D1 at Thr286 is necessary for ubiquitination by SCFLFBXW8.	SIGNOR-271624
P10275	P28482	phosphorylation	down-regulates	0.511	Map kinase-dependent phosphorylation at ar ser-515 was supported by the decrease in intensity of the slower migrating 23-kda band after treatment with both egf and increasing concentrations of the map kinase inhibitor, u0126	SIGNOR-178718
P19086	P35372	binding	up-regulates activity	0.51	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-257106
Q93009	O15355	dephosphorylation	down-regulates quantity by destabilization	0.51	We find that stabilization of Mdm2, and correspondingly p53 downregulation in unstressed cells, is accomplished by a specific isoform of USP7 (USP7S), which is phosphorylated at serine 18 by the protein kinase CK2. \|After ionizing radiation, dephosphorylation of USP7S by the ATM-dependent protein phosphatase PPM1G leads to USP7S downregulation, followed by Mdm2 downregulation and accumulation of p53.	SIGNOR-276531
P05412	Q02930	binding	up-regulates activity	0.51	CRE-BPa specifically binds to CRE as a homodimer or heterodimer with c-Jun or CRE-BP1. In CAT cotransfection experiments using CV-1 cells, transient expression of each of four CRE-BPa proteins caused a 1.6- to 3.4-fold increase of CRE-dependent transcription	SIGNOR-219634
Q9Y2D9	O75081	binding	down-regulates activity	0.51	Previously we reported that a classical C2H2 zinc finger DNA binding protein ZNF652 functionally interacts with CBFA2T3 to repress transcription of genes containing ZNF652 consensus DNA binding sequence within the promoters of these target genes.	SIGNOR-253954
Q9H257	Q9BVG3	ubiquitination	up-regulates activity	0.51	Importantly, using in vitro ubiquitination assays with purified proteins, we verified that CARD9 is directly ubiquitinated by TRIM62 at residue K125; this ubiquitination is dependent on the ligase activity of TRIM62 and does not occur in CARD9 Delta11 (XREF_FIG).	SIGNOR-278552
O00429	Q13546	phosphorylation	up-regulates activity	0.51	RIPK1 also activates DRP1 by phosphorylating DRP1 at Ser616 in a RIPK3-dependent fashion independent of MLKL.	SIGNOR-280104
P49768	Q00535	phosphorylation	up-regulates	0.51	Cyclin-dependent kinase-5/p35 phosphorylates presenilin 1 to regulate carboxy-terminal fragment stabilityhere we demonstrate that cyclin dependent kinase-5/p35 (cdk5/p35) phosphorylates ps1 on threonine(354) within c-ps1 both in vitro and in vivo. Threonine(354) phosphorylation functions to selectively stabilize c-ps1.	SIGNOR-89145
Q9UQL6	Q16566	phosphorylation	down-regulates	0.51	Recently, camkiv, a calcium-calmodulindependent protein kinase, was also shown to activate mef2s by dissociating class ii histone deacetylases (e.g., Hdac5) from mef2s, thus relieving the transcriptional repressive effect of hdacs.	SIGNOR-236571
Q9NYV4	P50613	phosphorylation	up-regulates activity	0.51	Although Cdk12/CycK kinase complex lacking T-loop phosphorylation showed some basal activity towards a CTD substrate prephosphorylated at position Ser7, its activity was significantly increased upon coexpression with the CAK from S. cerevisiae (Supplementary Fig. 9a). Mutation of T893 to E to mimic phosphorylation showed no effect on basal kinase activity. Quantitative phosphorylation of a single residue occurred upon coexpression with Cak1, as determined by ESI mass spectrometry (Supplementary Fig. 9b).	SIGNOR-275509
P54252	Q9UNE7	ubiquitination	down-regulates quantity by destabilization	0.51	Although our data show that CHIP may associate with Atx3 to ubiquitinate Atx3 in vitro, we still wonder whether CHIP is directly involved in the degradation of Atx3.\|As a result, silencing of CHIP significantly increases the amount of Atx3 (XREF_FIG), suggesting that CHIP may down-regulate the Atx3 level.	SIGNOR-278667
O15350	P53350	phosphorylation	down-regulates	0.51	P73-mediated transcriptional activity is negatively regulated by polo-like kinase 1. tap73 is phosphorylated by this kinase on threonine-27 (thr-27) within the ta domain.	SIGNOR-178253
P16949	Q8TAS1	phosphorylation	down-regulates	0.51	This promigratory phenotype resulted from increased stathmin protein levels, caused by a lack of kis-mediated stathmin phosphorylation at serine 38 and diminished stathmin protein degradation.	SIGNOR-182489
P02545	P12931	phosphorylation	up-regulates activity	0.51	In this study, we found that the constitutively active Src Y527F mutant caused the disassembly of lamin A/C. We demonstrate that Src directly phosphorylates lamin A mainly at Tyr45 both in vitro and in intact cells.	SIGNOR-279288
O75051	Q99985	binding	up-regulates activity	0.51	Genes encoding the neurovascular guiding molecule semaphorin 3C (SEMA3C) and its receptor plexin A2 (PLXNA2) appear to be regulated directly by GATA6, and both GATA6 mutant proteins failed to transactivate these genes.	SIGNOR-253151
O75496	O14965	phosphorylation	up-regulates activity	0.51	Aurora-A controls pre-replicative complex assembly and DNA replication by stabilizing geminin in mitosis.\|Thr25 of geminin is phosphorylated by Aurora-A.	SIGNOR-278509
O75449	Q92630	phosphorylation	down-regulates quantity by destabilization	0.509	DYRK2 mediated phosphorylation is required for Katanin p60 degradation. Serine 42, serine 109 and threonine 133 are likely to be the major DYRK2 phosphorylation sites as single mutations for these sites showed reduced phosphorylation by DYRK2 and the triple mutant showed almost no DYRK2 mediated phosphorylation (Fig. 5d).	SIGNOR-262847
P35222	P55289	binding	up-regulates activity	0.509	At its C-terminus, cadherin interacts with Î²-catenin, which dynamically associates with Î±-catenin, a direct binding partner of filamentous actin	SIGNOR-265852
Q9UQ80	Q05655	phosphorylation	up-regulates	0.509	Trk receptor activation by both ngf and bdnf induced phosphorylation of ebp1 at the s360 upon the activation of protein kinase c (pkc ) and triggered dissociation of p48 from retinoblastoma (rb	SIGNOR-170348
P55072	P31749	phosphorylation	up-regulates	0.509	Site-directed mutagenesis identified ser-351, ser-745, and ser-747 as akt phosphorylation sites on vcp. however, our study also suggests that other known biological activities of vcp, such as those related to intracellular trafficking, ubiquitin-mediated proteolysis, and activation of transcription (28), might be regulated by akt through the activation of vcp. I	SIGNOR-252491
P42568	O00141	phosphorylation	down-regulates activity	0.509	In addition to Nedd4-2, Sgk1 also phosphorylates Af9, forkhead like transcription factor FOXO3a and several other substrates.\|Sgk1 impairs the ability of Af9 to interact with Dot1a at these subregions without impacting Af9 DNA binding activity, leading to targeted histone H3 K79 hypomethylation.	SIGNOR-279111
Q9P055	Q99942	ubiquitination	down-regulates activity	0.509	RNF5 is a ubiquitin ligase anchored to the ER membrane implicated in ERAD via ubiquitination of misfolded proteins. This association results in Ubc13-dependent RNF5-mediated noncanonical ubiquitination of JAMP. This ubiquitination does not alter JAMP stability but rather inhibits its association with Rpt5 and p97.	SIGNOR-271483
O95863	Q9UKA1	binding	down-regulates quantity by destabilization	0.509	FBXL5 is located in the nucleus where it interacts with Snail1 promoting its polyubiquitination and affecting Snail1 protein stability and function by impairing DNA binding. Snail1 is ubiquitinated by the SCFFBXL5 complex. Snail1 downregulation by FBXL5 is prevented by Lats2, a protein kinase that phosphorylates Snail1 precluding its nuclear export but not its polyubiquitination. To demonstrate that FBXL5 has a direct activity on Snail1, we carried out polyubiquitination reactions in vitro. For this we purified Snail1 and the SCFFBXL5 complex from Sf9 insect cells infected with different baculoviruses corresponding to Flag-FBXL5, His-Skp1, HA-Cullin1 and Rbx1 (Supplementary Figure S3C).	SIGNOR-272135
O94761	Q7L590	binding	down-regulates	0.509	Mcm10 inhibits recq4 helicase activity.	SIGNOR-187701
P03372	P31751	phosphorylation	up-regulates activity	0.509	AKT activate ERalpha in the absence of estrogen. The consensus AKT phosphorylation site Ser-167 of ERalpha is required for phosphorylation and activation by AKT.	SIGNOR-251490
P27694	Q9UMS4	polyubiquitination	up-regulates activity	0.509	PRP19 is a ubiquitin ligase involved in pre-mRNA splicing and the DNA damage response (DDR). PRP19 ubiquitylates RPA and promotes ATRIP recruitment.	SIGNOR-272076
P11142	Q9NXW2	binding	up-regulates activity	0.509	JB12 cooperates with cytosolic Hsc70 and the ubiquitin ligase RMA1 to target CFTR and CFTRΔF508 for degradation. JB12 drives Hsc70 to associate with CFTR and the RMA1 E3 complex	SIGNOR-271491
P19838	P17612	phosphorylation	up-regulates	0.509	In this study, we demonstrate that the phosphorylation of p50 and p65 by the catalytic subunit of protein kinase a (pkac) is essential for nf-kappab dna binding and transactivation activity. treatment with h89 and knockdown of pkac in cells led to the inhibition of phosphorylation at p50 ser(337) and p65 ser(276) and loss of dna binding by nf-kappab.	SIGNOR-158595
O75962	Q05397	phosphorylation	up-regulates activity	0.509	A FAK phosphorylation site, tyrosine residue 2737, was identified in subdomain I of the Trio kinase domain. Additionally, in vitro phosphorylation assays and in vivo co-expression studies indicated that Trio enhances FAK kinase activity.	SIGNOR-249188
P38405	P21918	binding	up-regulates activity	0.509	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-256914
P30679	P32239	binding	up-regulates activity	0.509	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-257412
P35222	P49789	binding	down-regulates	0.509	Fhit interacts with _-catenin in vitro and in vivo / the tumor suppressor fhit acts as a repressor of _-catenin transcriptional activity	SIGNOR-159873
O15151	P31749	phosphorylation	up-regulates quantity by stabilization	0.509	We demonstrate that the serine/threonine kinase akt mediates phosphorylation of mdmx at ser367. This phosphorylation leads to stabilization of mdmx and consequent stabilization of mdm2.	SIGNOR-252517
Q92835	P07948	phosphorylation	up-regulates activity	0.509	In this line, Lyn has been demonstrated to tyrosine-phosphorylate and activate SHIP1, thereby constituting a negative feedback control of PI3K-mediated signals.	SIGNOR-279060
P42356	Q9Y2G0	binding	up-regulates quantity	0.509	PI4KA is recruited to plasma membrane by the adapter protein EFR3, which has two isoforms, EFR3A and EFR3B	SIGNOR-269093
Q06609	P53350	phosphorylation	up-regulates activity	0.508	Mechanistically, TOPBP1 physically binds PLK1 and promotes PLK1 kinase-mediated phosphorylation of RAD51 at serine 14, a modification required for RAD51 recruitment to chromatin.\|Mechanistically, TOPBP1 physically binds PLK1 and promotes PLK1 kinase\u2013mediated phosphorylation of RAD51 at serine 14, a modification required for RAD51 recruitment to chromatin.	SIGNOR-278187
Q9NYV6	P24941	phosphorylation	up-regulates	0.508	Cdk2/cyclin e-mediated phosphorylation at ser 44 activates tif-ia	SIGNOR-123231
P31327	Q9NXA8	post translational modification	up-regulates activity	0.508	Glutarylation suppresses CPS1 activity, which is targeted by SIRT5 for removal\|SIRT5 can catalyze the enzymatic removal of lysine glutarylation	SIGNOR-267643
P15927	P06493	phosphorylation	up-regulates activity	0.508	Cdc2 family kinases phosphorylate a human cell dna replication factor, rpa, and activate dna replication. therefore, the serines on rpa p34 that were necessary for phosphorylation by cdc2 kinase were also necessary for phosphorylation in the cell	SIGNOR-16975
Q9NX09	Q9H3M7	binding	up-regulates quantity by stabilization	0.508	In the present study, we identify TXNIP that inhibits mTOR activity by binding to and stabilizing Redd1 protein.	SIGNOR-277470
P27361	Q9BRX9	binding	up-regulates	0.508	Morg1 specifically associates with several components of the erk pathway, including mp1, raf-1, mek, and erk, and stabilizes their assembly into an oligomeric complex.	SIGNOR-124473
Q14994	Q15466	binding	down-regulates	0.508	The short heterodimer partner (shp), an orphan nuclear receptor that lacks a conventional dna binding domain, was initially identified by its interaction with car. We have examined the role of shp in car-mediated transactivation of the cyp2b gene. Coexpression of shp inhibited the transactivation of the cyp2b gene by car in cultured hepatoma cells and the p160 coactivator grip1 reversed the inhibition.	SIGNOR-123154
O95477	P17612	phosphorylation	up-regulates activity	0.508	Ser-1042 and Ser-2054, located in the nucleotide binding domains of ABCA1, are major phosphorylation sites for PKA. ABCA1 phosphorylation may affect ApoA-I-dependent phospholipid efflux by either altering the conformation of the protein to a more active state or by affecting the interaction between ABCA1 and its partner proteins.	SIGNOR-250326
P01112	Q92565	guanine nucleotide exchange factor	up-regulates	0.508	Gefs catalyse the transition from gdp-bound, inactive ras to gtp-bound, active ras.	SIGNOR-183732
P35222	Q8N752	phosphorylation	down-regulates	0.508	We show that a complex of axin and casein kinase i (cki) induces beta-catenin phosphorylation at a single site: serine 45 (s45).	SIGNOR-87430
Q9H6R0	Q9P275	deubiquitination	up-regulates quantity by stabilization	0.508	Loss of the deubiquitinase USP36 destabilizes the RNA helicase DHX33 and causes preimplantation lethality in mice.	SIGNOR-272289
O00470	P28356	binding	up-regulates activity	0.508	We find that DNA binding by MEIS1A is absolutely required for the formation of a cooperative complex with HOXD9	SIGNOR-220721
Q4V328	Q9Y3R0	binding	up-regulates activity	0.508	We have identified several GRIP-associated proteins (GRASPs) that bind to distinct PDZ domains within GRIP. GRASP-1 is a neuronal rasGEF associated with GRIP and AMPA receptors in vivo. GRIP1 has seven PDZ domains, which mediate protein–protein interactions, allowing the recruitment of GRASP-1 to a large signal-transducing complex	SIGNOR-260638
P49448	Q9Y6E7	glycosylation	down-regulates activity	0.508	We show that SIRT4 is a mitochondrial enzyme that uses NAD to ADP-ribosylate and downregulate glutamate dehydrogenase (GDH) activity.	SIGNOR-268559

Q06187

P42336

0

phosphorylation

up-regulates activity

0.514

Activation of Btk occurs by transphosphorylation of tyrosine 551 in the catalytic domain, resulting in a dramatic increase in the catalytic activity of the kinase (11, 12, 13). This allows for autophosphorylation at tyrosine 223 in the SH3 domain (14). Both Lyn and Syk have been demonstrated to be involved in BCR-mediated Btk activation (11), but processes that drive colocalization of these kinases are ill-defined. Recently, it was suggested that phosphatidylinositol 3-kinase (PI3-K) is also involved in Btk activation

SIGNOR-249610

Q9BUB5

P67775

0

dephosphorylation

down-regulates

0.514

Moreover, a dephosphorylation assay revealed that pp2a could directly dephosphorylate mnk1 and eif4e.

SIGNOR-168314

P28069

Q969G2

0

transcriptional regulation

up-regulates quantity by expression

0.514

We show that normal LHX4 binds to a human-specific element and subsequently activates transcription from the proximal upstream regulatory sequence of POUIF1, a gene encoding a POU homeodomain transcription factor known as the main regulator of GH expression.

SIGNOR-266056

P61586

Q8WZ64

0

gtpase-activating protein

down-regulates activity

0.514

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-260453

P15976

P31749

0

phosphorylation

up-regulates

0.514

We found that akt directly phosphorylates the transcription factor gata-1 at serine 310 and that this site-specific phosphorylation is required for the transcriptional activation of the timp-1 promoter.

SIGNOR-139782

P08754

P35372

0

binding

up-regulates activity

0.513

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-256854

P37231

P00533

0

phosphorylation

down-regulates quantity by destabilization

0.513

Here, we found that nuclear EGFR induced phosphorylation of PPARγ at Tyr-74 leading to PPARγ ubiquitination and degradation by mouse double minute 2 (MDM2) ubiquitin ligase.

SIGNOR-277190

Q96GX5

P06493

0

phosphorylation

up-regulates activity

0.513

We propose a model in which the initiating event for Gwl activation is phosphorylation by MPF of the proline-directed sites T193 and T206 in the presumptive activation loop

SIGNOR-249653

P35916

P12931

0

phosphorylation

up-regulates

0.513

Vegfr-3 is a direct c-src target and mass spectrometry analysis identified the sites phosphorylated by c-src as tyrosine 830, 833, 853, 1063, 1333, and 1337 vegfr-3 phosphorylation activates the recruitment to the receptor of the adaptor proteins crki/ii and shc inducing activation of jnk.

SIGNOR-165035

O60674

P28482

0

phosphorylation

down-regulates

0.513

We hypothesize that phosphorylation of ser523 in jak2 by erks 1 and/or 2 or other as-yet-unidentified kinases acts in a negative feedback manner

SIGNOR-236331

P55211

P00519

0

phosphorylation

up-regulates

0.513

C-abl phosphorylates casp9 on tyr-153 in vitro and in vivo in response to dna damage.The Present results demonstrate that c-abl binds directly to casp9.

SIGNOR-133260

P00519

P78527

0

phosphorylation

up-regulates activity

0.513

We show that DNA-PK phosphorylates and activates c-Abl in vitro.

SIGNOR-279268

O00418

Q15418

0

phosphorylation

down-regulates activity

0.513

We show that two such kinases, p70 s6 kinase (regulated via mtor) and p90(rsk1) (activated by erk), phosphorylate eef2k at a conserved serine and inhibit its activity

SIGNOR-109708

Q86YS7

P31751

0

phosphorylation

up-regulates activity

0.513

MS analysis of an HA-CDP138 sample from the in vitro kinase assay revealed that active Akt2 induces CDP138 phosphorylation at serine (Ser)197, which lies within a consensus Akt substrate motif RQRLIS 197 ( xref ).

SIGNOR-279585

Q00613

Q9UQM7

0

phosphorylation

up-regulates activity

0.513

Ser230 is located in the regulatory domain of HSF1, and promotes the magnitude of the inducible transcriptional activity. Ser230 lies within a consensus site for calcium/calmodulin-dependent protein kinase II (CaMKII), and CaMKII overexpression enhances both the level of in vivo Ser230 phosphorylation and transactivation of HSF1. The importance of Ser230 was further established by the S230A HSF1 mutant showing markedly reduced activity relative to wild-type HSF1 when expressed in hsf1(-/-) cells.

SIGNOR-250631

P63279

P06493

0

phosphorylation

up-regulates activity

0.512

Overall, these results suggest that Cdk1 and cyclin B mediates the phosphorylation of Ubc9 at serine 71.

SIGNOR-278174

P35240

Q13177

0

phosphorylation

down-regulates

0.512

Merlin contains a c-terminal serine 518, which is phosphorylated both by p21-activated kinase (pak) and protein kinase a (pka) (shaw et al., 2001;kissil et al., 2002;xiao et al., 2002;alfthan et al., 2004). Phosphorylation at this site is predicted to result in a more open conformation incapable of inhibiting cell growth,

SIGNOR-159768

P60953

Q9P107

0

gtpase-activating protein

down-regulates activity

0.512

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-260507

P35568

Q8WWQ0

0

binding

up-regulates activity

0.512

We have recently reported the isolation of a PH domain-interacting protein, PHIP, which selectively binds to the IRS-1 PH domain and is stably associated with IRS-1 in mammalian cells. Here we demonstrate that overexpression of PHIP in fibroblasts enhances insulin-induced transcriptional responses in a mitogen-activated protein kinase-dependent manner.

SIGNOR-266962

Q9NPA3

Q92748

0

binding

down-regulates activity

0.512

In the current study, we have determined the crystal structure of mouse S14 to 2.65-Å resolution. The structure of S14 reveals a helical protein arranged as a symmetric dimer. Cultured cell experiments indicate that S14 can form heterodimers with MIG12, suggesting a mechanism through which S14 could modulate ACC activity and subsequently rates of fatty acid synthesis via heterodimer formation with MIG12.In the current study, we have shown that regulating the levels of S14∶MIG12 heterodimers regulates the ability of MIG12 to activate ACC. Increasing S14∶MIG12 heterodimers by the overexpression of S14 resulted in decreased ACC activity and polymerization, whereas decreasing S14∶MIG12 heterodimers by knockdown of S14 increased ACC activity and polymerization.

SIGNOR-267113

Q969P5

P15173

0

binding

down-regulates activity

0.512

Myogenin had a MAFbx-recognition motif and interacted with MAFbx. MAFbx activated polyubiquitination of myogenin. The results of this study suggest that MAFbx functions as an F-box protein for ubiquitination of myogenin.

SIGNOR-237854

P63092

P47871

0

binding

up-regulates activity

0.512

Glucagon signals through its receptor on the cell surface (Fig.1). The binding of glucagon to the extracellular loops of the glucagon receptor results in conformational changes of the latter, leading to subsequent activation of the coupled G proteins. At least two classes of G proteins are known to be associated with and involved in the signal transduction of the glucagon receptor, namely Gsα and Gq. The activation of Gsα leads to activation of adenylate cyclase, increase in intracellular cAMP levels, and subsequent activation of protein kinase A (PKA).

SIGNOR-267715

Q13541

Q13315

0

phosphorylation

down-regulates

0.512

Here we report that atm... phosphorylates 4e-bp1 at ser 111cells lacking atm kinase activity exhibit a significant decrease in the insulin-induced dissociation of 4e-bp1 from eif-4e.

SIGNOR-85619

Q7LG56

Q13315

0

phosphorylation

up-regulates

0.512

Atm-mediated serine 72 phosphorylation stabilizes ribonucleotide reductase small subunit p53r2 protein against mdm2 to dna damage

SIGNOR-182423

P29992

P30556

0

binding

up-regulates activity

0.512

The angiotensin II type 1 receptor (AT1 R) is a G q/11-coupled G protein-coupled receptor that is widely expressed in multiple tissues, including vascular smooth muscle cells, brain, and kidney.

SIGNOR-278125

Q15642

Q99996

0

binding

up-regulates activity

0.512

Mechanistically, AKAP-9 interacted with cdc42 interacting protein 4 (CIP4) and regulated its expression. CIP4 levels were interrelated to the AKAP-9 level in CRC cells. Functionally, AKAP-9 was essential for TGF-β1-induced epithelial-mesenchymal transition of CRC cells, and CIP4 played a critical role in mediating the function of AKAP-9. Importantly, CIP4 expression was significantly up-regulated in human CRC tissues.|Co-immunoprecipitation assay revealed that AKAP-9 and CIP4 physically interacted with each other in Lovo and HT29 cells (Fig. 4B and C).

SIGNOR-260303

P18846

Q14012

0

phosphorylation

up-regulates activity

0.512

Phosphopeptide mapping analysis and Western blotting studies demonstrated that in vitro, CaMK II phosphorylates only Ser63 (corresponding to Ser133 of CREB), which is essential for the activation, and not Ser72 (corresponding to Ser142 of CREB), which is a negative regulation site.

SIGNOR-250611

P05412

Q99986

0

phosphorylation

up-regulates

0.512

Vrk1 phosphorylates c-jun in ser63 and ser73 in vitro...VRK1 Activates c-jun dependent transcription

SIGNOR-127073

O14965

P17612

0

phosphorylation

up-regulates activity

0.512

Aurora2 is regulated by phosphorylation. phosphorylation occurs on a conserved residue, Threonine 288, within the activation loop of the catalytic domain of the kinase and results in a significant increase in the enzymatic activity. Threonine 288 resides within a consensus motif for the cAMP dependent kinase and can be phosphorylated by PKA in vitro.

SIGNOR-250337

P20749

Q9NQC7

0

deubiquitination

down-regulates

0.512

Cyld binds and deubiquitinates bcl-3in cyld+/+ keratinocytes, tpa or uv light triggers the translocation of cyld from the cytoplasm to the perinuclear region, where cyld binds and deubiquitinates bcl-3, thereby preventing nuclear accumulation of bcl-3 and p50/bcl-3- or p52/bcl-3-dependent proliferation.

SIGNOR-146774

P19419

P45983

0

phosphorylation

up-regulates activity

0.512

However, both of these stimuli strongly activate two other mapks, jnk1 and jnk2, and stimulate elk-1 transcriptional activity and phosphorylation jnk phosphorylation sites include ser383 and ser389, the major residues whose phosphorylation is responsible for enhancement of elk-1 trascriptional activity.

SIGNOR-236432

O94875

P22681

0

ubiquitination

down-regulates

0.512

Cbl-argbp2 complex mediates ubiquitination and degradation of c-abl

SIGNOR-96325

P50221

P15863

0

binding

up-regulates activity

0.512

We show that Mox1 and Mox2 proteins are capable of interacting with Pax1 and Pax3. We propose that the Mox family of homeodomain proteins participates in the molecular signaling network regulating the diverse events of somite development through the physical interaction with the Pax1 and Pax3 members of the Pax family.

SIGNOR-222193

P32927

Q06124

0

dephosphorylation

up-regulates

0.511

Shp2 is thought to act as a positive mediator of growth factor signals.. Hp2 could act as an adaptor between the activated c and grb2, thus leading to activation of the ras/mitogen-activated protein kinase pathway, known to be activated by il-3

SIGNOR-48557

P04150

Q16539

0

phosphorylation

up-regulates

0.511

We found serine 211 of the human gr to be a substrate for p38 mapk both in vitro and intracellularly. Mutation of this site to alanine greatly diminished gr-driven gene transcription and apoptosis.

SIGNOR-135198

P23025

Q96EB6

0

deacetylation

up-regulates activity

0.511

SIRT1 deacetylates XPA at residues K63, K67, and K215 to promote interactions with ATR

SIGNOR-262294

P42345

O15111

0

phosphorylation

up-regulates activity

0.511

In those studies, we found that IKKalpha interacts with and phosphorylates mTOR in the mTORC1 complex to activate mTORC1, and that Akt signaling drives the IKKalpha-mTORC1 interaction.|We then studied whether IKKalpha promotes Akt and mTOR activity in other mammalian cancer cell lines.

SIGNOR-279607

O14950

O43293

0

phosphorylation

up-regulates

0.511

Hzipk phosphorylated the regulatory light chain of myosin ii (mrlc) at both ser19 and thr18 in vitro. Phosphorylation of mrlc is required to generate the driving force in the migration of the cells but not necessary for localization of myosin ii at the leading edge.

SIGNOR-16043

O43306

P08754

0

binding

down-regulates activity

0.511

Types V and VI adenylyl cyclase are most sensitive to inhibition by Gnai1, Gnai2, and Gnai3

SIGNOR-278079

P78317

Q9HBE1

0

binding

down-regulates

0.511

In vitro and in vivo interaction between rnf4 and patz was demonstrated / patz acted as a transcriptional repressor, whereas its partner rnf4 behaved as a transcriptional activator./ the association of patz with rnf4 switches activation to repression

SIGNOR-75775

Q13485

P28482

0

phosphorylation

up-regulates

0.511

Phosphorylation of thr276 is shown to be important for tgf-?-Induced nuclear accumulation and, as a consequence, transcriptional activity of smad4. these results suggest that smad4 can be phosphorylated by erk2 at thr276.

SIGNOR-101660

Q12778

P06493

0

phosphorylation

down-regulates

0.511

Overexpression of cdk1 inhibits the transcriptional activity of foxo1 in pca cells through s249 phosphorylation on foxo1.

SIGNOR-178202

Q96LB1

O00230

0

binding

up-regulates

0.511

The mrgx2 receptor has been shown to be activated by the peptides cortistatin and proadrenomedullin n-terminal peptides (pamp)

SIGNOR-139855

P63096

P08172

0

binding

up-regulates activity

0.511

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-256685

Q96R06

O14965

0

phosphorylation

up-regulates activity

0.511

We report here that Astrin acts as a mitotic phosphoprotein, and Aurora-A phosphorylates Astrin at Ser(115). The phosphorylation-deficient mutant Astrin S115A abnormally activates spindle assembly checkpoint and delays mitosis progression, decreases spindle stability, and induces chromosome misalignment. Mechanistic analyses reveal that Astrin phosphorylation mimicking mutant S115D, instead of S115A, binds and induces ubiquitination and degradation of securin, which sequentially activates Separase, an enzyme required for the separation of sister chromatids.

SIGNOR-276648

P41968

P42127

0

binding

down-regulates activity

0.511

The melanocortin (MC) receptor family consists of five Gs-coupled receptors that control various physiological functions in response to four distinct agonists, adrenocorticotropic hormone (ACTH, also known as corticotrophin) and alpha, beta, and gamma melanocyte-stimulating hormone (MSH), which are derived from the proopiomelanocortin precursor protein, and two inverse agonists, agouti and agouti-related proteins

SIGNOR-268703

Q14247

Q8WZ74

0

binding

up-regulates activity

0.511

Fluorescence recovery after photobleaching further suggested that CTTNBP2 modulates the mobility of cortactin in neurons. CTTNBP2 may thus help to immobilize cortactin in dendritic spines and control the density of dendritic spines.

SIGNOR-269703

P60953

Q92502

0

gtpase-activating protein

down-regulates activity

0.511

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-260520

P15172

P11802

0

binding

down-regulates

0.511

In contrast to cdk2, cyclin d/cdk4 blocks myod activity through an as yet unclear mechanism that may involve direct binding. Cyclin d/cdk4 can also block the activity of myogenin and all mef2 isoforms.

SIGNOR-176527

P16298

P0DP24

0

binding

up-regulates

0.511

Calcium-bound calmodulin associates with calcineurin (cn), releasing the phosphatase from the repressive effects on an autoinhibitory domain.

SIGNOR-266322

P24385

Q8N3Y1

0

binding

down-regulates quantity by destabilization

0.511

We next investigated whether in vitro ubiquitination of cyclin D1 through the SCF-like (SCFL) complex FBXW8 (SKP1-CUL7-FBXW8-RBX1/SCFLFBXW8) requires phosphorylation of cyclin D1 at Thr286 (Fig. 3F). Polyubiquitination through SCFLFBXW8 was dramatically reduced by the depletion of ERK2 (lane 2). Furthermore, cyclin D1 polyubiquitination was largely prevented by the alanine-for-Thr286 substitution (T286A, lane 3), suggesting that phosphorylation of cyclin D1 at Thr286 is necessary for ubiquitination by SCFLFBXW8.

SIGNOR-271624

P10275

P28482

0

phosphorylation

down-regulates

0.511

Map kinase-dependent phosphorylation at ar ser-515 was supported by the decrease in intensity of the slower migrating 23-kda band after treatment with both egf and increasing concentrations of the map kinase inhibitor, u0126

SIGNOR-178718

P19086

P35372

0

binding

up-regulates activity

0.51

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-257106

Q93009

O15355

0

dephosphorylation

down-regulates quantity by destabilization

0.51

We find that stabilization of Mdm2, and correspondingly p53 downregulation in unstressed cells, is accomplished by a specific isoform of USP7 (USP7S), which is phosphorylated at serine 18 by the protein kinase CK2. |After ionizing radiation, dephosphorylation of USP7S by the ATM-dependent protein phosphatase PPM1G leads to USP7S downregulation, followed by Mdm2 downregulation and accumulation of p53.

SIGNOR-276531

P05412

Q02930

0

binding

up-regulates activity

0.51

CRE-BPa specifically binds to CRE as a homodimer or heterodimer with c-Jun or CRE-BP1. In CAT cotransfection experiments using CV-1 cells, transient expression of each of four CRE-BPa proteins caused a 1.6- to 3.4-fold increase of CRE-dependent transcription

SIGNOR-219634

Q9Y2D9

O75081

0

binding

down-regulates activity

0.51

Previously we reported that a classical C2H2 zinc finger DNA binding protein ZNF652 functionally interacts with CBFA2T3 to repress transcription of genes containing ZNF652 consensus DNA binding sequence within the promoters of these target genes.

SIGNOR-253954

Q9H257

Q9BVG3

0

ubiquitination

up-regulates activity

0.51

Importantly, using in vitro ubiquitination assays with purified proteins, we verified that CARD9 is directly ubiquitinated by TRIM62 at residue K125; this ubiquitination is dependent on the ligase activity of TRIM62 and does not occur in CARD9 Delta11 (XREF_FIG).

SIGNOR-278552

O00429

Q13546

0

phosphorylation

up-regulates activity

0.51

RIPK1 also activates DRP1 by phosphorylating DRP1 at Ser616 in a RIPK3-dependent fashion independent of MLKL.

SIGNOR-280104

P49768

Q00535

0

phosphorylation

up-regulates

0.51

Cyclin-dependent kinase-5/p35 phosphorylates presenilin 1 to regulate carboxy-terminal fragment stabilityhere we demonstrate that cyclin dependent kinase-5/p35 (cdk5/p35) phosphorylates ps1 on threonine(354) within c-ps1 both in vitro and in vivo. Threonine(354) phosphorylation functions to selectively stabilize c-ps1.

SIGNOR-89145

Q9UQL6

Q16566

0

phosphorylation

down-regulates

0.51

Recently, camkiv, a calcium-calmodulindependent protein kinase, was also shown to activate mef2s by dissociating class ii histone deacetylases (e.g., Hdac5) from mef2s, thus relieving the transcriptional repressive effect of hdacs.

SIGNOR-236571

Q9NYV4

P50613

0

phosphorylation

up-regulates activity

0.51

Although Cdk12/CycK kinase complex lacking T-loop phosphorylation showed some basal activity towards a CTD substrate prephosphorylated at position Ser7, its activity was significantly increased upon coexpression with the CAK from S. cerevisiae (Supplementary Fig. 9a). Mutation of T893 to E to mimic phosphorylation showed no effect on basal kinase activity. Quantitative phosphorylation of a single residue occurred upon coexpression with Cak1, as determined by ESI mass spectrometry (Supplementary Fig. 9b).

SIGNOR-275509

P54252

Q9UNE7

0

ubiquitination

down-regulates quantity by destabilization

0.51

Although our data show that CHIP may associate with Atx3 to ubiquitinate Atx3 in vitro, we still wonder whether CHIP is directly involved in the degradation of Atx3.|As a result, silencing of CHIP significantly increases the amount of Atx3 (XREF_FIG), suggesting that CHIP may down-regulate the Atx3 level.

SIGNOR-278667

O15350

P53350

0

phosphorylation

down-regulates

0.51

P73-mediated transcriptional activity is negatively regulated by polo-like kinase 1. tap73 is phosphorylated by this kinase on threonine-27 (thr-27) within the ta domain.

SIGNOR-178253

P16949

Q8TAS1

0

phosphorylation

down-regulates

0.51

This promigratory phenotype resulted from increased stathmin protein levels, caused by a lack of kis-mediated stathmin phosphorylation at serine 38 and diminished stathmin protein degradation.

SIGNOR-182489

P02545

P12931

0

phosphorylation

up-regulates activity

0.51

In this study, we found that the constitutively active Src Y527F mutant caused the disassembly of lamin A/C. We demonstrate that Src directly phosphorylates lamin A mainly at Tyr45 both in vitro and in intact cells.

SIGNOR-279288

O75051

Q99985

0

binding

up-regulates activity

0.51

Genes encoding the neurovascular guiding molecule semaphorin 3C (SEMA3C) and its receptor plexin A2 (PLXNA2) appear to be regulated directly by GATA6, and both GATA6 mutant proteins failed to transactivate these genes.

SIGNOR-253151

O75496

O14965

0

phosphorylation

up-regulates activity

0.51

Aurora-A controls pre-replicative complex assembly and DNA replication by stabilizing geminin in mitosis.|Thr25 of geminin is phosphorylated by Aurora-A.

SIGNOR-278509

O75449

Q92630

0

phosphorylation

down-regulates quantity by destabilization

0.509

DYRK2 mediated phosphorylation is required for Katanin p60 degradation. Serine 42, serine 109 and threonine 133 are likely to be the major DYRK2 phosphorylation sites as single mutations for these sites showed reduced phosphorylation by DYRK2 and the triple mutant showed almost no DYRK2 mediated phosphorylation (Fig. 5d).

SIGNOR-262847

P35222

P55289

0

binding

up-regulates activity

0.509

At its C-terminus, cadherin interacts with Î²-catenin, which dynamically associates with Î±-catenin, a direct binding partner of filamentous actin

SIGNOR-265852

Q9UQ80

Q05655

0

phosphorylation

up-regulates

0.509

Trk receptor activation by both ngf and bdnf induced phosphorylation of ebp1 at the s360 upon the activation of protein kinase c (pkc ) and triggered dissociation of p48 from retinoblastoma (rb

SIGNOR-170348

P55072

P31749

0

phosphorylation

up-regulates

0.509

Site-directed mutagenesis identified ser-351, ser-745, and ser-747 as akt phosphorylation sites on vcp. however, our study also suggests that other known biological activities of vcp, such as those related to intracellular trafficking, ubiquitin-mediated proteolysis, and activation of transcription (28), might be regulated by akt through the activation of vcp. I

SIGNOR-252491

P42568

O00141

0

phosphorylation

down-regulates activity

0.509

In addition to Nedd4-2, Sgk1 also phosphorylates Af9, forkhead like transcription factor FOXO3a and several other substrates.|Sgk1 impairs the ability of Af9 to interact with Dot1a at these subregions without impacting Af9 DNA binding activity, leading to targeted histone H3 K79 hypomethylation.

SIGNOR-279111

Q9P055

Q99942

0

ubiquitination

down-regulates activity

0.509

RNF5 is a ubiquitin ligase anchored to the ER membrane implicated in ERAD via ubiquitination of misfolded proteins. This association results in Ubc13-dependent RNF5-mediated noncanonical ubiquitination of JAMP. This ubiquitination does not alter JAMP stability but rather inhibits its association with Rpt5 and p97.

SIGNOR-271483

O95863

Q9UKA1

0

binding

down-regulates quantity by destabilization

0.509

FBXL5 is located in the nucleus where it interacts with Snail1 promoting its polyubiquitination and affecting Snail1 protein stability and function by impairing DNA binding. Snail1 is ubiquitinated by the SCFFBXL5 complex. Snail1 downregulation by FBXL5 is prevented by Lats2, a protein kinase that phosphorylates Snail1 precluding its nuclear export but not its polyubiquitination. To demonstrate that FBXL5 has a direct activity on Snail1, we carried out polyubiquitination reactions in vitro. For this we purified Snail1 and the SCFFBXL5 complex from Sf9 insect cells infected with different baculoviruses corresponding to Flag-FBXL5, His-Skp1, HA-Cullin1 and Rbx1 (Supplementary Figure S3C).

SIGNOR-272135

O94761

Q7L590

0

binding

down-regulates

0.509

Mcm10 inhibits recq4 helicase activity.

SIGNOR-187701

P03372

P31751

0

phosphorylation

up-regulates activity

0.509

AKT activate ERalpha in the absence of estrogen. The consensus AKT phosphorylation site Ser-167 of ERalpha is required for phosphorylation and activation by AKT.

SIGNOR-251490

P27694

Q9UMS4

0

polyubiquitination

up-regulates activity

0.509

PRP19 is a ubiquitin ligase involved in pre-mRNA splicing and the DNA damage response (DDR). PRP19 ubiquitylates RPA and promotes ATRIP recruitment.

SIGNOR-272076

P11142

Q9NXW2

0

binding

up-regulates activity

0.509

JB12 cooperates with cytosolic Hsc70 and the ubiquitin ligase RMA1 to target CFTR and CFTRΔF508 for degradation. JB12 drives Hsc70 to associate with CFTR and the RMA1 E3 complex

SIGNOR-271491

P19838

P17612

0

phosphorylation

up-regulates

0.509

In this study, we demonstrate that the phosphorylation of p50 and p65 by the catalytic subunit of protein kinase a (pkac) is essential for nf-kappab dna binding and transactivation activity. treatment with h89 and knockdown of pkac in cells led to the inhibition of phosphorylation at p50 ser(337) and p65 ser(276) and loss of dna binding by nf-kappab.

SIGNOR-158595

O75962

Q05397

0

phosphorylation

up-regulates activity

0.509

A FAK phosphorylation site, tyrosine residue 2737, was identified in subdomain I of the Trio kinase domain. Additionally, in vitro phosphorylation assays and in vivo co-expression studies indicated that Trio enhances FAK kinase activity.

SIGNOR-249188

P38405

P21918

0

binding

up-regulates activity

0.509

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-256914

P30679

P32239

0

binding

up-regulates activity

0.509

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-257412

P35222

P49789

0

binding

down-regulates

0.509

Fhit interacts with _-catenin in vitro and in vivo / the tumor suppressor fhit acts as a repressor of _-catenin transcriptional activity

SIGNOR-159873

O15151

P31749

0

phosphorylation

up-regulates quantity by stabilization

0.509

We demonstrate that the serine/threonine kinase akt mediates phosphorylation of mdmx at ser367. This phosphorylation leads to stabilization of mdmx and consequent stabilization of mdm2.

SIGNOR-252517

Q92835

P07948

0

phosphorylation

up-regulates activity

0.509

In this line, Lyn has been demonstrated to tyrosine-phosphorylate and activate SHIP1, thereby constituting a negative feedback control of PI3K-mediated signals.

SIGNOR-279060

P42356

Q9Y2G0

0

binding

up-regulates quantity

0.509

PI4KA is recruited to plasma membrane by the adapter protein EFR3, which has two isoforms, EFR3A and EFR3B

SIGNOR-269093

Q06609

P53350

0

phosphorylation

up-regulates activity

0.508

Mechanistically, TOPBP1 physically binds PLK1 and promotes PLK1 kinase-mediated phosphorylation of RAD51 at serine 14, a modification required for RAD51 recruitment to chromatin.|Mechanistically, TOPBP1 physically binds PLK1 and promotes PLK1 kinase\u2013mediated phosphorylation of RAD51 at serine 14, a modification required for RAD51 recruitment to chromatin.

SIGNOR-278187

Q9NYV6

P24941

0

phosphorylation

up-regulates

0.508

Cdk2/cyclin e-mediated phosphorylation at ser 44 activates tif-ia

SIGNOR-123231

P31327

Q9NXA8

0

post translational modification

up-regulates activity

0.508

Glutarylation suppresses CPS1 activity, which is targeted by SIRT5 for removal|SIRT5 can catalyze the enzymatic removal of lysine glutarylation

SIGNOR-267643

P15927

P06493

0

phosphorylation

up-regulates activity

0.508

Cdc2 family kinases phosphorylate a human cell dna replication factor, rpa, and activate dna replication. therefore, the serines on rpa p34 that were necessary for phosphorylation by cdc2 kinase were also necessary for phosphorylation in the cell

SIGNOR-16975

Q9NX09

Q9H3M7

0

binding

up-regulates quantity by stabilization

0.508

In the present study, we identify TXNIP that inhibits mTOR activity by binding to and stabilizing Redd1 protein.

SIGNOR-277470

P27361

Q9BRX9

0

binding

up-regulates

0.508

Morg1 specifically associates with several components of the erk pathway, including mp1, raf-1, mek, and erk, and stabilizes their assembly into an oligomeric complex.

SIGNOR-124473

Q14994

Q15466

0

binding

down-regulates

0.508

The short heterodimer partner (shp), an orphan nuclear receptor that lacks a conventional dna binding domain, was initially identified by its interaction with car. We have examined the role of shp in car-mediated transactivation of the cyp2b gene. Coexpression of shp inhibited the transactivation of the cyp2b gene by car in cultured hepatoma cells and the p160 coactivator grip1 reversed the inhibition.

SIGNOR-123154

O95477

P17612

0

phosphorylation

up-regulates activity

0.508

Ser-1042 and Ser-2054, located in the nucleotide binding domains of ABCA1, are major phosphorylation sites for PKA. ABCA1 phosphorylation may affect ApoA-I-dependent phospholipid efflux by either altering the conformation of the protein to a more active state or by affecting the interaction between ABCA1 and its partner proteins.

SIGNOR-250326

P01112

Q92565

0

guanine nucleotide exchange factor

up-regulates

0.508

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

SIGNOR-183732

P35222

Q8N752

0

phosphorylation

down-regulates

0.508

We show that a complex of axin and casein kinase i (cki) induces beta-catenin phosphorylation at a single site: serine 45 (s45).

SIGNOR-87430

Q9H6R0

Q9P275

0

deubiquitination

up-regulates quantity by stabilization

0.508

Loss of the deubiquitinase USP36 destabilizes the RNA helicase DHX33 and causes preimplantation lethality in mice.

SIGNOR-272289

O00470

P28356

0

binding

up-regulates activity

0.508

We find that DNA binding by MEIS1A is absolutely required for the formation of a cooperative complex with HOXD9

SIGNOR-220721

Q4V328

Q9Y3R0

0

binding

up-regulates activity

0.508

We have identified several GRIP-associated proteins (GRASPs) that bind to distinct PDZ domains within GRIP. GRASP-1 is a neuronal rasGEF associated with GRIP and AMPA receptors in vivo. GRIP1 has seven PDZ domains, which mediate protein–protein interactions, allowing the recruitment of GRASP-1 to a large signal-transducing complex

SIGNOR-260638

P49448

Q9Y6E7

0

glycosylation

down-regulates activity

0.508

We show that SIRT4 is a mitochondrial enzyme that uses NAD to ADP-ribosylate and downregulate glutamate dehydrogenase (GDH) activity.

SIGNOR-268559