GleghornLab/Signor_processed · Datasets at Hugging Face

IdA stringlengths 6 21	IdB stringlengths 6 21	labels float64 0 2	mechanism stringclasses 40 values	effect stringclasses 10 values	score float64 0.1 0.99 ⌀	sentence stringlengths 10 1.63k ⌀	signor_id stringlengths 12 14
Q13535	P16220	1	phosphorylation	down-regulates	0.347	Atm phosphorylated creb in vitro and in vivo in response to ionizing radiation (ir) and h(2)o(2) on a stress-inducible domain. Ir-induced phosphorylation of creb correlated with a decrease in creb transactivation potential and reduced interaction between creb and its transcriptional coactivator, creb-binding protein (cbp). A creb mutant containing ala substitutions at atm phosphorylation sites displayed enhanced transactivation potentialit is, therefore, likely that atm and atr regulate creb phosphorylation collectively in response to stress stimuli.	SIGNOR-124060
P36507	P55211	1	phosphorylation	down-regulates activity	0.347	Inhibition of caspase-9 through phosphorylation at Thr 125 by ERK MAPK\|The opposing protein kinase activity is overcome by treatment with the broad-specificity kinase inhibitor staurosporine or with inhibitors of MEK1/2	SIGNOR-249386
P12956	Q16763	1	relocalization	up-regulates activity	0.347	As shown in Figure 4, we found that Ku70 (Figure 4b) and Ku80 (Figure 4c) co-immunoprecipitated with UBE2S.>Taken together, these results demonstrate that ETO enhances the UBE2S–Ku70 interaction, and UBE2S can be recruited to the same sites of DSBs with Ku70 upon ETO treatment.	SIGNOR-265079
Q969V5	O75385	1	ubiquitination	down-regulates quantity	0.347	MUL1 promotes ubiquitination of ULK1.\|Overexpression of MUL1 and treatment with selenite promotes ULK1 degradation through the proteasome pathway.	SIGNOR-278759
P41145	P09471	1	binding	up-regulates activity	0.347	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-256989
Q15797	O14640	1	binding	up-regulates	0.347	These results identify a potential mechanism whereby bmp-2 antagonizes wnt signaling in osteoblast progenitors by promoting an interaction between smad1 and dvl-1 that restricts beta-catenin activation.	SIGNOR-146131
A1X283	Q86UR1	1	binding	up-regulates activity	0.347	Tks4 and Tks5 bind NoxA1 through their SH3 domains in a Rac-independent manner\|NoxO1 is required for full Nox1 and Nox3 oxidase activity at least partially because of its role in the plasma membrane recruitment of the NoxA1 activator protein\|Tks4 and Tks5 support Nox1- and Nox3-dependent ROS generation	SIGNOR-264707
Q9BXM7	Q9Y2N7	1	phosphorylation	down-regulates activity	0.347	Here we show that IPAS is a key molecule involved in neuronal cell death in Parkinson's disease (PD). IPAS was ubiquitinated by Parkin for proteasomal degradation following carbonyl cyanide m-chlorophenyl hydrazone treatment. Phosphorylation of IPAS at Thr12 by PTEN-induced putative kinase 1 (PINK1) was required for ubiquitination to occur.	SIGNOR-263090
P19784	P42768	1	phosphorylation	up-regulates activity	0.347	We identify two phosphorylation sites in the VCA domain of WASP at serines 483 and 484. S483 and S484 are substrates for casein kinase 2 in vitro and in vivo. Phosphorylation of these residues increases the affinity of the VCA domain for the Arp2/3 complex 7-fold and is required for efficient in vitro actin polymerization by the full-length WASP molecule.	SIGNOR-251048
P62258	P20226	1	binding	up-regulates activity	0.347	The in vitro binding with general transcription factors TBP and TFIIB together with its nuclear location provide evidence supporting a role for 14-3-3 proteins as transcriptional activators or coactivators when part of a DNA binding complex.	SIGNOR-262834
P49841	Q9UQB3	1	phosphorylation	down-regulates quantity	0.347	Therefore, our data which supports that partial inhibition of GSK-3beta increases delta-catenin expression, raises an interesting possibility that delta-catenin may be an important downstream target of GSK-3beta signaling that participates in modulating neuronal morphology.\|We demonstrate that GSK-3beta forms a stable complex with delta-catenin and phosphorylates delta-catenin in neurons, an event that mediates ubiquitination and subsequent proteasome degradation of delta-catenin.	SIGNOR-279719
O43791	Q96KS0	1	ubiquitination	down-regulates quantity by destabilization	0.347	Tumor suppressor SPOP ubiquitinates and degrades EglN2 to compromise growth of prostate cancer cells	SIGNOR-261996
P53350	Q99708	1	phosphorylation	up-regulates activity	0.347	PLK1 targets CtIP to promote microhomology mediated end joining.\|We further showed that the DSB repair factor CtIP is jointly phosphorylated by CDK1 and Aurora A and PLK1.	SIGNOR-279253
P24941	Q92698	1	phosphorylation	down-regulates activity	0.347	Effect of CDK2 phosphorylation on the RAD54 activities. We find that the RAD54 N-terminal domain (NTD) is responsible for initiation of BM through two coupled, but distinct steps; specific binding to Holliday junctions and RAD54 oligomerization. Furthermore, we find that the RAD54 oligomeric state can be controlled by NTD phosphorylation at S49, a CDK2 consensus site, which inhibits RAD54 oligomerization and, consequently, BM.	SIGNOR-273599
P67775	P06730	1	dephosphorylation	down-regulates	0.347	A recent study using genetically engineered mouse models has clearly shown that mnk-mediated eif4e phosphorylation is absolutely required for eif4e's oncogenic action. Taken together, we conclude that pp2a negatively regulates eif4e phosphorylation and eif4f complex assembly through dephosphorylation of mnk and eif4e, thus suggesting a novel mechanism by which pp2a exerts its tumor-suppressive function.	SIGNOR-168306
P06241	P42681	1	phosphorylation	up-regulates activity	0.347	We further demonstrate that Rlk can be phosphorylated and activated by Src kinases, leading to a decrease in its half-life. A specific tyrosine in the activation loop of Rlk, Y420, is required for phosphorylation and activation, as well as for decreased stability, but is not required for lipid RAFT association.	SIGNOR-249341
P63096	P08631	1	binding	up-regulates activity	0.347	Galphas and Galphai similarly modulate Hck, another member of Src-family tyrosine kinases.	SIGNOR-256528
Q9UQ26	Q01668	1	binding	up-regulates activity	0.347	Here, we report an interaction of the C2B domain of RIM2α and RIM3γ with the C-terminus of the pore-forming α-subunit of CaV1.3 channels (CaV1.3α1), which mediate stimulus-secretion coupling at the ribbon synapses of cochlear inner hair cells (IHCs). In conclusion, we propose that RIM2α and RIM3γ directly interact with the C-terminus of the pore-forming subunit of CaV1.3 Ca2+ channels and positively regulate their plasma membrane expression in HEK293 cells.	SIGNOR-264356
Q96JY6	Q04206	1	polyubiquitination	down-regulates quantity by destabilization	0.347	Here we report that PDLIM2 negatively regulated NF-kappaB activity, acting as a nuclear ubiquitin E3 ligase targeting the p65 subunit of NF-kappaB. PDLIM2 bound to p65 and promoted p65 polyubiquitination.	SIGNOR-271651
Q9UBE8	P40763	1	phosphorylation	up-regulates	0.347	Phosphorylation of s727 induces pin1 binding which increases transcription. Pin1 binding increases stat3 interaction with p300 and dna.	SIGNOR-155828
P41146	P09471	1	binding	up-regulates activity	0.347	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-257001
P78347	Q15853	1	binding	up-regulates activity	0.347	TFII-I has been shown to interact with USF and to associate with either E-box elements or initiator sequences to activate gene transcription	SIGNOR-268537
Q9H270	P35241	1	binding	up-regulates activity	0.347	Vps11 was found to interact with radixin. ERM proteins and the HOPS complex are required for the transition from early to late endosomes. We report that an interaction between subunits of the HOPS complex and the ERM (ezrin, radixin, moesin) proteins is required for the delivery of EGF receptor (EGFR) to lysosomes. Inhibiting either ERM proteins or the HOPS complex leads to the accumulation of the EGFR into early endosomes, delaying its degradation.	SIGNOR-261312
P49137	P27815	1	phosphorylation	down-regulates activity	0.347	Phosphorylation of cAMP-specific PDE4A5 (phosphodiesterase-4A5) by MK2 (MAPKAPK2) attenuates its activation through protein kinase A phosphorylation. In the present study, we show that PDE4A5 is phosphorylated at Ser147, within the regulatory UCR1 (ultraconserved region 1) domain conserved among PDE4 long isoforms, by MK2 (MAPK-activated protein kinase 2, also called MAPKAPK2). Phosphorylation by MK2, although not altering PDE4A5 activity, markedly attenuates PDE4A5 activation through phosphorylation by protein kinase A. This modification confers the amplification of intracellular cAMP accumulation in response to adenylate cyclase activation by attenuating a major desensitization system to cAMP.	SIGNOR-263078
Q92997	Q9NQ66	1	null	up-regulates activity	0.347	Dsh through PLC activates IP3, which leads to release of intracellular Ca2+, which in turn activates CamK11 and calcineurin	SIGNOR-258980
P07948	O15492	1	phosphorylation	up-regulates activity	0.346	Lyn kinase phosphorylated recombinant RGS16 in vitro. Induction of RGS16 tyrosine phosphorylation was associated with increased RGS16 protein levels and enhanced GAP activity in cell membranes.	SIGNOR-251410
P53350	P11413	1	phosphorylation	up-regulates activity	0.346	We find that Plk1 interacts with and directly phosphorylates glucose-6-phosphate dehydrogenase (G6PD). By activating G6PD through promoting the formation of its active dimer, Plk1 increases PPP flux and directs glucose to the synthesis of macromolecules.\|the kinase domain of Plk1 phosphorylates T406, T466 of G6PD	SIGNOR-267581
P01100	P11511	1	transcriptional regulation	up-regulates quantity by expression	0.346	We found that both SF1 and LRH1 can transcriptionally cooperate with the AP-1 family members c-JUN and c-FOS, known to be associated with enhanced proliferation of endometrial carcinoma cells, to further enhance activation of the STAR, HSD3B2, and CYP19A1 PII promoters.	SIGNOR-254879
P49841	Q14103	1	phosphorylation	down-regulates activity	0.346	In kinase assays pka phosphorylated ser-87 of hnrnp d, whereas glycogen synthase kinase-3 beta (gsk-3 beta) phosphorylated ser-83, but only if ser-87 had been pre-phosphorylated by pka. Phosphorylation of ser-87 enhanced, whereas phosphorylation of ser-83 repressed, transactivation.	SIGNOR-102582
P28482	P46527	1	phosphorylation	up-regulates	0.346	Phosphorylation on ser-10 of kip1 is the major site of phosphorylation in resting cells, takes place at the g(0)-g1 phase and leads to protein stability.	SIGNOR-77651
P68400	Q9H257	1	phosphorylation	down-regulates activity	0.346	PVHL Acts as an Adaptor to Promote the Inhibitory Phosphorylation of the NF-κB Agonist Card9 by CK2	SIGNOR-257601
Q969Q6	P53041	1	binding	up-regulates activity	0.346	Protein phosphatase complex PP5/PPP2R3C dephosphorylates P-glycoprotein/ABCB1 and down-regulates the expression and function	SIGNOR-272480
Q969T4	P25963	1	sumoylation	up-regulates quantity by stabilization	0.346	In the presence of an E1 SUMO-1-activating enzyme, Ubch9 conjugated SUMO-1 to IkappaBalpha primarily on K21, which is also utilized for ubiquitin modification. Thus, SUMO-1-modified IkappaBalpha cannot be ubiquitinated and is resistant to proteasome-mediated degradation.	SIGNOR-270545
O95198	Q9HA47	1	ubiquitination	down-regulates quantity by destabilization	0.346	We demonstrated that the ubiquitin E3 ligase KLHL2 interacted with UCK1 and mediated its polyubiquitination at the K81 residue and degradation. We showed that deubiquitinase USP28 antagonized KLHL2-mediated polyubiquitylation of UCK1.	SIGNOR-275962
P68400	Q14676	1	phosphorylation	up-regulates	0.346	The mdc1-nbs1 interaction occurs through a specific region (residues 200-420) of mdc1, which contains multiple consensus casein kinase 2 (ck2) phosphorylation sites.	SIGNOR-179887
P18031	Q05397	1	dephosphorylation	down-regulates activity	0.346	The focal adhesion kinase (FAK) is a key regulator of cell migration. Phosphorylation at Tyr-397 activates FAK \|The dephosphorylation at Tyr-397 in FAK triggered by wild-type alpha-actinin and PTP 1B caused a significant increase in cell migration.	SIGNOR-248431
Q86V86	Q92934	1	phosphorylation	down-regulates activity	0.346	Pim kinases phosphorylate multiple sites on Bad and promote 14-3-3 binding and dissociation from Bcl-XL. pim kinases are constitutively active when expressed in HEK-293 cells and are able to phosphorylate the Bcl-2 family member Bad on three residues, Ser112, Ser136 and Ser155 in vitro and in cells.	SIGNOR-250399
Q70E73	Q9UI08	1	binding	up-regulates activity	0.346	Here we show that Lpd is a substrate of Abl kinases and binds to the Abl SH2 domain. Phosphorylation of Lpd positively regulates the interaction between Lpd and Ena/VASP proteins.	SIGNOR-268427
Q05655	Q01543	1	phosphorylation	down-regulates	0.346	We have previously demonstrated that in response to transforming growth factor _ (tgf_), fli-1 activity is repressed through a series of sequential posttranslational modifications, consisting of protein kinase c_ (pkc_)-induced thr312 phosphorylation, acetylation by p300/creb binding protein-associated factor, and detachment from the collagen promoter.	SIGNOR-172113
P01106	Q02127	1	transcriptional regulation	up-regulates quantity by expression	0.346	PPAT, catalyzing the first step of purine synthesis, and DHODH, an enzyme generating uridine in the middle of the pyrimidine synthesis pathway, were validated as direct c-MYC target genes by all criteria.	SIGNOR-267382
Q96EP1	Q96KB5	1	polyubiquitination	down-regulates quantity by destabilization	0.346	CHFR ubiquitinates and degrades TOPK. Our in vivo ubiquitination assays revealed that the polyubiquitination of TOPK occurs only in the presence of full length CHFR but not with the ΔRING or Δcysteine-rich domain deletion mutants (Fig. 2a).	SIGNOR-271471
P24941	O75533	1	phosphorylation	up-regulates	0.346	To map the set of phosphorylation sites in sap155-(223-322) that determine its interaction with nipp1, we have identified phosphorylation sites of cyclin e-cdk2 by the sequencing of proteolytically derived phosphopeptide). Three phosphorylation sites were identified as thr244, thr248, and thr313	SIGNOR-90434
P49841	P33076	1	phosphorylation	up-regulates	0.346	Here we report that CIITA represses collagen transcription through a phosphorylation-dependent interaction between its proline/serine/threonine domain and co-repressor molecules such as histone deacetylase (HDAC2) and Sin3B. Mutation of a serine (S373A) in CIITA, within a glycogen synthase kinase 3 (GSK3) consensus site, decreases repression of collagen transcription by blocking interaction with Sin3B	SIGNOR-158959
Q5JUK2	P10721	1	transcriptional regulation	up-regulates quantity by expression	0.346	Our results suggest that SOHLH1 and SOHLH2 directly stimulate Kit transcription in postnatal spermatogonia, thus activating the signaling involved in spermatogonia differentiation and spermatogenetic progression.	SIGNOR-266205
O14965	P35222	1	phosphorylation	up-regulates quantity	0.346	In addition, Aurora-A overexpression is significantly correlated with increased cytoplasmic \u03b2-catenin expression in esophageal squamous cell carcinoma tissues.\|We also demonstrate for the first time that Aurora-A directly interacts with \u03b2-catenin and phosphorylates \u03b2-catenin at Ser552 and Ser675.	SIGNOR-278468
Q13315	Q15911	1	phosphorylation	up-regulates activity	0.346	Indeed, ATM phosphorylates ATBF1 at Ser1180 in HEK293T cells exposed to 10-Gy radiation [ xref ].\|We also found in this study that ATBF1 mediated neuronal death is dependent on ATM signals because the blockage of ATM by treatment with ATM inhibitors, caffeine and KU55933, abolished ATBF1 functions in neuronal death.	SIGNOR-279138
Q8WUJ0	Q969H0	1	binding	down-regulates activity	0.346	STYX acts as a direct inhibitor of FBXW7, affecting the cellular levels of its substrates. Furthermore, we find that levels of STYX and FBXW7 are anti-correlated in breast cancer patients,	SIGNOR-251663
O15294	P08237	1	glycosylation	down-regulates activity	0.346	Our previous investigation on O-GlcNAcylation of PFK1 has demonstrated that O-GlcNAcylation inhibits PFK1 enzyme activity\|In cells, a single set of antagonistic enzymes-O-GlcNAc transferase (OGT) and O-GlcNAc hydrolase are responsible for the addition and removal of GlcNAc moiety, respectively.	SIGNOR-267584
P12931	O15492	1	phosphorylation	up-regulates	0.346	Src-mediated rgs16 tyrosine phosphorylation promotes rgs16 stability. / this result suggests src phosphorylates native rgs16 at residue tyr177 in vitro.	SIGNOR-98271
P49841	Q14653	1	phosphorylation	up-regulates activity	0.346	Invitro, both GSK3alpha and GSK3beta phosphorylate IRF3 at the linker region.	SIGNOR-279182
Q9H2X6	Q9NY61	1	phosphorylation	down-regulates quantity	0.346	HIPK2 phosphorylates Che-1.\|Here we demonstrate that HIPK2, a proapoptotic kinase, is involved in Che-1 degradation.	SIGNOR-278942
Q92630	O95863	1	phosphorylation	down-regulates activity	0.346	DYRK2 mediated Snail degradation protects against tumor cell metastasis.\|DYRK2 phosphorylation of Snail at Ser104 triggers sequential phosphorylation by GSK3.	SIGNOR-279328
P17612	Q13698	1	phosphorylation	up-regulates activity	0.346	To identify the regulatory sites of phosphorylation under physiologically relevant conditions, Ca(V)1.1 channels were purified from skeletal muscle and sites of phosphorylation on the α1 subunit were identified by mass spectrometry. Two phosphorylation sites were identified in the proximal C-terminal domain, serine 1575 (S1575) and threonine 1579 (T1579), which are conserved in cardiac Ca(V)1.2 channels (S1700 and T1704, respectively). In vitro phosphorylation revealed that Ca(V)1.1-S1575 is a substrate for both cAMP-dependent protein kinase and calcium/calmodulin-dependent protein kinase II, whereas Ca(V)1.1-T1579 is a substrate for casein kinase 2.	SIGNOR-263112
Q9Y5X3	Q14185	1	binding	up-regulates activity	0.346	SNX5 Is a Novel Binding Partner of the DHR1 Domain of DOCK180. In summary, we found that DOCK180 regulates transport of CI-MPR via SNX5 binding.	SIGNOR-269441
P02533	Q15628	1	binding	down-regulates activity	0.346	TRADD specifically bound K18 and K14, type I (acidic) keratins. it is possible that epidermal K14 may function as an inhibitor of TNF–TNFR1 signaling through an association with TRADD.	SIGNOR-251907
Q8TD08	Q15717	1	phosphorylation	down-regulates activity	0.346	ERK8 phosphorylates HuR to prevent its binding to PDCD4 mRNA A. ERK8 or control siRNA was transfected into HeLa cells for 48 h followed by treatment of cells with 0.5 mM H2O2 or PBS for 1 h. Cells were fixed and immunofluorescence was performed to monitor HuR localization.	SIGNOR-278314
P37231	P11310	1	binding	down-regulates activity	0.346	This truncated PPARγ translocates to mitochondria, where it directly interacts with medium-chain acyl-CoA dehydrogenase (MCAD). This binding event attenuates MCAD activity and inhibits fatty acid oxidation	SIGNOR-261264
A6ND36	Q9Y5K6	1	binding	up-regulates activity	0.346	PAWS1 interacts in a dynamic fashion with the actin/cytoskeletal regulator CD2AP at lamellae\|Loss of PAWS1 causes severe defects in F-actin organization and distribution as well as in lamellipodial organization, resulting in impaired cell migration.	SIGNOR-264768
P06702	Q15109	1	binding	up-regulates activity	0.346	RAGE and TLR4 are well-characterized S100A8 and S100A9 receptors and expressed in AML cells Once secreted, S100A8 and S100A9 induce immune and inflammatory responses9 through interaction with receptors such as Toll-like receptor 4 (TLR4), receptor for advanced glycation end-product (RAGE), and CD33	SIGNOR-261920
Q9BT56	O60755	1	binding	up-regulates activity	0.346	Coevolution of the spexin/galanin/kisspeptin family: Spexin activates galanin receptor type II and III.	SIGNOR-268575
Q8N163	O43463	1	binding	down-regulates activity	0.346	Besides SIRT1, CCAR2 inhibits the activity of the histone-modifying enzymes SUV39H1 and HDAC3 [9, 10], thus playing an important role in chromatin structure regulation.	SIGNOR-267664
P23760	Q13207	1	transcriptional regulation	up-regulates quantity by expression	0.346	We have recently found that a T-box gene family member, TBX2, is highly overexpressed in both ERMS and ARMS cells (Zhu et al, 2014). The regulation of TBX2 is uncharacterised in RMS cells, but is likely to link TBX2 expression to the known deregulation of signalling pathways in RMS. In melanoma cells, TBX2 is regulated by PAX3	SIGNOR-249596
O14672	P16070	1	cleavage	up-regulates activity	0.346	The ADAM proteases are best known for their role in shedding the extracellular domain of transmembrane proteins. Among the transmembrane proteins shed by ADAM10 are notch, HER2, E-cadherin, CD44, L1 and the EGFR ligands, EGF and betacellulin.	SIGNOR-259847
Q5VWQ8	P40763	1	binding	down-regulates activity	0.346	DAB2IP could interact with the signal transducer and activator of transcription 3 (STAT3) via its unique PR domain and suppress STAT3 phosphorylation and transactivation, leading to the inhibition of survivin expression in PCa cells.	SIGNOR-254761
P51608	Q06413	1	transcriptional regulation	down-regulates quantity by repression	0.346	MeCP2 binds to the promoter region of six target genes. ChIP with anti-MeCP2 antibody shows that MeCP2 binds to the promoter regions of activated targets Sst, Oprk1, Gamt, and Gprin1, and repressed targets Mef2c and A2bp1.	SIGNOR-264680
Q16649	O15534	1	transcriptional regulation	down-regulates quantity by repression	0.346	E4BP4, a basic leucine zipper transcription factor, contains a DNA-binding domain closely related to DBP, HLF, and TEF, which are PAR proteins. Here, we show that the phase of e4bp4 mRNA rhythm is opposite to that of the dbp, hlf, and tef rhythms in the suprachiasmatic nucleus (SCN), the mammalian circadian center, and the liver. The protein levels of E4BP4 and DBP also fluctuate in almost the opposite phase. All PAR proteins activate, whereas E4BP4 suppresses the mPer1 promoter through the same sequence	SIGNOR-268056
P48730	Q00987	1	phosphorylation	down-regulates	0.345	Phosphorylation by casein kinase i promotes the turnover of the mdm2 oncoprotein via the scf(beta-trcp) ubiquitin ligase.	SIGNOR-167497
Q01726	P50148	1	binding	up-regulates activity	0.345	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-256956
P17252	Q969H0	1	phosphorylation	down-regulates activity	0.345	Here, we report that Fbw7α, the only Fbw7 isoform detected in eggs, is phosphorylated by PKC (protein kinase C) at a key residue (S18) in a manner coincident with Fbw7α inactivation.	SIGNOR-277249
P49674	P55957	1	phosphorylation	up-regulates activity	0.345	Here we report that Bid is phosphorylated by casein kinase I (CKI) and casein kinase II (CKII). Inhibition of CKI and CKII accelerated Fas-mediated apoptosis and Bid cleavage, whereas hyperactivity of the kinases delayed apoptosis. \| These results suggest that residues S61, S64, and to a much lesser extent T58 are sites of phosphorylation of Bid.	SIGNOR-250806
P78347	P54821	1	binding	up-regulates	0.345	Spin binds specifically to multiple sequences in the c-fos promoter and interacts cooperatively withphox1to promote serum-inducible transcription of a reporter gene driven by the c-fos serum response element (sre).	SIGNOR-52654
Q13207	P38936	1	transcriptional regulation	down-regulates quantity by repression	0.345	TBX2 and TBX3 function as transcriptional repressors and both have been shown to inhibit myogenesis (Carlson et al, 2002; Zhu et al, 2014). Abnormal expression of TBX2 has been reported in several cancers including breast, pancreas, and melanoma, where it has been shown to drive proliferation (reviewed in Abrahams et al (2010)). As has been previously shown in other cell types, TBX2 was found to induce a downregulation of p14/19ARF and function as a direct repressor of p21 in RMS	SIGNOR-249593
Q9BYM8	O14867	1	ubiquitination	down-regulates quantity by destabilization	0.345	HOIL-1 bound Bach1 in vivo and thus stimulated its polyubiquitination in vitro. These results suggest that heme regulates the polyubiquitination of Bach1 and subsequent degradation and that HOIL-1 may function as an E3 ligase in this process.	SIGNOR-236971
P42345	O00429	1	phosphorylation	up-regulates activity	0.345	Furthermore, we confirmed also in Jurkat cells that the specific silencing of both ERK1/2 and mTOR by siRNA downregulates Drp1 phosphorylation on Ser616	SIGNOR-275430
Q00535	P53779	1	phosphorylation	down-regulates activity	0.345	Here, we show that cdk5 directly phosphorylates c-Jun N-terminal kinase 3 (JNK3) on Thr131 and inhibits its kinase activity, leading to reduced c-Jun phosphorylation.	SIGNOR-250668
P27361	P61978	1	phosphorylation	down-regulates	0.345	Erk phosphorylation drives cytoplasmic accumulation of hnrnp-k and inhibition of mrna translation mitogen-activated protein kinase/extracellular-signal-regulated kinase (mapk/erk) efficiently phosphorylates hnrnp-k both in vitro and in vivo at serines 284 and 353.	SIGNOR-145375
P49841	P23246	1	phosphorylation	down-regulates	0.345	Psf is directly phosphorylated by gsk3, thus promoting interaction of psf with trap150, which prevents psf from binding cd45 pre-mrna. / threonine phosphorylation of psf by gsk3 primarily occurs on residue t687	SIGNOR-168392
P06493	P10415	1	phosphorylation	up-regulates activity	0.345	Using synthetic peptides and mutant cell lines, we identified threonine 56, one of two consensus sites for cdc2 within the bcl-2 sequence, as a residue phosphorylated by cdc2. Mutation at threonine 56 abrogated the cell cycle inhibitory effect of bcl-2 without affecting anti-apoptotic function.Taken together, our present findings indicate that phosphorylation of bcl-2 at threonine 56 by cdc2 is required for bcl-2-mediated cell cycle inhibition, which may have some roles during mitosis in the normal cell cycle.	SIGNOR-76837
A6NNM3	Q86UR5	1	binding	down-regulates activity	0.345	SH3 domains of RBPs interact with RIMs. The enhancement of depolarization-induced secretion in PC12 cells by fusion proteins that suppress the associations of RBPs with RIMs and α1 suggests that RBPs may repress RIMs, either directly or through associated proteins.	SIGNOR-264364
P42226	O43474	1	transcriptional regulation	up-regulates quantity by expression	0.345	STAT6 coordinates and synergizes with both PPAR? and Krppel-like factor 4 (KLF4), a member of a family of proteins that contribute to macrophage function.	SIGNOR-249568
P00533	P0DP24	1	phosphorylation	down-regulates	0.345	Phosphorylation of calmodulin by the epidermal-growth-factor-receptor tyrosine kinase. Phosphorylated calmodulin does not exhibit the characteristic ca2+ shift normally observed with calmodulin in electrophoretic gels, an observation that is consistent with this modification affecting the biological activity of the molecule.	SIGNOR-266319
Q16539	P42566	1	phosphorylation	up-regulates	0.345	Tnf-_ induces phosphorylation of eps15 at ser-796eps15 is a substrate for p38_these results suggest an attractive model in which p38 phosphorylates both eps15 and egfr to trigger efficient endocytosis	SIGNOR-203315
P12931	P15514	1	cleavage	up-regulates	0.345	Ep2 can also promote the transactivation of epidermal growth factor receptor (egfr) expressed in colon cancer cells through src, which activates the proteolytic release of the egfr ligands amphiregulin (ar) and transforming growth factor-alfa (tgfalfa)125, thereby stimulating the egfr- network.	SIGNOR-236537
P17252	P49840	1	phosphorylation	down-regulates	0.345	Convergence of multiple signaling cascades at glycogen synthase kinase 3: edg receptor-mediated phosphorylation and inactivation by lysophosphatidic acid through a protein kinase c-dependent intracellular pathway.	SIGNOR-115714
Q9Y4K3	O43561	1	ubiquitination	up-regulates activity	0.345	Interestingly, this study has demonstrated that the membrane-proximal region of linker for activation of T cells preceding tyrosine-132 mediates its association with TRAF6, which promotes the ubiquitination of linker for activation of T cells and, in turn, the phosphorylation of tyrosine residues on linker for activation of T cells.\|Moreover, LAT was ubiquitinated at Lysine 88 by TRAF6 via K63 linked chain.	SIGNOR-278675
P06493	Q13586	1	phosphorylation	down-regulates	0.345	Stim1 is phosphorylated during mitosis. Removal of ten mpm-2 recognition sites by truncation at amino acid 482 abolished mpm-2 recognition of mitotic stim1, and significantly rescued stim1 rearrangement and soce response in mitosis. We identified ser 486 and ser 668 as mitosis-specific phosphorylation sites, and stim1 containing mutations of these sites to alanine also significantly rescued mitotic soce.	SIGNOR-189017
Q9UEW8	P13569	1	phosphorylation	down-regulates activity	0.345	SPAK phosphorylates the transporters to reduce their surface expression and thus their activity and consequently inhibits ductal secretion to stabilize the resting state. PP1 reverses the effect of SPAK. Molecular analysis revealed that the WNK kinases acted as scaffolds to recruit SPAK, which phosphorylated CFTR and NBCe1-B, reducing their cell surface expression.	SIGNOR-263134
P06493	P29590	1	phosphorylation	down-regulates	0.345	Here, we show that klhl20, a cullin3 (cul3) substrate adaptor induced by hif-1, coordinates with the actions of cdk1/2 and pin1 to mediate hypoxia-induced pml proteasomal degradation.	SIGNOR-176033
Q9UKB1	Q9HAW4	1	ubiquitination	down-regulates	0.345	Claspin degradation was triggered by its interaction with, and ubiquitylation by, the scfbetatrcp ubiquitin ligase.	SIGNOR-148438
Q00535	O75469	1	phosphorylation	down-regulates activity	0.345	In vitro kinase assays showed that Cdk5 directly phosphorylates PXR.\|Taken together, these data indicate that Cdk5 negatively regulates PXR activity, and that inhibition of Cdk5 is at least partially responsible for flavonoids induced activation of PXR.	SIGNOR-279402
Q06413	P35580	1	transcriptional regulation	up-regulates quantity by expression	0.345	Myocyte enhancer factor-2 and serum response factor binding elements regulate fast Myosin heavy chain transcription in vivo. We show that the upstream promoter region of the gene most abundantly expressed in mouse skeletal muscles, IIb MyHC, retains binding activity and transcriptional activation for three positive transcription factors, the serum response factor, Oct-1, and myocyte enhancer factor-2, whereas the other two genes (IIa and IId/x) have nucleotide substitutions in these sites that reduce binding and transcriptional activation	SIGNOR-238769
Q9C026	P50552	1	ubiquitination	down-regulates quantity	0.345	TRIM9 ubiquitinates VASP but not Mena or EVL.\|Thus TRIM9 negatively regulates VASP localization to filopodia tips, whereas netrin promotes VASP tip localization.	SIGNOR-278580
Q96A56	O95166	1	binding	up-regulates	0.345	Tp53inp1 is also able to interact with atg8-family proteins	SIGNOR-196664
P43250	O75581	1	phosphorylation	up-regulates activity	0.345	In contrast to the GRK5 and GRK6 stimulated activity of wild-type LRP6, the LRP6 M5 mutant failed to respond to the expression of GRK5 or GRK6 (XREF_FIG C) by increased TOPflash reporter activity, indicating that PPPSP motifs are indispensable for GRK5- and GRK6 mediated LRP6 activation.\|Our findings that GRK5 and GRK6 phosphorylate the single membrane-spanning receptor LRP6 on defined serine/threonine sites ( i.e. serine 1490) within proline-rich PPPSP motifs and thereby activate LRP6 are important and interesting in two respects.	SIGNOR-279412
O95071	Q96BY2	1	ubiquitination	down-regulates quantity by destabilization	0.345	We demonstrate that UBR5 interacts physically with MOAP-1, ubiquitylates MOAP-1 in vitro and inhibits MOAP-1 stability in cultured cells.	SIGNOR-278581
P53350	Q38SD2	1	phosphorylation	up-regulates activity	0.345	Here we show that LRRK1 is a PLK1 substrate that is phosphorylated on Ser 1790. PLK1 phosphorylation is required for CDK1-mediated activation of LRRK1 at the centrosomes	SIGNOR-275467
P40189	P29353	1	binding	up-regulates	0.345	Shc mediates IL-6 signaling by interacting with gp130 and Jak2 kinase.	SIGNOR-250574
O00141	O00213	1	phosphorylation	down-regulates activity	0.345	In the present study, we demonstrated that phosphorylation of FE65 Ser 610 by SGK1 attenuates the interaction between FE65 and APP (XREF_FIG).\|In this regard, we demonstrated that phosphorylation of FE65 Ser 610 by SGK1 abolishes the effect of FE65 on APP processing and the amount of secreted Abeta is comparable to APP + Mock control (XREF_FIG).	SIGNOR-278220
P45983	Q5JR12	1	phosphorylation	down-regulates	0.344	Specific phosphorylation of pp2czeta at ser (92) by stress-activated jnk attenuates its phosphatase activity in cells.	SIGNOR-178930
Q00536	O43663	1	phosphorylation	up-regulates activity	0.344	Mechanistically, CDK16 exerts its function by phosphorylating protein regulator of cytokinesis 1 (PRC1) to regulate spindle formation during mitosis.\|Indeed, immunoblot analysis showed that PRC1 phosphorylation at the T481 site (CDK-dependent major phosphorylation site) fluctuated with the abundance of CDK16 protein in the cell cycle process	SIGNOR-273017

Q13535

P16220

1

phosphorylation

down-regulates

0.347

Atm phosphorylated creb in vitro and in vivo in response to ionizing radiation (ir) and h(2)o(2) on a stress-inducible domain. Ir-induced phosphorylation of creb correlated with a decrease in creb transactivation potential and reduced interaction between creb and its transcriptional coactivator, creb-binding protein (cbp). A creb mutant containing ala substitutions at atm phosphorylation sites displayed enhanced transactivation potentialit is, therefore, likely that atm and atr regulate creb phosphorylation collectively in response to stress stimuli.

SIGNOR-124060

P36507

P55211

1

phosphorylation

down-regulates activity

0.347

Inhibition of caspase-9 through phosphorylation at Thr 125 by ERK MAPK|The opposing protein kinase activity is overcome by treatment with the broad-specificity kinase inhibitor staurosporine or with inhibitors of MEK1/2

SIGNOR-249386

P12956

Q16763

1

relocalization

up-regulates activity

0.347

As shown in Figure 4, we found that Ku70 (Figure 4b) and Ku80 (Figure 4c) co-immunoprecipitated with UBE2S.>Taken together, these results demonstrate that ETO enhances the UBE2S–Ku70 interaction, and UBE2S can be recruited to the same sites of DSBs with Ku70 upon ETO treatment.

SIGNOR-265079

Q969V5

O75385

1

ubiquitination

down-regulates quantity

0.347

MUL1 promotes ubiquitination of ULK1.|Overexpression of MUL1 and treatment with selenite promotes ULK1 degradation through the proteasome pathway.

SIGNOR-278759

P41145

P09471

1

binding

up-regulates activity

0.347

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-256989

Q15797

O14640

1

binding

up-regulates

0.347

These results identify a potential mechanism whereby bmp-2 antagonizes wnt signaling in osteoblast progenitors by promoting an interaction between smad1 and dvl-1 that restricts beta-catenin activation.

SIGNOR-146131

A1X283

Q86UR1

1

binding

up-regulates activity

0.347

Tks4 and Tks5 bind NoxA1 through their SH3 domains in a Rac-independent manner|NoxO1 is required for full Nox1 and Nox3 oxidase activity at least partially because of its role in the plasma membrane recruitment of the NoxA1 activator protein|Tks4 and Tks5 support Nox1- and Nox3-dependent ROS generation

SIGNOR-264707

Q9BXM7

Q9Y2N7

1

phosphorylation

down-regulates activity

0.347

Here we show that IPAS is a key molecule involved in neuronal cell death in Parkinson's disease (PD). IPAS was ubiquitinated by Parkin for proteasomal degradation following carbonyl cyanide m-chlorophenyl hydrazone treatment. Phosphorylation of IPAS at Thr12 by PTEN-induced putative kinase 1 (PINK1) was required for ubiquitination to occur.

SIGNOR-263090

P19784

P42768

1

phosphorylation

up-regulates activity

0.347

We identify two phosphorylation sites in the VCA domain of WASP at serines 483 and 484. S483 and S484 are substrates for casein kinase 2 in vitro and in vivo. Phosphorylation of these residues increases the affinity of the VCA domain for the Arp2/3 complex 7-fold and is required for efficient in vitro actin polymerization by the full-length WASP molecule.

SIGNOR-251048

P62258

P20226

1

binding

up-regulates activity

0.347

The in vitro binding with general transcription factors TBP and TFIIB together with its nuclear location provide evidence supporting a role for 14-3-3 proteins as transcriptional activators or coactivators when part of a DNA binding complex.

SIGNOR-262834

P49841

Q9UQB3

1

phosphorylation

down-regulates quantity

0.347

Therefore, our data which supports that partial inhibition of GSK-3beta increases delta-catenin expression, raises an interesting possibility that delta-catenin may be an important downstream target of GSK-3beta signaling that participates in modulating neuronal morphology.|We demonstrate that GSK-3beta forms a stable complex with delta-catenin and phosphorylates delta-catenin in neurons, an event that mediates ubiquitination and subsequent proteasome degradation of delta-catenin.

SIGNOR-279719

O43791

Q96KS0

1

ubiquitination

down-regulates quantity by destabilization

0.347

Tumor suppressor SPOP ubiquitinates and degrades EglN2 to compromise growth of prostate cancer cells

SIGNOR-261996

P53350

Q99708

1

phosphorylation

up-regulates activity

0.347

PLK1 targets CtIP to promote microhomology mediated end joining.|We further showed that the DSB repair factor CtIP is jointly phosphorylated by CDK1 and Aurora A and PLK1.

SIGNOR-279253

P24941

Q92698

1

phosphorylation

down-regulates activity

0.347

Effect of CDK2 phosphorylation on the RAD54 activities. We find that the RAD54 N-terminal domain (NTD) is responsible for initiation of BM through two coupled, but distinct steps; specific binding to Holliday junctions and RAD54 oligomerization. Furthermore, we find that the RAD54 oligomeric state can be controlled by NTD phosphorylation at S49, a CDK2 consensus site, which inhibits RAD54 oligomerization and, consequently, BM.

SIGNOR-273599

P67775

P06730

1

dephosphorylation

down-regulates

0.347

A recent study using genetically engineered mouse models has clearly shown that mnk-mediated eif4e phosphorylation is absolutely required for eif4e's oncogenic action. Taken together, we conclude that pp2a negatively regulates eif4e phosphorylation and eif4f complex assembly through dephosphorylation of mnk and eif4e, thus suggesting a novel mechanism by which pp2a exerts its tumor-suppressive function.

SIGNOR-168306

P06241

P42681

1

phosphorylation

up-regulates activity

0.347

We further demonstrate that Rlk can be phosphorylated and activated by Src kinases, leading to a decrease in its half-life. A specific tyrosine in the activation loop of Rlk, Y420, is required for phosphorylation and activation, as well as for decreased stability, but is not required for lipid RAFT association.

SIGNOR-249341

P63096

P08631

1

binding

up-regulates activity

0.347

Galphas and Galphai similarly modulate Hck, another member of Src-family tyrosine kinases.

SIGNOR-256528

Q9UQ26

Q01668

1

binding

up-regulates activity

0.347

Here, we report an interaction of the C2B domain of RIM2α and RIM3γ with the C-terminus of the pore-forming α-subunit of CaV1.3 channels (CaV1.3α1), which mediate stimulus-secretion coupling at the ribbon synapses of cochlear inner hair cells (IHCs). In conclusion, we propose that RIM2α and RIM3γ directly interact with the C-terminus of the pore-forming subunit of CaV1.3 Ca2+ channels and positively regulate their plasma membrane expression in HEK293 cells.

SIGNOR-264356

Q96JY6

Q04206

1

polyubiquitination

down-regulates quantity by destabilization

0.347

Here we report that PDLIM2 negatively regulated NF-kappaB activity, acting as a nuclear ubiquitin E3 ligase targeting the p65 subunit of NF-kappaB. PDLIM2 bound to p65 and promoted p65 polyubiquitination.

SIGNOR-271651

Q9UBE8

P40763

1

phosphorylation

up-regulates

0.347

Phosphorylation of s727 induces pin1 binding which increases transcription. Pin1 binding increases stat3 interaction with p300 and dna.

SIGNOR-155828

P41146

P09471

1

binding

up-regulates activity

0.347

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-257001

P78347

Q15853

1

binding

up-regulates activity

0.347

TFII-I has been shown to interact with USF and to associate with either E-box elements or initiator sequences to activate gene transcription

SIGNOR-268537

Q9H270

P35241

1

binding

up-regulates activity

0.347

Vps11 was found to interact with radixin. ERM proteins and the HOPS complex are required for the transition from early to late endosomes. We report that an interaction between subunits of the HOPS complex and the ERM (ezrin, radixin, moesin) proteins is required for the delivery of EGF receptor (EGFR) to lysosomes. Inhibiting either ERM proteins or the HOPS complex leads to the accumulation of the EGFR into early endosomes, delaying its degradation.

SIGNOR-261312

P49137

P27815

1

phosphorylation

down-regulates activity

0.347

Phosphorylation of cAMP-specific PDE4A5 (phosphodiesterase-4A5) by MK2 (MAPKAPK2) attenuates its activation through protein kinase A phosphorylation. In the present study, we show that PDE4A5 is phosphorylated at Ser147, within the regulatory UCR1 (ultraconserved region 1) domain conserved among PDE4 long isoforms, by MK2 (MAPK-activated protein kinase 2, also called MAPKAPK2). Phosphorylation by MK2, although not altering PDE4A5 activity, markedly attenuates PDE4A5 activation through phosphorylation by protein kinase A. This modification confers the amplification of intracellular cAMP accumulation in response to adenylate cyclase activation by attenuating a major desensitization system to cAMP.

SIGNOR-263078

Q92997

Q9NQ66

1

null

up-regulates activity

0.347

Dsh through PLC activates IP3, which leads to release of intracellular Ca2+, which in turn activates CamK11 and calcineurin

SIGNOR-258980

P07948

O15492

1

phosphorylation

up-regulates activity

0.346

Lyn kinase phosphorylated recombinant RGS16 in vitro. Induction of RGS16 tyrosine phosphorylation was associated with increased RGS16 protein levels and enhanced GAP activity in cell membranes.

SIGNOR-251410

P53350

P11413

1

phosphorylation

up-regulates activity

0.346

We find that Plk1 interacts with and directly phosphorylates glucose-6-phosphate dehydrogenase (G6PD). By activating G6PD through promoting the formation of its active dimer, Plk1 increases PPP flux and directs glucose to the synthesis of macromolecules.|the kinase domain of Plk1 phosphorylates T406, T466 of G6PD

SIGNOR-267581

P01100

P11511

1

transcriptional regulation

up-regulates quantity by expression

0.346

We found that both SF1 and LRH1 can transcriptionally cooperate with the AP-1 family members c-JUN and c-FOS, known to be associated with enhanced proliferation of endometrial carcinoma cells, to further enhance activation of the STAR, HSD3B2, and CYP19A1 PII promoters.

SIGNOR-254879

P49841

Q14103

1

phosphorylation

down-regulates activity

0.346

In kinase assays pka phosphorylated ser-87 of hnrnp d, whereas glycogen synthase kinase-3 beta (gsk-3 beta) phosphorylated ser-83, but only if ser-87 had been pre-phosphorylated by pka. Phosphorylation of ser-87 enhanced, whereas phosphorylation of ser-83 repressed, transactivation.

SIGNOR-102582

P28482

P46527

1

phosphorylation

up-regulates

0.346

Phosphorylation on ser-10 of kip1 is the major site of phosphorylation in resting cells, takes place at the g(0)-g1 phase and leads to protein stability.

SIGNOR-77651

P68400

Q9H257

1

phosphorylation

down-regulates activity

0.346

PVHL Acts as an Adaptor to Promote the Inhibitory Phosphorylation of the NF-κB Agonist Card9 by CK2

SIGNOR-257601

Q969Q6

P53041

1

binding

up-regulates activity

0.346

Protein phosphatase complex PP5/PPP2R3C dephosphorylates P-glycoprotein/ABCB1 and down-regulates the expression and function

SIGNOR-272480

Q969T4

P25963

1

sumoylation

up-regulates quantity by stabilization

0.346

In the presence of an E1 SUMO-1-activating enzyme, Ubch9 conjugated SUMO-1 to IkappaBalpha primarily on K21, which is also utilized for ubiquitin modification. Thus, SUMO-1-modified IkappaBalpha cannot be ubiquitinated and is resistant to proteasome-mediated degradation.

SIGNOR-270545

O95198

Q9HA47

1

ubiquitination

down-regulates quantity by destabilization

0.346

We demonstrated that the ubiquitin E3 ligase KLHL2 interacted with UCK1 and mediated its polyubiquitination at the K81 residue and degradation. We showed that deubiquitinase USP28 antagonized KLHL2-mediated polyubiquitylation of UCK1.

SIGNOR-275962

P68400

Q14676

1

phosphorylation

up-regulates

0.346

The mdc1-nbs1 interaction occurs through a specific region (residues 200-420) of mdc1, which contains multiple consensus casein kinase 2 (ck2) phosphorylation sites.

SIGNOR-179887

P18031

Q05397

1

dephosphorylation

down-regulates activity

0.346

The focal adhesion kinase (FAK) is a key regulator of cell migration. Phosphorylation at Tyr-397 activates FAK |The dephosphorylation at Tyr-397 in FAK triggered by wild-type alpha-actinin and PTP 1B caused a significant increase in cell migration.

SIGNOR-248431

Q86V86

Q92934

1

phosphorylation

down-regulates activity

0.346

Pim kinases phosphorylate multiple sites on Bad and promote 14-3-3 binding and dissociation from Bcl-XL. pim kinases are constitutively active when expressed in HEK-293 cells and are able to phosphorylate the Bcl-2 family member Bad on three residues, Ser112, Ser136 and Ser155 in vitro and in cells.

SIGNOR-250399

Q70E73

Q9UI08

1

binding

up-regulates activity

0.346

Here we show that Lpd is a substrate of Abl kinases and binds to the Abl SH2 domain. Phosphorylation of Lpd positively regulates the interaction between Lpd and Ena/VASP proteins.

SIGNOR-268427

Q05655

Q01543

1

phosphorylation

down-regulates

0.346

We have previously demonstrated that in response to transforming growth factor _ (tgf_), fli-1 activity is repressed through a series of sequential posttranslational modifications, consisting of protein kinase c_ (pkc_)-induced thr312 phosphorylation, acetylation by p300/creb binding protein-associated factor, and detachment from the collagen promoter.

SIGNOR-172113

P01106

Q02127

1

transcriptional regulation

up-regulates quantity by expression

0.346

PPAT, catalyzing the first step of purine synthesis, and DHODH, an enzyme generating uridine in the middle of the pyrimidine synthesis pathway, were validated as direct c-MYC target genes by all criteria.

SIGNOR-267382

Q96EP1

Q96KB5

1

polyubiquitination

down-regulates quantity by destabilization

0.346

CHFR ubiquitinates and degrades TOPK. Our in vivo ubiquitination assays revealed that the polyubiquitination of TOPK occurs only in the presence of full length CHFR but not with the ΔRING or Δcysteine-rich domain deletion mutants (Fig. 2a).

SIGNOR-271471

P24941

O75533

1

phosphorylation

up-regulates

0.346

To map the set of phosphorylation sites in sap155-(223-322) that determine its interaction with nipp1, we have identified phosphorylation sites of cyclin e-cdk2 by the sequencing of proteolytically derived phosphopeptide). Three phosphorylation sites were identified as thr244, thr248, and thr313

SIGNOR-90434

P49841

P33076

1

phosphorylation

up-regulates

0.346

Here we report that CIITA represses collagen transcription through a phosphorylation-dependent interaction between its proline/serine/threonine domain and co-repressor molecules such as histone deacetylase (HDAC2) and Sin3B. Mutation of a serine (S373A) in CIITA, within a glycogen synthase kinase 3 (GSK3) consensus site, decreases repression of collagen transcription by blocking interaction with Sin3B

SIGNOR-158959

Q5JUK2

P10721

1

transcriptional regulation

up-regulates quantity by expression

0.346

Our results suggest that SOHLH1 and SOHLH2 directly stimulate Kit transcription in postnatal spermatogonia, thus activating the signaling involved in spermatogonia differentiation and spermatogenetic progression.

SIGNOR-266205

O14965

P35222

1

phosphorylation

up-regulates quantity

0.346

In addition, Aurora-A overexpression is significantly correlated with increased cytoplasmic \u03b2-catenin expression in esophageal squamous cell carcinoma tissues.|We also demonstrate for the first time that Aurora-A directly interacts with \u03b2-catenin and phosphorylates \u03b2-catenin at Ser552 and Ser675.

SIGNOR-278468

Q13315

Q15911

1

phosphorylation

up-regulates activity

0.346

Indeed, ATM phosphorylates ATBF1 at Ser1180 in HEK293T cells exposed to 10-Gy radiation [ xref ].|We also found in this study that ATBF1 mediated neuronal death is dependent on ATM signals because the blockage of ATM by treatment with ATM inhibitors, caffeine and KU55933, abolished ATBF1 functions in neuronal death.

SIGNOR-279138

Q8WUJ0

Q969H0

1

binding

down-regulates activity

0.346

STYX acts as a direct inhibitor of FBXW7, affecting the cellular levels of its substrates. Furthermore, we find that levels of STYX and FBXW7 are anti-correlated in breast cancer patients,

SIGNOR-251663

O15294

P08237

1

glycosylation

down-regulates activity

0.346

Our previous investigation on O-GlcNAcylation of PFK1 has demonstrated that O-GlcNAcylation inhibits PFK1 enzyme activity|In cells, a single set of antagonistic enzymes-O-GlcNAc transferase (OGT) and O-GlcNAc hydrolase are responsible for the addition and removal of GlcNAc moiety, respectively.

SIGNOR-267584

P12931

O15492

1

phosphorylation

up-regulates

0.346

Src-mediated rgs16 tyrosine phosphorylation promotes rgs16 stability. / this result suggests src phosphorylates native rgs16 at residue tyr177 in vitro.

SIGNOR-98271

P49841

Q14653

1

phosphorylation

up-regulates activity

0.346

Invitro, both GSK3alpha and GSK3beta phosphorylate IRF3 at the linker region.

SIGNOR-279182

Q9H2X6

Q9NY61

1

phosphorylation

down-regulates quantity

0.346

HIPK2 phosphorylates Che-1.|Here we demonstrate that HIPK2, a proapoptotic kinase, is involved in Che-1 degradation.

SIGNOR-278942

Q92630

O95863

1

phosphorylation

down-regulates activity

0.346

DYRK2 mediated Snail degradation protects against tumor cell metastasis.|DYRK2 phosphorylation of Snail at Ser104 triggers sequential phosphorylation by GSK3.

SIGNOR-279328

P17612

Q13698

1

phosphorylation

up-regulates activity

0.346

To identify the regulatory sites of phosphorylation under physiologically relevant conditions, Ca(V)1.1 channels were purified from skeletal muscle and sites of phosphorylation on the α1 subunit were identified by mass spectrometry. Two phosphorylation sites were identified in the proximal C-terminal domain, serine 1575 (S1575) and threonine 1579 (T1579), which are conserved in cardiac Ca(V)1.2 channels (S1700 and T1704, respectively). In vitro phosphorylation revealed that Ca(V)1.1-S1575 is a substrate for both cAMP-dependent protein kinase and calcium/calmodulin-dependent protein kinase II, whereas Ca(V)1.1-T1579 is a substrate for casein kinase 2.

SIGNOR-263112

Q9Y5X3

Q14185

1

binding

up-regulates activity

0.346

SNX5 Is a Novel Binding Partner of the DHR1 Domain of DOCK180. In summary, we found that DOCK180 regulates transport of CI-MPR via SNX5 binding.

SIGNOR-269441

P02533

Q15628

1

binding

down-regulates activity

0.346

TRADD specifically bound K18 and K14, type I (acidic) keratins. it is possible that epidermal K14 may function as an inhibitor of TNF–TNFR1 signaling through an association with TRADD.

SIGNOR-251907

Q8TD08

Q15717

1

phosphorylation

down-regulates activity

0.346

ERK8 phosphorylates HuR to prevent its binding to PDCD4 mRNA A. ERK8 or control siRNA was transfected into HeLa cells for 48 h followed by treatment of cells with 0.5 mM H2O2 or PBS for 1 h. Cells were fixed and immunofluorescence was performed to monitor HuR localization.

SIGNOR-278314

P37231

P11310

1

binding

down-regulates activity

0.346

This truncated PPARγ translocates to mitochondria, where it directly interacts with medium-chain acyl-CoA dehydrogenase (MCAD). This binding event attenuates MCAD activity and inhibits fatty acid oxidation

SIGNOR-261264

A6ND36

Q9Y5K6

1

binding

up-regulates activity

0.346

PAWS1 interacts in a dynamic fashion with the actin/cytoskeletal regulator CD2AP at lamellae|Loss of PAWS1 causes severe defects in F-actin organization and distribution as well as in lamellipodial organization, resulting in impaired cell migration.

SIGNOR-264768

P06702

Q15109

1

binding

up-regulates activity

0.346

RAGE and TLR4 are well-characterized S100A8 and S100A9 receptors and expressed in AML cells Once secreted, S100A8 and S100A9 induce immune and inflammatory responses9 through interaction with receptors such as Toll-like receptor 4 (TLR4), receptor for advanced glycation end-product (RAGE), and CD33

SIGNOR-261920

Q9BT56

O60755

1

binding

up-regulates activity

0.346

Coevolution of the spexin/galanin/kisspeptin family: Spexin activates galanin receptor type II and III.

SIGNOR-268575

Q8N163

O43463

1

binding

down-regulates activity

0.346

Besides SIRT1, CCAR2 inhibits the activity of the histone-modifying enzymes SUV39H1 and HDAC3 [9, 10], thus playing an important role in chromatin structure regulation.

SIGNOR-267664

P23760

Q13207

1

transcriptional regulation

up-regulates quantity by expression

0.346

We have recently found that a T-box gene family member, TBX2, is highly overexpressed in both ERMS and ARMS cells (Zhu et al, 2014). The regulation of TBX2 is uncharacterised in RMS cells, but is likely to link TBX2 expression to the known deregulation of signalling pathways in RMS. In melanoma cells, TBX2 is regulated by PAX3

SIGNOR-249596

O14672

P16070

1

cleavage

up-regulates activity

0.346

The ADAM proteases are best known for their role in shedding the extracellular domain of transmembrane proteins. Among the transmembrane proteins shed by ADAM10 are notch, HER2, E-cadherin, CD44, L1 and the EGFR ligands, EGF and betacellulin.

SIGNOR-259847

Q5VWQ8

P40763

1

binding

down-regulates activity

0.346

DAB2IP could interact with the signal transducer and activator of transcription 3 (STAT3) via its unique PR domain and suppress STAT3 phosphorylation and transactivation, leading to the inhibition of survivin expression in PCa cells.

SIGNOR-254761

P51608

Q06413

1

transcriptional regulation

down-regulates quantity by repression

0.346

MeCP2 binds to the promoter region of six target genes. ChIP with anti-MeCP2 antibody shows that MeCP2 binds to the promoter regions of activated targets Sst, Oprk1, Gamt, and Gprin1, and repressed targets Mef2c and A2bp1.

SIGNOR-264680

Q16649

O15534

1

transcriptional regulation

down-regulates quantity by repression

0.346

E4BP4, a basic leucine zipper transcription factor, contains a DNA-binding domain closely related to DBP, HLF, and TEF, which are PAR proteins. Here, we show that the phase of e4bp4 mRNA rhythm is opposite to that of the dbp, hlf, and tef rhythms in the suprachiasmatic nucleus (SCN), the mammalian circadian center, and the liver. The protein levels of E4BP4 and DBP also fluctuate in almost the opposite phase. All PAR proteins activate, whereas E4BP4 suppresses the mPer1 promoter through the same sequence

SIGNOR-268056

P48730

Q00987

1

phosphorylation

down-regulates

0.345

Phosphorylation by casein kinase i promotes the turnover of the mdm2 oncoprotein via the scf(beta-trcp) ubiquitin ligase.

SIGNOR-167497

Q01726

P50148

1

binding

up-regulates activity

0.345

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-256956

P17252

Q969H0

1

phosphorylation

down-regulates activity

0.345

Here, we report that Fbw7α, the only Fbw7 isoform detected in eggs, is phosphorylated by PKC (protein kinase C) at a key residue (S18) in a manner coincident with Fbw7α inactivation.

SIGNOR-277249

P49674

P55957

1

phosphorylation

up-regulates activity

0.345

Here we report that Bid is phosphorylated by casein kinase I (CKI) and casein kinase II (CKII). Inhibition of CKI and CKII accelerated Fas-mediated apoptosis and Bid cleavage, whereas hyperactivity of the kinases delayed apoptosis. | These results suggest that residues S61, S64, and to a much lesser extent T58 are sites of phosphorylation of Bid.

SIGNOR-250806

P78347

P54821

1

binding

up-regulates

0.345

Spin binds specifically to multiple sequences in the c-fos promoter and interacts cooperatively withphox1to promote serum-inducible transcription of a reporter gene driven by the c-fos serum response element (sre).

SIGNOR-52654

Q13207

P38936

1

transcriptional regulation

down-regulates quantity by repression

0.345

TBX2 and TBX3 function as transcriptional repressors and both have been shown to inhibit myogenesis (Carlson et al, 2002; Zhu et al, 2014). Abnormal expression of TBX2 has been reported in several cancers including breast, pancreas, and melanoma, where it has been shown to drive proliferation (reviewed in Abrahams et al (2010)). As has been previously shown in other cell types, TBX2 was found to induce a downregulation of p14/19ARF and function as a direct repressor of p21 in RMS

SIGNOR-249593

Q9BYM8

O14867

1

ubiquitination

down-regulates quantity by destabilization

0.345

HOIL-1 bound Bach1 in vivo and thus stimulated its polyubiquitination in vitro. These results suggest that heme regulates the polyubiquitination of Bach1 and subsequent degradation and that HOIL-1 may function as an E3 ligase in this process.

SIGNOR-236971

P42345

O00429

1

phosphorylation

up-regulates activity

0.345

Furthermore, we confirmed also in Jurkat cells that the specific silencing of both ERK1/2 and mTOR by siRNA downregulates Drp1 phosphorylation on Ser616

SIGNOR-275430

Q00535

P53779

1

phosphorylation

down-regulates activity

0.345

Here, we show that cdk5 directly phosphorylates c-Jun N-terminal kinase 3 (JNK3) on Thr131 and inhibits its kinase activity, leading to reduced c-Jun phosphorylation.

SIGNOR-250668

P27361

P61978

1

phosphorylation

down-regulates

0.345

Erk phosphorylation drives cytoplasmic accumulation of hnrnp-k and inhibition of mrna translation mitogen-activated protein kinase/extracellular-signal-regulated kinase (mapk/erk) efficiently phosphorylates hnrnp-k both in vitro and in vivo at serines 284 and 353.

SIGNOR-145375

P49841

P23246

1

phosphorylation

down-regulates

0.345

Psf is directly phosphorylated by gsk3, thus promoting interaction of psf with trap150, which prevents psf from binding cd45 pre-mrna. / threonine phosphorylation of psf by gsk3 primarily occurs on residue t687

SIGNOR-168392

P06493

P10415

1

phosphorylation

up-regulates activity

0.345

Using synthetic peptides and mutant cell lines, we identified threonine 56, one of two consensus sites for cdc2 within the bcl-2 sequence, as a residue phosphorylated by cdc2. Mutation at threonine 56 abrogated the cell cycle inhibitory effect of bcl-2 without affecting anti-apoptotic function.Taken together, our present findings indicate that phosphorylation of bcl-2 at threonine 56 by cdc2 is required for bcl-2-mediated cell cycle inhibition, which may have some roles during mitosis in the normal cell cycle.

SIGNOR-76837

A6NNM3

Q86UR5

1

binding

down-regulates activity

0.345

SH3 domains of RBPs interact with RIMs. The enhancement of depolarization-induced secretion in PC12 cells by fusion proteins that suppress the associations of RBPs with RIMs and α1 suggests that RBPs may repress RIMs, either directly or through associated proteins.

SIGNOR-264364

P42226

O43474

1

transcriptional regulation

up-regulates quantity by expression

0.345

STAT6 coordinates and synergizes with both PPAR? and Krppel-like factor 4 (KLF4), a member of a family of proteins that contribute to macrophage function.

SIGNOR-249568

P00533

P0DP24

1

phosphorylation

down-regulates

0.345

Phosphorylation of calmodulin by the epidermal-growth-factor-receptor tyrosine kinase. Phosphorylated calmodulin does not exhibit the characteristic ca2+ shift normally observed with calmodulin in electrophoretic gels, an observation that is consistent with this modification affecting the biological activity of the molecule.

SIGNOR-266319

Q16539

P42566

1

phosphorylation

up-regulates

0.345

Tnf-_ induces phosphorylation of eps15 at ser-796eps15 is a substrate for p38_these results suggest an attractive model in which p38 phosphorylates both eps15 and egfr to trigger efficient endocytosis

SIGNOR-203315

P12931

P15514

1

cleavage

up-regulates

0.345

Ep2 can also promote the transactivation of epidermal growth factor receptor (egfr) expressed in colon cancer cells through src, which activates the proteolytic release of the egfr ligands amphiregulin (ar) and transforming growth factor-alfa (tgfalfa)125, thereby stimulating the egfr- network.

SIGNOR-236537

P17252

P49840

1

phosphorylation

down-regulates

0.345

Convergence of multiple signaling cascades at glycogen synthase kinase 3: edg receptor-mediated phosphorylation and inactivation by lysophosphatidic acid through a protein kinase c-dependent intracellular pathway.

SIGNOR-115714

Q9Y4K3

O43561

1

ubiquitination

up-regulates activity

0.345

Interestingly, this study has demonstrated that the membrane-proximal region of linker for activation of T cells preceding tyrosine-132 mediates its association with TRAF6, which promotes the ubiquitination of linker for activation of T cells and, in turn, the phosphorylation of tyrosine residues on linker for activation of T cells.|Moreover, LAT was ubiquitinated at Lysine 88 by TRAF6 via K63 linked chain.

SIGNOR-278675

P06493

Q13586

1

phosphorylation

down-regulates

0.345

Stim1 is phosphorylated during mitosis. Removal of ten mpm-2 recognition sites by truncation at amino acid 482 abolished mpm-2 recognition of mitotic stim1, and significantly rescued stim1 rearrangement and soce response in mitosis. We identified ser 486 and ser 668 as mitosis-specific phosphorylation sites, and stim1 containing mutations of these sites to alanine also significantly rescued mitotic soce.

SIGNOR-189017

Q9UEW8

P13569

1

phosphorylation

down-regulates activity

0.345

SPAK phosphorylates the transporters to reduce their surface expression and thus their activity and consequently inhibits ductal secretion to stabilize the resting state. PP1 reverses the effect of SPAK. Molecular analysis revealed that the WNK kinases acted as scaffolds to recruit SPAK, which phosphorylated CFTR and NBCe1-B, reducing their cell surface expression.

SIGNOR-263134

P06493

P29590

1

phosphorylation

down-regulates

0.345

Here, we show that klhl20, a cullin3 (cul3) substrate adaptor induced by hif-1, coordinates with the actions of cdk1/2 and pin1 to mediate hypoxia-induced pml proteasomal degradation.

SIGNOR-176033

Q9UKB1

Q9HAW4

1

ubiquitination

down-regulates

0.345

Claspin degradation was triggered by its interaction with, and ubiquitylation by, the scfbetatrcp ubiquitin ligase.

SIGNOR-148438

Q00535

O75469

1

phosphorylation

down-regulates activity

0.345

In vitro kinase assays showed that Cdk5 directly phosphorylates PXR.|Taken together, these data indicate that Cdk5 negatively regulates PXR activity, and that inhibition of Cdk5 is at least partially responsible for flavonoids induced activation of PXR.

SIGNOR-279402

Q06413

P35580

1

transcriptional regulation

up-regulates quantity by expression

0.345

Myocyte enhancer factor-2 and serum response factor binding elements regulate fast Myosin heavy chain transcription in vivo. We show that the upstream promoter region of the gene most abundantly expressed in mouse skeletal muscles, IIb MyHC, retains binding activity and transcriptional activation for three positive transcription factors, the serum response factor, Oct-1, and myocyte enhancer factor-2, whereas the other two genes (IIa and IId/x) have nucleotide substitutions in these sites that reduce binding and transcriptional activation

SIGNOR-238769

Q9C026

P50552

1

ubiquitination

down-regulates quantity

0.345

TRIM9 ubiquitinates VASP but not Mena or EVL.|Thus TRIM9 negatively regulates VASP localization to filopodia tips, whereas netrin promotes VASP tip localization.

SIGNOR-278580

Q96A56

O95166

1

binding

up-regulates

0.345

Tp53inp1 is also able to interact with atg8-family proteins

SIGNOR-196664

P43250

O75581

1

phosphorylation

up-regulates activity

0.345

In contrast to the GRK5 and GRK6 stimulated activity of wild-type LRP6, the LRP6 M5 mutant failed to respond to the expression of GRK5 or GRK6 (XREF_FIG C) by increased TOPflash reporter activity, indicating that PPPSP motifs are indispensable for GRK5- and GRK6 mediated LRP6 activation.|Our findings that GRK5 and GRK6 phosphorylate the single membrane-spanning receptor LRP6 on defined serine/threonine sites ( i.e. serine 1490) within proline-rich PPPSP motifs and thereby activate LRP6 are important and interesting in two respects.

SIGNOR-279412

O95071

Q96BY2

1

ubiquitination

down-regulates quantity by destabilization

0.345

We demonstrate that UBR5 interacts physically with MOAP-1, ubiquitylates MOAP-1 in vitro and inhibits MOAP-1 stability in cultured cells.

SIGNOR-278581

P53350

Q38SD2

1

phosphorylation

up-regulates activity

0.345

Here we show that LRRK1 is a PLK1 substrate that is phosphorylated on Ser 1790. PLK1 phosphorylation is required for CDK1-mediated activation of LRRK1 at the centrosomes

SIGNOR-275467

P40189

P29353

1

binding

up-regulates

0.345

Shc mediates IL-6 signaling by interacting with gp130 and Jak2 kinase.

SIGNOR-250574

O00141

O00213

1

phosphorylation

down-regulates activity

0.345

In the present study, we demonstrated that phosphorylation of FE65 Ser 610 by SGK1 attenuates the interaction between FE65 and APP (XREF_FIG).|In this regard, we demonstrated that phosphorylation of FE65 Ser 610 by SGK1 abolishes the effect of FE65 on APP processing and the amount of secreted Abeta is comparable to APP + Mock control (XREF_FIG).

SIGNOR-278220

P45983

Q5JR12

1

phosphorylation

down-regulates

0.344

Specific phosphorylation of pp2czeta at ser (92) by stress-activated jnk attenuates its phosphatase activity in cells.

SIGNOR-178930

Q00536

O43663

1

phosphorylation

up-regulates activity

0.344

Mechanistically, CDK16 exerts its function by phosphorylating protein regulator of cytokinesis 1 (PRC1) to regulate spindle formation during mitosis.|Indeed, immunoblot analysis showed that PRC1 phosphorylation at the T481 site (CDK-dependent major phosphorylation site) fluctuated with the abundance of CDK16 protein in the cell cycle process

SIGNOR-273017