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
Q13501	P50542	binding	up-regulates activity	0.372	Specificity for autophagy of peroxisomes (pexophagy) is provided by ATM phosphorylation of PEX5 at Ser 141, which promotes PEX5 monoubiquitylation at Lys 209, and recognition of ubiquitylated PEX5 by the autophagy adaptor protein p62, directing the autophagosome to peroxisomes to induce pexophagy.	SIGNOR-262793
Q9Y286	O14543	binding	down-regulates quantity by destabilization	0.372	SOCS proteins can act as E3 ligases by forming a complex with Elongin B/C and Cul5/Rbx1/2.SOCS3 targets Siglec 7 for degradation	SIGNOR-272642
P28329	Q9UQM7	phosphorylation	up-regulates	0.372	We show that chat is differentially phosphorylated by protein kinase c (pkc) isoforms on four serines (ser-440, ser-346, ser-347, and ser-476) and one threonine (thr-255). This phosphorylation is hierarchical, with phosphorylation at ser-476 required for phosphorylation at other serines. Phosphorylation at some, but not all, sites regulates basal catalysis and activation.	SIGNOR-96628
P15923	P27361	phosphorylation	down-regulates quantity by destabilization	0.372	Notch-induced degradation requires phosphorylation of E47 by p42/p44 MAP kinases. \|Wild_type E47 but not the Mm mutant reacted to the antibodies, suggesting that E47 is at least phosphorylated at the M2 site (Figure 3A)\|anti_phospho_M2 peptide (SSPSpTPVGSPQG)	SIGNOR-249117
P06213	P54646	phosphorylation	up-regulates	0.372	Ampk phosphorylates and activates theinsulinreceptor, providing a direct link between ampk and theinsulin pathway.	SIGNOR-195324
Q96RK0	P28482	phosphorylation	down-regulates	0.372	Specifically, 14-3-3 binds to p90(rsk)-phosphorylated ser?_??_ Of capic?_A thereby modulating dna binding to its hmg (high-mobility group) box, whereas erk phosphorylations prevent binding of a c-terminal nls (nuclear localization sequence) to importin ?4 (kpna3))[...] These results suggest that erk phosphorylation of ser1382 and ser1409 masks the nls and prevents its binding to kpna3	SIGNOR-169875
Q96HP0	P31749	phosphorylation	up-regulates activity	0.372	Akt and PP2A reciprocally regulate the guanine nucleotide exchange factor Dock6 to control axon growth of sensory neurons\|At later developmental stages, the abundance of the kinase Akt increased, resulting in the binding of Akt to Dock6 and the phosphorylation of Dock6 at Ser(1194). \| In dorsal root ganglion neurons from mice lacking Dock6, reintroduction of Dock6 with a nonphosphorylatable S1194A mutation rescued axon extension but not branch number, whereas reintroduction of Dock6 with a phosphomimetic S1194E mutation resulted in premature branching	SIGNOR-275666
P49840	P17612	phosphorylation	down-regulates	0.372	Phosphorylation of ser21 and inactivation of glycogen synthase kinase 3 by protein kinase a.	SIGNOR-83221
Q9UHV7	Q969H0	ubiquitination	down-regulates quantity by destabilization	0.371	The SCF-Fbw7 ubiquitin ligase degrades MED13 and MED13L and regulates CDK8 module association with Mediator. We show that Fbw7, a tumor suppressor and ubiquitin ligase, binds to CDK8-Mediator and targets MED13/13L for degradation. MED13/13L physically link the CDK8 module to Mediator, and Fbw7 loss increases CDK8 module-Mediator association.	SIGNOR-266690
Q92934	P11309	phosphorylation	down-regulates activity	0.371	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-250390
P98177	Q13131	phosphorylation	up-regulates	0.371	The energy sensor amp-activated protein kinase (ampk) has been shown to directly phosphorylate foxo factors at six regulatory sites that are distinct from the akt phosphorylation sites, resulting in foxo activation	SIGNOR-157947
P37840	P48729	phosphorylation	up-regulates	0.371	In vitro experiments and two-dimensional phosphopeptide mapping provided further evidence that serine 129 was phosphorylated by ck-1 and ck-2. Moreover, phosphorylation of serine 129 was reduced in vivo upon inhibition of ck-1 or ck-2. These data demonstrate that alpha-synuclein is constitutively phosphorylated within its c terminus and may indicate that the function of alpha-synuclein is regulated by phosphorylation/dephosphorylation.From these data we conclude that _-synuclein is predominantly phosphorylated at serine residue 129. However, a second serine at position 87 is also used for phosphorylation to some extent. together, these data may indicate that ck-1 and ck-2 are involved in the regulation of neuronal function and one may speculate that phosphorylation of _-synuclein could affect its binding to membranes.	SIGNOR-73799
P29474	Q00535	phosphorylation	down-regulates	0.371	Together, our data suggest that cdk5 can phosphorylate enos at the ser-113 site and down-regulate enos-derived no levels.	SIGNOR-164080
P00533	Q9UQM7	phosphorylation	down-regulates activity	0.371	We show that serines 1046/1047 are sites for CaM kinase II phosphorylation, although there is a preference for serine 1047, which resides within the consensus -R-X-X-S-. In addition, we have identified major phosphorylation sites at serine 1142 and serine 1057, which lie within a novel -S-X-D- consensus. Mutation of serines 1046/1047 in full-length EGFR enhanced both fibroblast transformation and tyrosine autokinase activity that was significantly potentiated by additional mutation of serines 1057 and 1142. A single CaM kinase II site was also identified at serine 744 within sub-kinase domain III, and autokinase activity was significantly affected by mutation of this serine to an aspartic acid making this site appear constitutively phosphorylated. We have addressed the mechanism by which CaM kinase II phosphorylation of the EGFR might regulate receptor autokinase activity and show that this modification can hinder association of the cytoplasmic tail with the kinase domain to prevent an enzyme-substrate interaction.	SIGNOR-250621
P22681	Q8IZP0	binding	up-regulates	0.371	Here we uncover a novel interaction between abi-1 and the cbl ubiquitin ligase and show that abi-1 mediates cbl accumulation to the plasma membrane upon stimulation by egf.	SIGNOR-154162
Q96QB1	Q15139	phosphorylation	down-regulates	0.371	The tumor suppressor protein dlc1 is regulated by pkd-mediated gap domain phosphorylation.Our results thus show that pkd-mediated phosphorylation of dlc1 on serine 807 negatively regulates dlc1 cellular function.	SIGNOR-169994
P01106	P15884	transcriptional regulation	up-regulates quantity by expression	0.371	Association of c-Jun, β-catenin, and TCF4 specifically with the downstream enhancer underlies mitogen stimulation of c-Myc transcription.	SIGNOR-253324
P35354	Q13469	transcriptional regulation	up-regulates quantity by expression	0.371	NFAT induces the transcription of the COX2 (cyclo-oxygenase-2) gene incancer cells thereby enhancing invasive migration	SIGNOR-264025
P49715	P27361	phosphorylation	down-regulates	0.371	Ccaat/enhancer-binding protein alpha (c/ebpalpha) is one of the key transcription factors that mediate lineage specification and differentiation of multipotent myeloid progenitors into mature granulocytes.Here we report that inducers of monocyte differentiation inhibit the alternate cell fate choice, that of granulopoiesis, through inhibition of c/ebpalpha. This inhibition is mediated by extracellular signal-regulated kinases 1 and/or 2 (erk1/2), which interact with c/ebpalpha through an fxfp docking site and phosphorylate serine 21.	SIGNOR-120570
P14618	P45983	phosphorylation	up-regulates activity	0.371	Active JNK1 specifically activates PKM2 but not PKM1. Mechanistically, PARP14 inhibits the pro-apoptotic kinase JNK1, which results in the activation of PKM2 through phosphorylation of Thr365.	SIGNOR-276933
Q9Y3Q4	P12931	phosphorylation	up-regulates	0.371	These results demonstrate that src tyrosine kinase enhances hcn4 currents by shifting their activation to more positive potentials and increasing the whole cell channel conductance as well as speeding the channel kinetics. The tyrosine residue that mediates most of src s actions on hcn4 channels is tyr531.	SIGNOR-158707
O94782	P06493	phosphorylation	up-regulates activity	0.371	In this study, we show that Ser313 phosphorylation in USP1 is required for its interaction with UAF1 and for the stimulation of USP1's activity. We further demonstrated that CDK1 is responsible for Ser313 phosphorylation, and protein phosphatase treatment of USP1 can lead to inactivation of USP1/UAF1.	SIGNOR-276423
Q15058	Q8TDX7	phosphorylation	up-regulates activity	0.371	Nek7 direct phosphorylation is required for the anaphase localization of Kif14. we generated an EGFP-Kif14-5A construct in which Ser56, Ser607, Ser1217, Ser1219, and Ser1220 were all mutated to Ala. When transfected into HeLa cells, EGFP-Kif14-5A was expressed to similar levels as WT Kif14 (Fig. S3 C), but its localization to the central spindle in anaphase cells was completely abolished (Fig. 6 C).	SIGNOR-266420
P04629	Q9BV47	dephosphorylation	down-regulates activity	0.371	NEAP and DUSP26 dephosphorylated TrkA and FGFR1 directly.\|We found that NEAP, but not its phosphatase-defective mutant, suppressed nerve growth factor (NGF) receptor TrkA and fibroblast growth factor receptor 1 (FGFR1) activation in PC12 cells	SIGNOR-277105
P61073	P14174	binding	up-regulates activity	0.371	We identify the chemokine receptors CXCR2 and CXCR4 as functional receptors for MIF [] By activating both CXCR2 and CXCR4, MIF displays chemokine-like functions and acts as a major regulator of inflammatory cell recruitment and atherogenesis.	SIGNOR-252062
P35222	Q00535	phosphorylation	up-regulates activity	0.371	By combining multiple network relations with PTM proteoform specific functional information, we proposed a mechanism to explain the observation that the cyclin dependent kinase CDK5 positively regulates beta-catenin co-activator activity.\|CDK5 phosphorylates beta-catenin on Ser 191 and Ser 246 (PR :000037229)	SIGNOR-279516
Q8NEB9	Q15139	phosphorylation	up-regulates activity	0.371	PKD phosphorylates Vps34, leading to activation of Vps34, phosphatydilinositol-3-phosphate formation, and autophagosome formation.\|Therefore, PKD phosphorylates Vps34 on multiple sites, including Thr677 within the catalytic domain.	SIGNOR-278495
P15336	Q99986	phosphorylation	up-regulates	0.371	Vrk1 phosphorylates atf2 mainly on thr-73, stabilizing the atf2 protein and increasing its intracellular level.	SIGNOR-124330
Q15154	Q86YT6	ubiquitination	down-regulates	0.371	We demonstrate that the E3 ubiquitin ligase MIB1 is a new component of centriolar satellites, which interacts with and ubiquitylates AZI1 and PCM1 and suppresses primary cilium formation.	SIGNOR-272878
P63104	P45983	phosphorylation	down-regulates	0.371	Jnk phosphorylated 14-3-3 at ser-184 and 14-3-3 at ser-186 both in vitro and in vivo, and such phosphorylation reduced the affinity of 14-3-3 proteins for bax	SIGNOR-124020
Q9NR28	P45983	phosphorylation	up-regulates activity	0.371	JNK1\u2011mediated phosphorylation of Smac/DIABLO at the serine 6 residue is functionally linked to its mitochondrial release during TNF\u2011\u03b1-\u2011induced apoptosis of HeLa cells.	SIGNOR-280029
Q08050	O14757	phosphorylation	up-regulates activity	0.371	In addition, upon treatment with genotoxic agents, the checkpoint kinases Chk1 and Chk2 also phosphorylate and activate FOXM1.	SIGNOR-280224
Q9NS71	A6NJ46	transcriptional regulation	up-regulates quantity by expression	0.371	In particular, NKX6.3 transcriptional factor was found to bind specifically to the upstream sequences of GKN1, a gastric-specific tumor suppressor, and dramatically increase expression of the latter.	SIGNOR-266096
Q66K89	P52926	binding	down-regulates	0.371	Here we show that hmga2 associates with the e1a-regulated transcriptional repressor p120(e4f), interfering with p120(e4f) binding to the cyclin a promoter	SIGNOR-119537
P08908	Q6P1N0	transcriptional regulation	down-regulates quantity by repression	0.371	Akt kinase-interacting protein 1 (Aki1)/Freud-1/CC2D1A is localized in the cytosol, nucleus, and centrosome. Aki1 plays distinct roles depending on its localization. In the cytosol, it acts as a scaffold protein in the phosphoinositide 3-kinase (PI3K)/3-phosphoinositide-dependent protein kinase 1 (PDK1)/Akt pathway. In the nucleus, it is a transcriptional repressor of the serotonin-1A (5-HT1A) receptor.	SIGNOR-268295
O15151	P48729	phosphorylation	up-regulates	0.371	Previous studies showed that casein kinase 1? (ck1?) Stably associates with mdmx, stimulates mdmx-p53 binding, and cooperates with mdmx to inactivate p53ck1? Binding to the mdmx central domain and phosphorylation of s289 disrupts the intramolecular interaction, allowing the n terminus to bind p53 with increased affinity. After dna damage, the mdmx-ck1? Complex is disrupted by chk2-mediated phosphorylation of mdmx at s367, leading to reduced mdmx-p53 binding.	SIGNOR-199015
Q16236	Q05655	phosphorylation	up-regulates activity	0.371	Phosphorylation of Nrf2 at Ser-40 by protein kinase C regulates antioxidant response element-mediated transcription.	SIGNOR-249161
Q8WU20	P06213	phosphorylation	up-regulates activity	0.371	We found that insulin receptor can directly phosphorylate FRS2.	SIGNOR-278945
P29474	Q05513	phosphorylation	down-regulates activity	0.371	The phosphorylation of both S617 and S635 have also been shown to promote increased eNOS-derived NO release (Michell et al., 2002). The phosphorylaiton of S617 can be induced by PKA or Akt activity, and may serve to sensitize eNOS to calmodulin binding and modulate the phosphorylation of other eNOS sites	SIGNOR-251637
P10275	Q00535	phosphorylation	up-regulates	0.371	Cdk5 enables phosphorylation of ar at ser-81 site through direct biochemical interaction and, therefore, results in the stabilization of ar proteins	SIGNOR-175696
P36873	Q69YH5	binding	up-regulates activity	0.371	This result demonstrates that the three sites of Repo-Man (Ser-543, Ser-977, and Ser-981) are phosphorylated by Aurora B in early mitosis. We uncover that PP1γ is recruited to mitotic chromosomes by its regulatory subunit Repo-Man in the absence of Aurora B activity and that Aurora B regulates dissociation of PP1γ by phosphorylating and disrupting PP1γ-Repo-Man interactions on chromatin.	SIGNOR-274003
P45983	Q7Z6J0	binding	up-regulates	0.371	Posh activates jnk1 in cos-1 cells.	SIGNOR-55759
Q9Y496	O00203	binding	up-regulates activity	0.371	Here, we show that the beta subunit of AP-3, a clathrin-associated protein complex required for HIV-1 release, is a target of IP(7)-mediated pyrophosphorylation. We have identified Kif3A, a motor protein of the kinesin superfamily, as an AP3B1-binding partner and demonstrate that Kif3A, like the AP-3 complex, is involved in an intracellular process required for HIV-1 Gag release.	SIGNOR-260398
P36956	Q8N6T7	binding	up-regulates activity	0.371	SIRT6 directs chromatin recruitment of CLOCK:BMAL1 and SREBP1.Importantly, SIRT6 also controls SREBP-1 recruitment to target promoters, such as Fasn, and helps maintain proper cyclic transcription. In fact, circadian metabolomics analyses reveal that SIRT6 controls lipid metabolism, contributing to the regulation of pathways involved in fatty acid synthesis and beta oxidation, triglyceride storage, signaling, and cellular membrane lipids.	SIGNOR-268158
Q14790	P53350	phosphorylation	down-regulates quantity by destabilization	0.371	By phosphorylating S387 in procaspase-8 Cdk1/cyclin B1 generates a phospho-epitope for the binding of the PBD of Plk1. Subsequently, S305 in procaspase-8 is phosphorylated by Plk1 during mitosis. Using an RNAi-based strategy we could demonstrate that the extrinsic cell death is increased upon Fas-stimulation when endogenous caspase-8 is replaced by a mutant (S305A) mimicking the non-phosphorylated form. Together, our data show that sequential phosphorylation by Cdk1/cyclin B1 and Plk1 decreases the sensitivity of cells toward stimuli of the extrinsic pathway during mitosis.	SIGNOR-272989
P53805	Q5S007	phosphorylation	up-regulates activity	0.371	LRRK2 Directly Phosphorylates RCAN1.	SIGNOR-278340
Q6NUN9	Q9BXM7	phosphorylation	up-regulates activity	0.37	PINK1 directly phosphorylates PARIS at S322 and S613, priming it for ubiquitination by Parkin, which interacts with the C-terminus zinc finger of PARIS and tags it for destruction [ xref \u2013 xref , xref ].\|Thus, by tagging PARIS for destruction, PINK1/Parkin drive the generation of new mitochondria by increasing PGC-1\u03b1 levels (Fig. 1d).	SIGNOR-278268
P01106	Q9NVW2	ubiquitination	down-regulates quantity by destabilization	0.37	This suggests that RLIM negatively regulates the transcriptional activity of c-Myc.\|We further showed that RLIM can promote polyubiquitination of c-Myc in cells.	SIGNOR-278551
P14618	Q9P1W9	phosphorylation	up-regulates quantity by stabilization	0.37	Here, we identified the protein-serine/threonine kinase PIM2, a known oncogene, as a novel binding partner of PKM2. The interaction between PIM2 and PKM2 was confirmed by multiple biochemical approaches in vitro and in cultured cells. Importantly, we found that PIM2 could directly phosphorylate PKM2 on the Thr-454 residue, resulting in an increase of PKM2 protein levels. Compared with wild type, PKM2 with the phosphorylation-defective mutation displayed a reduced effect on glycolysis	SIGNOR-267472
Q96CN5	P51955	phosphorylation	down-regulates activity	0.37	Moreover, LRRC45 interacts with both C-Nap1 and rootletin and is phosphorylated by Nek2A at S661 during mitosis. After phosphorylation, both LRRC45 centrosomal localization and fiber-like structures are significantly reduced, which subsequently leads to centrosome separation.	SIGNOR-273707
Q9Y4C1	Q07912	phosphorylation	down-regulates activity	0.37	We report that ACK1 phosphorylates the ER co-activator, KDM3A, a H3K9 demethylase, at an evolutionary conserved tyrosine 1114 site in a heregulin-dependent manner, even in the presence of tamoxifen.	SIGNOR-276842
Q9Y5T5	P33981	phosphorylation	down-regulates quantity by destabilization	0.37	Usp16 is a TTK phosphorylation substrate.	SIGNOR-277351
P23677	P17252	null	down-regulates activity	0.37	In contrast, phosphorylation of the A isoform with PKC caused a significant decrease in activity whether assayed in the presence or absence of calcium/calmodulin (to _25% of the unphosphorylated enzyme activity).	SIGNOR-248991
Q13568	O14920	phosphorylation	up-regulates activity	0.37	Here we present evidence that the kinase IKKbeta phosphorylates and activates IRF5 in response to stimulation in several inflammatory pathways, including those emanated from Toll like receptors and retinoic acid inducible gene I like receptors.\|Recombinant IKK\u03b2 phosphorylated IRF5 at Ser-445 in vitro, and a point mutation of this serine abolished IRF5 activation and cytokine production.	SIGNOR-279466
Q13887	Q9HAU4	ubiquitination	down-regulates quantity by destabilization	0.37	Consistent with these observations, another study documented that Smurf2 specifically destabilizes KLF5, that the degradation of KLF5 by Smurf2 is disrupted by the proteasome inhibitor MG132, and that Smurf2 ubiquitinates KLF5 .	SIGNOR-278781
O15350	Q9P2P5	ubiquitination	up-regulates quantity by stabilization	0.37	P73 was efficiently ubiquitinated but stabilized in a NEDL2-dependent manner. Accordingly, p73 decayed at faster rates in the absence of NEDL2 than in its presence. Consistent with the NEDL2-mediated stabilization of p73, NEDL2 enhanced the p73-dependent transcriptional activation. Thus, our results suggest that NEDL2 activates the function of p73 by increasing its stability.	SIGNOR-269457
P31946	O14920	phosphorylation	down-regulates	0.37	We provide a mechanism for these observations through the phosphorylation of 14-3-3beta by ikkbeta and pkcdelta on serine residues ser132 and ser60, respectively, which interferes with its binding to ttp and hence the retention of ttp in the cytoplasm.	SIGNOR-138608
P52789	P01106	transcriptional regulation	up-regulates quantity	0.37	Here, using the P493-6 Burkitt's lymphoma model with an inducible MYC, we demonstrate that HIF-1 cooperates with dysregulated c-Myc to promote glycolysis by induction of hexokinase 2, which catalyzes the first step of glycolysis, and pyruvate dehydrogenase kinase 1, which inactivates pyruvate dehydrogenase and diminishes mitochondrial respiration.	SIGNOR-259986
P78352	Q9NT99	binding	up-regulates activity	0.37	A possible function for the NGL–PSD-95 interaction is to couple trans-synaptic adhesion events to the recruitment of PSD-95 and other PSD-95-associated postsynaptic proteins. PSD-95 and liprin-α may be key synaptic scaffolding proteins that couple trans-synaptic adhesions to the assembly of synaptic proteins/vesicles	SIGNOR-264052
P01189	P16220	transcriptional regulation	up-regulates quantity by expression	0.37	Transcriptional activation of the proopiomelanocortin gene by cyclic AMP-responsive element binding protein\|Further, expression of a dominant inhibitory mutant of CREB reduced cAMP stimulated transcription of the full length POMC promoter and the PTRE.	SIGNOR-268620
P13349	Q99750	binding	down-regulates activity	0.37	We demonstrate that I-mf inhibits the transactivation activity of the MyoD family and represses myogenesis. I-mf associates with MyoD family members and retains them in the cytoplasm by masking their nuclear localization signals.	SIGNOR-240433
Q00613	P68400	phosphorylation	up-regulates activity	0.37	Transcriptional activity and DNA binding of heat shock factor-1 involve phosphorylation on threonine 142 by CK2.	SIGNOR-250898
Q13144	P19784	phosphorylation	up-regulates activity	0.37	Two conserved sites (Ser712/713) are phosphorylated by casein kinase 2. They lie at the extreme C-terminus and are required for the interaction of eIF2Bepsilon with its substrate, eIF2, in vivo and for eIF2B activity in vitro.	SIGNOR-250990
Q15796	P10398	phosphorylation	down-regulates quantity by destabilization	0.37	Araf promotes Smad2 linker phosphorylation through S253.\|In this study, we demonstrate that Araf can directly bind to and phosphorylate the linker of Smad2, leading to degradation of activated Smad2.	SIGNOR-279391
P41235	P04150	transcriptional regulation	up-regulates quantity by expression	0.37	Electrophoretic mobility shift, chromatin immunoprecipitation (ChIP), and streptavidin DNA binding assays revealed that DEX increased binding of HNF4alpha to the HNF4-RE and that an interaction of GR and HNF4alpha occurred at this site.	SIGNOR-251684
Q16637	P35637	relocalization	up-regulates activity	0.37	Here, we report that FUS associates with the SMN complex, mediated by U1 snRNP and by direct interactions between FUS and SMN.\|The FUS IP and pulldown revealed that FUS also associates with components of the SMN complex, including SMN and Gemins 4 and 6 \|Remarkably, the number of SMN-stained nuclear bodies was dramatically reduced in the FUS knockdown cells	SIGNOR-262107
P04637	P34947	phosphorylation	down-regulates	0.37	Grk5, but not grk2 or grk6, phosphorylates p53 at thr-55, which promotes the degradation of p53, leading to inhibition of p53-dependent apoptotic response to genotoxic damage.	SIGNOR-163707
P02751	P80370	binding	up-regulates	0.37	We show a direct interaction of pref-1 and fibronectin via the pref-1 juxtamembrane domain and fibronectin c-terminal domain	SIGNOR-165347
P16615	O00165	binding	down-regulates quantity by destabilization	0.37	The anti-apoptotic protein HAX-1 interacts with SERCA2 and regulates its protein levels to promote cell survival.\|Importantly, HAX-1 overexpression was associated with down-regulation of SERCA2 expression levels, resulting in significant reduction of apparent ER Ca(2+) levels.	SIGNOR-262052
P49459	P06493	phosphorylation	up-regulates	0.37	Hhr6a is phosphorylated in vitro by cdk-1 and -2 on ser120, a residue conserved in all hhr6a homologues, resulting in a 4-fold increase in its ubiquitin-conjugating activity.	SIGNOR-116504
Q9NXV6	Q00987	ubiquitination	down-regulates	0.37	Carf interacts with hdm2 and is ubiquitinated and negatively regulated by hdm2 by proteasome-dependent degradation.	SIGNOR-160974
Q99466	Q00987	ubiquitination	down-regulates	0.37	We demonstrate that the intracellular domain of notch 4 is targeted for ubiquitylation and hence degradation by the ubiquitin ligase mdm2.	SIGNOR-172826
P04637	Q9HCI7	ubiquitination	down-regulates activity	0.37	Here we describe MSL2, a novel E3 ligase for p53 that promotes ubiquitin-dependent cytoplasmic p53 localization. Unlike Mdm2 or most other p53 E3 ligases, MSL2-mediated p53 ubiquitination does not affect the stability of p53. Moreover, the MSL2-mediated effect on p53 is Mdm2-independent. Thus, our study identifies an important ubiquitin-ligase for modulating p53 subcellular localization. MSL2 ubiquitination of p53 is required for p53 cytoplasmic localization.	SIGNOR-271774
Q14790	Q9NZS9	binding	down-regulates	0.37	We also demonstrate that the mitochondrial protein bar, which has been shown to simultaneously bind caspase-8 and bcl-2	SIGNOR-112585
P41594	Q05513	phosphorylation	up-regulates activity	0.37	Thus, we showed that it is phosphorylation of Ser-839, not Thr-840, that is absolutely required for the unique Ca2+ oscillations produced by mGluR5 activation. The Thr-840 residue is important only in that it is permissive for the PKC-dependent phosphorylation of Ser-839.	SIGNOR-249284
Q9Y251	P18146	transcriptional regulation	up-regulates quantity by expression	0.37	Promoter CpG hypomethylation and transcription factor EGR1 hyperactivate heparanase expression in bladder cancer.	SIGNOR-254267
Q99558	Q9UHD2	phosphorylation	down-regulates quantity by destabilization	0.37	TBK1 induces NIK phosphorylation and degradation.	SIGNOR-279767
Q9Y385	Q13490	ubiquitination	down-regulates quantity by destabilization	0.37	We also found that ubiquitin-ligase (E3), c-IAP1 preferentially interacts with phosphorylated Ube2j1. Moreover, we noticed that phosphorylated Ube2j1 is rapidly degraded by the proteasome during ER stress cell recovery. Taken together, these data suggest that Ube2j1 and its phosphorylation is important for transient ER stress cell recovery and the phosphorylated Ube2j1 is degraded by the proteasome.	SIGNOR-263092
Q9UKV8	P48729	phosphorylation	down-regulates activity	0.369	Our experiments demonstrated that target engagement by AGO2 stimulates its hierarchical, multi-site phosphorylation by CSNK1A1 on a series of highly conserved residues (S824-S834).Although this impairs target binding, dephosphorylation by ANKRD52-PPP6C allows AGO2 to engage new targets. Inactivation of this cycle strongly inhibits global miRNA-mediated repression.	SIGNOR-276510
P16885	P07333	null	up-regulates	0.369	Studies with multipotent precursor cell lines (Fig. 4A) indicate that CSF-1R Tyr-807 and Tyr-721 promote macrophage differentiation via the PLC-Œ≥2 pathway	SIGNOR-255570
Q01167	P24941	phosphorylation	up-regulates	0.369	We have mapped two cdk phosphorylation sites, serines 368 and 423, which play a role in defining foxk2 function through regulating its stability and its activity as a transcriptional repressor protein. These two cdk sites appear vital for foxk2 function because expression of a mutant lacking these sites cannot be tolerated and causes apoptosis.	SIGNOR-167834
P37231	P23769	null	down-regulates activity	0.369	GATA2 interacts directly with PPARG and C/EBP a , which may deplete PPARG involved in the promotion of adipogenesis	SIGNOR-132949
Q9GZQ8	Q9H2P0	binding	up-regulates activity	0.369	Here, we show for the first time that hippocampal ADNP deficiency paralleled reduced beclin1 expression which, in turn, parallels increased tauopathy and cell death. We now show that ADNP directly interacts with LC3B, implicating the requirement of a healthy ADNP system for the apoptotic/autophagy processes.	SIGNOR-266759
P22681	P29376	phosphorylation	up-regulates	0.369	Although c-cbl is found to be phosphorylated by ltk and therefore is a second candidate linking ltk with the pi3-kinase pathway along with irs-1, we found that the p85 subunit of pi3 kinase directly binds to tyrosine 753 of ltk, which is located within a yxxm motif, a consensus binding amino acid sequence for the sh2 domain of p85.	SIGNOR-49528
Q9UJ55	O00327	binding	down-regulates activity	0.369	Magel2 represses the activity of the Clock:Bmal1 heterodimer in a Per2-luciferase assay. Magel2 interacts with Bmal1 and with Per2 as measured by co-immunoprecipitation in co-transfected cells, and exhibits a subcellular distribution consistent with these interactions when visualized by immunofluorescence. As well, Magel2 induces the redistribution of the subcellular localization of Clock towards the cytoplasm, in contrast to the nucleus-directed effect of Bmal1 on Clock subcellular localization.	SIGNOR-253517
P11137	Q76NI1	phosphorylation	up-regulates activity	0.369	V-KIND enhances Thr phosphorylation of MAP2.	SIGNOR-278950
P15559	P31749	phosphorylation	down-regulates quantity by destabilization	0.369	Akt phosphorylates NQO1 on S40 and T128 residues. Here we show that Akt phosphorylates NQO1 at T128 residues and triggers its polyubiquitination and proteasomal degradation, abrogating its antioxidative effects in PD. Akt binds NQO1 in a phosphorylation-dependent manner. Interestingly, Akt, but not PINK1, provokes NQO1 phosphorylation and polyubiquitination with Parkin as an E3 ligase.	SIGNOR-276868
P11831	Q9UQM7	phosphorylation	up-regulates activity	0.369	Skeletal muscle CaMKII enriches in nuclei and phosphorylates myogenic factor SRF at multiple sites. \| Microsequencing of these phosphorylated peptides identified that both Ser-103 and a novel residue, Thr-160 in the MADS box of SRF, were sites of phosphorylation. \| The location of Thr-160 in the 3-D structure of SRF suggests that its phosphorylation by nuclear CaMKII may directly influence DNA binding of SRF and other MADS box factors.	SIGNOR-250639
P42702	P28482	phosphorylation	down-regulates	0.369	Indeed, phosphorylation of the cytoplasmic domain of the low-affinity lif receptor alpha-subunit (lifr) in mono q-fractionated, lif-stimulated 3t3-l1 extracts occurred only in those fractions containing activated mapk;ser-1044 served as the major phosphorylation site in the human lifr for mapk both in agonist-stimulated 3t3-l1 lysates and by recombinant extracellular signal-regulated kinase 2 in vitro	SIGNOR-32753
Q14934	Q00526	phosphorylation	up-regulates activity	0.369	CDK3 enhances the transactivation and transcription activity of NFAT3.\|NFAT3 can be phosphorylated by CDK3 at Ser259, which is critical for its transactivation activity and cell transformation.	SIGNOR-278511
P05412	Q9H4B4	phosphorylation	up-regulates	0.369	Stress-induced c-jun activation mediated by polo-like kinase 3 in corneal epithelial cells. Hypoxia/reoxygenation activated plk3 in hce cells to directly phosphorylate c-jun proteins at phosphorylation sites ser-63 and ser-73, and to increase dna binding activity of c-jun.	SIGNOR-157721
P35568	O14733	phosphorylation	down-regulates activity	0.369	Tyrosine phosphorylation of IRS-1 initiates insulin signaling, whereas serine/threonine phosphorylation alters the ability of IRS-1 to transduce the insulin signalInsulin increased the phosphorylation of Ser312, Ser616, Ser636, Ser892, Ser1101, and Ser1223 Ser312 can be phosphorylated by kinases, such as c-jun NH2-terminal kinase and inhibitor of _B kinase	SIGNOR-217920
Q96P20	P45983	phosphorylation	up-regulates activity	0.369	Ethanol induced JNK1 phosphorylation activated the NLRP3 inflammasome that induced caspase-1 dependent mitophagy inhibition, thereby exacerbating ROS accumulation and causing cell death.\|However, recent studies suggested that Ser 194 phosphorylation of NLRP3 was essential for the control of inflammasome activation and that JNK1 directly phosphorylates NLRP3, which stimulates the self-association and oligomerization of NLRP3 [ xref , xref ].	SIGNOR-280034
Q15653	Q15418	phosphorylation	down-regulates quantity by destabilization	0.369	By using recombinant wild-type and mutant IkappaBbeta proteins, both active ERK2 and RSK1 were found to directly phosphorylate IkappaBbeta, but only active RSK1 phosphorylated IkappaBbeta on Ser19 and Ser23, two sites known to mediate the subsequent ubiquitination and degradation.	SIGNOR-280114
P68400	P28482	phosphorylation	up-regulates	0.369	Erk2, which is activated by egfr signaling, directly binds to ck2alpha via the erk2 docking groove and phosphorylates ck2alpha primarily at t360/s362, subsequently enhancing ck2alpha activity	SIGNOR-161855
Q14790	P51812	phosphorylation	down-regulates quantity by destabilization	0.369	The ribosomal S6 kinase 2 (RSK2) is a member of the p90 ribosomal S6 kinase (p90RSK) family of proteins and plays a critical role in proliferation, cell cycle, and cell transformation. Here, we report that RSK2 phosphorylates caspase-8, and Thr-263 was identified as a novel caspase-8 phosphorylation site. In addition, we showed that EGF induces caspase-8 ubiquitination and degradation through the proteasome pathway, and phosphorylation of Thr-263 is associated with caspase-8 stability.	SIGNOR-272997
P38398	Q9H4M3	binding	down-regulates quantity by destabilization	0.369	The F-box protein FBXO44 mediates BRCA1 ubiquitination and degradation. The Skp1-Cul1-F-box-protein44 (SCF(FBXO44)) complex ubiquitinates full-length BRCA1 in vitro.	SIGNOR-272037
P19174	Q12913	dephosphorylation	down-regulates	0.369	Cd148 can dephosphorylate lat and plc?1 In vitro. / plc?1 Undergoes inducible tyrosine phosphorylation following tcr stimulation (46), and this phosphorylation is required to stimulate its catalytic activity	SIGNOR-105790
Q13469	Q86Y07	phosphorylation	up-regulates	0.369	We demonstrate that vrk2 directly interacts and phosphorylates nfat1 in ser-32 within its n-terminal transactivation domain.	SIGNOR-199263
Q13547	Q99801	binding	down-regulates activity	0.369	NKX3.1 also binds HDAC1 and releases p53 from p53-MDM2-HDAC1 complex, promoting p53 acetylation and activity.	SIGNOR-251549

Q13501

P50542

0

binding

up-regulates activity

0.372

Specificity for autophagy of peroxisomes (pexophagy) is provided by ATM phosphorylation of PEX5 at Ser 141, which promotes PEX5 monoubiquitylation at Lys 209, and recognition of ubiquitylated PEX5 by the autophagy adaptor protein p62, directing the autophagosome to peroxisomes to induce pexophagy.

SIGNOR-262793

Q9Y286

O14543

0

binding

down-regulates quantity by destabilization

0.372

SOCS proteins can act as E3 ligases by forming a complex with Elongin B/C and Cul5/Rbx1/2.SOCS3 targets Siglec 7 for degradation

SIGNOR-272642

P28329

Q9UQM7

0

phosphorylation

up-regulates

0.372

We show that chat is differentially phosphorylated by protein kinase c (pkc) isoforms on four serines (ser-440, ser-346, ser-347, and ser-476) and one threonine (thr-255). This phosphorylation is hierarchical, with phosphorylation at ser-476 required for phosphorylation at other serines. Phosphorylation at some, but not all, sites regulates basal catalysis and activation.

SIGNOR-96628

P15923

P27361

0

phosphorylation

down-regulates quantity by destabilization

0.372

Notch-induced degradation requires phosphorylation of E47 by p42/p44 MAP kinases. |Wild_type E47 but not the Mm mutant reacted to the antibodies, suggesting that E47 is at least phosphorylated at the M2 site (Figure 3A)|anti_phospho_M2 peptide (SSPSpTPVGSPQG)

SIGNOR-249117

P06213

P54646

0

phosphorylation

up-regulates

0.372

Ampk phosphorylates and activates theinsulinreceptor, providing a direct link between ampk and theinsulin pathway.

SIGNOR-195324

Q96RK0

P28482

0

phosphorylation

down-regulates

0.372

Specifically, 14-3-3 binds to p90(rsk)-phosphorylated ser?_??_ Of capic?_A thereby modulating dna binding to its hmg (high-mobility group) box, whereas erk phosphorylations prevent binding of a c-terminal nls (nuclear localization sequence) to importin ?4 (kpna3))[...] These results suggest that erk phosphorylation of ser1382 and ser1409 masks the nls and prevents its binding to kpna3

SIGNOR-169875

Q96HP0

P31749

0

phosphorylation

up-regulates activity

0.372

Akt and PP2A reciprocally regulate the guanine nucleotide exchange factor Dock6 to control axon growth of sensory neurons|At later developmental stages, the abundance of the kinase Akt increased, resulting in the binding of Akt to Dock6 and the phosphorylation of Dock6 at Ser(1194). | In dorsal root ganglion neurons from mice lacking Dock6, reintroduction of Dock6 with a nonphosphorylatable S1194A mutation rescued axon extension but not branch number, whereas reintroduction of Dock6 with a phosphomimetic S1194E mutation resulted in premature branching

SIGNOR-275666

P49840

P17612

0

phosphorylation

down-regulates

0.372

Phosphorylation of ser21 and inactivation of glycogen synthase kinase 3 by protein kinase a.

SIGNOR-83221

Q9UHV7

Q969H0

0

ubiquitination

down-regulates quantity by destabilization

0.371

The SCF-Fbw7 ubiquitin ligase degrades MED13 and MED13L and regulates CDK8 module association with Mediator. We show that Fbw7, a tumor suppressor and ubiquitin ligase, binds to CDK8-Mediator and targets MED13/13L for degradation. MED13/13L physically link the CDK8 module to Mediator, and Fbw7 loss increases CDK8 module-Mediator association.

SIGNOR-266690

Q92934

P11309

0

phosphorylation

down-regulates activity

0.371

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-250390

P98177

Q13131

0

phosphorylation

up-regulates

0.371

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

SIGNOR-157947

P37840

P48729

0

phosphorylation

up-regulates

0.371

In vitro experiments and two-dimensional phosphopeptide mapping provided further evidence that serine 129 was phosphorylated by ck-1 and ck-2. Moreover, phosphorylation of serine 129 was reduced in vivo upon inhibition of ck-1 or ck-2. These data demonstrate that alpha-synuclein is constitutively phosphorylated within its c terminus and may indicate that the function of alpha-synuclein is regulated by phosphorylation/dephosphorylation.From these data we conclude that _-synuclein is predominantly phosphorylated at serine residue 129. However, a second serine at position 87 is also used for phosphorylation to some extent. together, these data may indicate that ck-1 and ck-2 are involved in the regulation of neuronal function and one may speculate that phosphorylation of _-synuclein could affect its binding to membranes.

SIGNOR-73799

P29474

Q00535

0

phosphorylation

down-regulates

0.371

Together, our data suggest that cdk5 can phosphorylate enos at the ser-113 site and down-regulate enos-derived no levels.

SIGNOR-164080

P00533

Q9UQM7

0

phosphorylation

down-regulates activity

0.371

We show that serines 1046/1047 are sites for CaM kinase II phosphorylation, although there is a preference for serine 1047, which resides within the consensus -R-X-X-S-. In addition, we have identified major phosphorylation sites at serine 1142 and serine 1057, which lie within a novel -S-X-D- consensus. Mutation of serines 1046/1047 in full-length EGFR enhanced both fibroblast transformation and tyrosine autokinase activity that was significantly potentiated by additional mutation of serines 1057 and 1142. A single CaM kinase II site was also identified at serine 744 within sub-kinase domain III, and autokinase activity was significantly affected by mutation of this serine to an aspartic acid making this site appear constitutively phosphorylated. We have addressed the mechanism by which CaM kinase II phosphorylation of the EGFR might regulate receptor autokinase activity and show that this modification can hinder association of the cytoplasmic tail with the kinase domain to prevent an enzyme-substrate interaction.

SIGNOR-250621

P22681

Q8IZP0

0

binding

up-regulates

0.371

Here we uncover a novel interaction between abi-1 and the cbl ubiquitin ligase and show that abi-1 mediates cbl accumulation to the plasma membrane upon stimulation by egf.

SIGNOR-154162

Q96QB1

Q15139

0

phosphorylation

down-regulates

0.371

The tumor suppressor protein dlc1 is regulated by pkd-mediated gap domain phosphorylation.Our results thus show that pkd-mediated phosphorylation of dlc1 on serine 807 negatively regulates dlc1 cellular function.

SIGNOR-169994

P01106

P15884

0

transcriptional regulation

up-regulates quantity by expression

0.371

Association of c-Jun, β-catenin, and TCF4 specifically with the downstream enhancer underlies mitogen stimulation of c-Myc transcription.

SIGNOR-253324

P35354

Q13469

0

transcriptional regulation

up-regulates quantity by expression

0.371

NFAT induces the transcription of the COX2 (cyclo-oxygenase-2) gene incancer cells thereby enhancing invasive migration

SIGNOR-264025

P49715

P27361

0

phosphorylation

down-regulates

0.371

Ccaat/enhancer-binding protein alpha (c/ebpalpha) is one of the key transcription factors that mediate lineage specification and differentiation of multipotent myeloid progenitors into mature granulocytes.Here we report that inducers of monocyte differentiation inhibit the alternate cell fate choice, that of granulopoiesis, through inhibition of c/ebpalpha. This inhibition is mediated by extracellular signal-regulated kinases 1 and/or 2 (erk1/2), which interact with c/ebpalpha through an fxfp docking site and phosphorylate serine 21.

SIGNOR-120570

P14618

P45983

0

phosphorylation

up-regulates activity

0.371

Active JNK1 specifically activates PKM2 but not PKM1. Mechanistically, PARP14 inhibits the pro-apoptotic kinase JNK1, which results in the activation of PKM2 through phosphorylation of Thr365.

SIGNOR-276933

Q9Y3Q4

P12931

0

phosphorylation

up-regulates

0.371

These results demonstrate that src tyrosine kinase enhances hcn4 currents by shifting their activation to more positive potentials and increasing the whole cell channel conductance as well as speeding the channel kinetics. The tyrosine residue that mediates most of src s actions on hcn4 channels is tyr531.

SIGNOR-158707

O94782

P06493

0

phosphorylation

up-regulates activity

0.371

In this study, we show that Ser313 phosphorylation in USP1 is required for its interaction with UAF1 and for the stimulation of USP1's activity. We further demonstrated that CDK1 is responsible for Ser313 phosphorylation, and protein phosphatase treatment of USP1 can lead to inactivation of USP1/UAF1.

SIGNOR-276423

Q15058

Q8TDX7

0

phosphorylation

up-regulates activity

0.371

Nek7 direct phosphorylation is required for the anaphase localization of Kif14. we generated an EGFP-Kif14-5A construct in which Ser56, Ser607, Ser1217, Ser1219, and Ser1220 were all mutated to Ala. When transfected into HeLa cells, EGFP-Kif14-5A was expressed to similar levels as WT Kif14 (Fig. S3 C), but its localization to the central spindle in anaphase cells was completely abolished (Fig. 6 C).

SIGNOR-266420

P04629

Q9BV47

0

dephosphorylation

down-regulates activity

0.371

NEAP and DUSP26 dephosphorylated TrkA and FGFR1 directly.|We found that NEAP, but not its phosphatase-defective mutant, suppressed nerve growth factor (NGF) receptor TrkA and fibroblast growth factor receptor 1 (FGFR1) activation in PC12 cells

SIGNOR-277105

P61073

P14174

0

binding

up-regulates activity

0.371

We identify the chemokine receptors CXCR2 and CXCR4 as functional receptors for MIF [] By activating both CXCR2 and CXCR4, MIF displays chemokine-like functions and acts as a major regulator of inflammatory cell recruitment and atherogenesis.

SIGNOR-252062

P35222

Q00535

0

phosphorylation

up-regulates activity

0.371

By combining multiple network relations with PTM proteoform specific functional information, we proposed a mechanism to explain the observation that the cyclin dependent kinase CDK5 positively regulates beta-catenin co-activator activity.|CDK5 phosphorylates beta-catenin on Ser 191 and Ser 246 (PR :000037229)

SIGNOR-279516

Q8NEB9

Q15139

0

phosphorylation

up-regulates activity

0.371

PKD phosphorylates Vps34, leading to activation of Vps34, phosphatydilinositol-3-phosphate formation, and autophagosome formation.|Therefore, PKD phosphorylates Vps34 on multiple sites, including Thr677 within the catalytic domain.

SIGNOR-278495

P15336

Q99986

0

phosphorylation

up-regulates

0.371

Vrk1 phosphorylates atf2 mainly on thr-73, stabilizing the atf2 protein and increasing its intracellular level.

SIGNOR-124330

Q15154

Q86YT6

0

ubiquitination

down-regulates

0.371

We demonstrate that the E3 ubiquitin ligase MIB1 is a new component of centriolar satellites, which interacts with and ubiquitylates AZI1 and PCM1 and suppresses primary cilium formation.

SIGNOR-272878

P63104

P45983

0

phosphorylation

down-regulates

0.371

Jnk phosphorylated 14-3-3 at ser-184 and 14-3-3 at ser-186 both in vitro and in vivo, and such phosphorylation reduced the affinity of 14-3-3 proteins for bax

SIGNOR-124020

Q9NR28

P45983

0

phosphorylation

up-regulates activity

0.371

JNK1\u2011mediated phosphorylation of Smac/DIABLO at the serine 6 residue is functionally linked to its mitochondrial release during TNF\u2011\u03b1-\u2011induced apoptosis of HeLa cells.

SIGNOR-280029

Q08050

O14757

0

phosphorylation

up-regulates activity

0.371

In addition, upon treatment with genotoxic agents, the checkpoint kinases Chk1 and Chk2 also phosphorylate and activate FOXM1.

SIGNOR-280224

Q9NS71

A6NJ46

0

transcriptional regulation

up-regulates quantity by expression

0.371

In particular, NKX6.3 transcriptional factor was found to bind specifically to the upstream sequences of GKN1, a gastric-specific tumor suppressor, and dramatically increase expression of the latter.

SIGNOR-266096

Q66K89

P52926

0

binding

down-regulates

0.371

Here we show that hmga2 associates with the e1a-regulated transcriptional repressor p120(e4f), interfering with p120(e4f) binding to the cyclin a promoter

SIGNOR-119537

P08908

Q6P1N0

0

transcriptional regulation

down-regulates quantity by repression

0.371

Akt kinase-interacting protein 1 (Aki1)/Freud-1/CC2D1A is localized in the cytosol, nucleus, and centrosome. Aki1 plays distinct roles depending on its localization. In the cytosol, it acts as a scaffold protein in the phosphoinositide 3-kinase (PI3K)/3-phosphoinositide-dependent protein kinase 1 (PDK1)/Akt pathway. In the nucleus, it is a transcriptional repressor of the serotonin-1A (5-HT1A) receptor.

SIGNOR-268295

O15151

P48729

0

phosphorylation

up-regulates

0.371

Previous studies showed that casein kinase 1? (ck1?) Stably associates with mdmx, stimulates mdmx-p53 binding, and cooperates with mdmx to inactivate p53ck1? Binding to the mdmx central domain and phosphorylation of s289 disrupts the intramolecular interaction, allowing the n terminus to bind p53 with increased affinity. After dna damage, the mdmx-ck1? Complex is disrupted by chk2-mediated phosphorylation of mdmx at s367, leading to reduced mdmx-p53 binding.

SIGNOR-199015

Q16236

Q05655

0

phosphorylation

up-regulates activity

0.371

Phosphorylation of Nrf2 at Ser-40 by protein kinase C regulates antioxidant response element-mediated transcription.

SIGNOR-249161

Q8WU20

P06213

0

phosphorylation

up-regulates activity

0.371

We found that insulin receptor can directly phosphorylate FRS2.

SIGNOR-278945

P29474

Q05513

0

phosphorylation

down-regulates activity

0.371

The phosphorylation of both S617 and S635 have also been shown to promote increased eNOS-derived NO release (Michell et al., 2002). The phosphorylaiton of S617 can be induced by PKA or Akt activity, and may serve to sensitize eNOS to calmodulin binding and modulate the phosphorylation of other eNOS sites

SIGNOR-251637

P10275

Q00535

0

phosphorylation

up-regulates

0.371

Cdk5 enables phosphorylation of ar at ser-81 site through direct biochemical interaction and, therefore, results in the stabilization of ar proteins

SIGNOR-175696

P36873

Q69YH5

0

binding

up-regulates activity

0.371

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

SIGNOR-274003

P45983

Q7Z6J0

0

binding

up-regulates

0.371

Posh activates jnk1 in cos-1 cells.

SIGNOR-55759

Q9Y496

O00203

0

binding

up-regulates activity

0.371

Here, we show that the beta subunit of AP-3, a clathrin-associated protein complex required for HIV-1 release, is a target of IP(7)-mediated pyrophosphorylation. We have identified Kif3A, a motor protein of the kinesin superfamily, as an AP3B1-binding partner and demonstrate that Kif3A, like the AP-3 complex, is involved in an intracellular process required for HIV-1 Gag release.

SIGNOR-260398

P36956

Q8N6T7

0

binding

up-regulates activity

0.371

SIRT6 directs chromatin recruitment of CLOCK:BMAL1 and SREBP1.Importantly, SIRT6 also controls SREBP-1 recruitment to target promoters, such as Fasn, and helps maintain proper cyclic transcription. In fact, circadian metabolomics analyses reveal that SIRT6 controls lipid metabolism, contributing to the regulation of pathways involved in fatty acid synthesis and beta oxidation, triglyceride storage, signaling, and cellular membrane lipids.

SIGNOR-268158

Q14790

P53350

0

phosphorylation

down-regulates quantity by destabilization

0.371

By phosphorylating S387 in procaspase-8 Cdk1/cyclin B1 generates a phospho-epitope for the binding of the PBD of Plk1. Subsequently, S305 in procaspase-8 is phosphorylated by Plk1 during mitosis. Using an RNAi-based strategy we could demonstrate that the extrinsic cell death is increased upon Fas-stimulation when endogenous caspase-8 is replaced by a mutant (S305A) mimicking the non-phosphorylated form. Together, our data show that sequential phosphorylation by Cdk1/cyclin B1 and Plk1 decreases the sensitivity of cells toward stimuli of the extrinsic pathway during mitosis.

SIGNOR-272989

P53805

Q5S007

0

phosphorylation

up-regulates activity

0.371

LRRK2 Directly Phosphorylates RCAN1.

SIGNOR-278340

Q6NUN9

Q9BXM7

0

phosphorylation

up-regulates activity

0.37

PINK1 directly phosphorylates PARIS at S322 and S613, priming it for ubiquitination by Parkin, which interacts with the C-terminus zinc finger of PARIS and tags it for destruction [ xref \u2013 xref , xref ].|Thus, by tagging PARIS for destruction, PINK1/Parkin drive the generation of new mitochondria by increasing PGC-1\u03b1 levels (Fig. 1d).

SIGNOR-278268

P01106

Q9NVW2

0

ubiquitination

down-regulates quantity by destabilization

0.37

This suggests that RLIM negatively regulates the transcriptional activity of c-Myc.|We further showed that RLIM can promote polyubiquitination of c-Myc in cells.

SIGNOR-278551

P14618

Q9P1W9

0

phosphorylation

up-regulates quantity by stabilization

0.37

Here, we identified the protein-serine/threonine kinase PIM2, a known oncogene, as a novel binding partner of PKM2. The interaction between PIM2 and PKM2 was confirmed by multiple biochemical approaches in vitro and in cultured cells. Importantly, we found that PIM2 could directly phosphorylate PKM2 on the Thr-454 residue, resulting in an increase of PKM2 protein levels. Compared with wild type, PKM2 with the phosphorylation-defective mutation displayed a reduced effect on glycolysis

SIGNOR-267472

Q96CN5

P51955

0

phosphorylation

down-regulates activity

0.37

Moreover, LRRC45 interacts with both C-Nap1 and rootletin and is phosphorylated by Nek2A at S661 during mitosis. After phosphorylation, both LRRC45 centrosomal localization and fiber-like structures are significantly reduced, which subsequently leads to centrosome separation.

SIGNOR-273707

Q9Y4C1

Q07912

0

phosphorylation

down-regulates activity

0.37

We report that ACK1 phosphorylates the ER co-activator, KDM3A, a H3K9 demethylase, at an evolutionary conserved tyrosine 1114 site in a heregulin-dependent manner, even in the presence of tamoxifen.

SIGNOR-276842

Q9Y5T5

P33981

0

phosphorylation

down-regulates quantity by destabilization

0.37

Usp16 is a TTK phosphorylation substrate.

SIGNOR-277351

P23677

P17252

0

null

down-regulates activity

0.37

In contrast, phosphorylation of the A isoform with PKC caused a significant decrease in activity whether assayed in the presence or absence of calcium/calmodulin (to _25% of the unphosphorylated enzyme activity).

SIGNOR-248991

Q13568

O14920

0

phosphorylation

up-regulates activity

0.37

Here we present evidence that the kinase IKKbeta phosphorylates and activates IRF5 in response to stimulation in several inflammatory pathways, including those emanated from Toll like receptors and retinoic acid inducible gene I like receptors.|Recombinant IKK\u03b2 phosphorylated IRF5 at Ser-445 in vitro, and a point mutation of this serine abolished IRF5 activation and cytokine production.

SIGNOR-279466

Q13887

Q9HAU4

0

ubiquitination

down-regulates quantity by destabilization

0.37

Consistent with these observations, another study documented that Smurf2 specifically destabilizes KLF5, that the degradation of KLF5 by Smurf2 is disrupted by the proteasome inhibitor MG132, and that Smurf2 ubiquitinates KLF5 .

SIGNOR-278781

O15350

Q9P2P5

0

ubiquitination

up-regulates quantity by stabilization

0.37

P73 was efficiently ubiquitinated but stabilized in a NEDL2-dependent manner. Accordingly, p73 decayed at faster rates in the absence of NEDL2 than in its presence. Consistent with the NEDL2-mediated stabilization of p73, NEDL2 enhanced the p73-dependent transcriptional activation. Thus, our results suggest that NEDL2 activates the function of p73 by increasing its stability.

SIGNOR-269457

P31946

O14920

0

phosphorylation

down-regulates

0.37

We provide a mechanism for these observations through the phosphorylation of 14-3-3beta by ikkbeta and pkcdelta on serine residues ser132 and ser60, respectively, which interferes with its binding to ttp and hence the retention of ttp in the cytoplasm.

SIGNOR-138608

P52789

P01106

0

transcriptional regulation

up-regulates quantity

0.37

Here, using the P493-6 Burkitt's lymphoma model with an inducible MYC, we demonstrate that HIF-1 cooperates with dysregulated c-Myc to promote glycolysis by induction of hexokinase 2, which catalyzes the first step of glycolysis, and pyruvate dehydrogenase kinase 1, which inactivates pyruvate dehydrogenase and diminishes mitochondrial respiration.

SIGNOR-259986

P78352

Q9NT99

0

binding

up-regulates activity

0.37

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

SIGNOR-264052

P01189

P16220

0

transcriptional regulation

up-regulates quantity by expression

0.37

Transcriptional activation of the proopiomelanocortin gene by cyclic AMP-responsive element binding protein|Further, expression of a dominant inhibitory mutant of CREB reduced cAMP stimulated transcription of the full length POMC promoter and the PTRE.

SIGNOR-268620

P13349

Q99750

0

binding

down-regulates activity

0.37

We demonstrate that I-mf inhibits the transactivation activity of the MyoD family and represses myogenesis. I-mf associates with MyoD family members and retains them in the cytoplasm by masking their nuclear localization signals.

SIGNOR-240433

Q00613

P68400

0

phosphorylation

up-regulates activity

0.37

Transcriptional activity and DNA binding of heat shock factor-1 involve phosphorylation on threonine 142 by CK2.

SIGNOR-250898

Q13144

P19784

0

phosphorylation

up-regulates activity

0.37

Two conserved sites (Ser712/713) are phosphorylated by casein kinase 2. They lie at the extreme C-terminus and are required for the interaction of eIF2Bepsilon with its substrate, eIF2, in vivo and for eIF2B activity in vitro.

SIGNOR-250990

Q15796

P10398

0

phosphorylation

down-regulates quantity by destabilization

0.37

Araf promotes Smad2 linker phosphorylation through S253.|In this study, we demonstrate that Araf can directly bind to and phosphorylate the linker of Smad2, leading to degradation of activated Smad2.

SIGNOR-279391

P41235

P04150

0

transcriptional regulation

up-regulates quantity by expression

0.37

Electrophoretic mobility shift, chromatin immunoprecipitation (ChIP), and streptavidin DNA binding assays revealed that DEX increased binding of HNF4alpha to the HNF4-RE and that an interaction of GR and HNF4alpha occurred at this site.

SIGNOR-251684

Q16637

P35637

0

relocalization

up-regulates activity

0.37

Here, we report that FUS associates with the SMN complex, mediated by U1 snRNP and by direct interactions between FUS and SMN.|The FUS IP and pulldown revealed that FUS also associates with components of the SMN complex, including SMN and Gemins 4 and 6 |Remarkably, the number of SMN-stained nuclear bodies was dramatically reduced in the FUS knockdown cells

SIGNOR-262107

P04637

P34947

0

phosphorylation

down-regulates

0.37

Grk5, but not grk2 or grk6, phosphorylates p53 at thr-55, which promotes the degradation of p53, leading to inhibition of p53-dependent apoptotic response to genotoxic damage.

SIGNOR-163707

P02751

P80370

0

binding

up-regulates

0.37

We show a direct interaction of pref-1 and fibronectin via the pref-1 juxtamembrane domain and fibronectin c-terminal domain

SIGNOR-165347

P16615

O00165

0

binding

down-regulates quantity by destabilization

0.37

The anti-apoptotic protein HAX-1 interacts with SERCA2 and regulates its protein levels to promote cell survival.|Importantly, HAX-1 overexpression was associated with down-regulation of SERCA2 expression levels, resulting in significant reduction of apparent ER Ca(2+) levels.

SIGNOR-262052

P49459

P06493

0

phosphorylation

up-regulates

0.37

Hhr6a is phosphorylated in vitro by cdk-1 and -2 on ser120, a residue conserved in all hhr6a homologues, resulting in a 4-fold increase in its ubiquitin-conjugating activity.

SIGNOR-116504

Q9NXV6

Q00987

0

ubiquitination

down-regulates

0.37

Carf interacts with hdm2 and is ubiquitinated and negatively regulated by hdm2 by proteasome-dependent degradation.

SIGNOR-160974

Q99466

Q00987

0

ubiquitination

down-regulates

0.37

We demonstrate that the intracellular domain of notch 4 is targeted for ubiquitylation and hence degradation by the ubiquitin ligase mdm2.

SIGNOR-172826

P04637

Q9HCI7

0

ubiquitination

down-regulates activity

0.37

Here we describe MSL2, a novel E3 ligase for p53 that promotes ubiquitin-dependent cytoplasmic p53 localization. Unlike Mdm2 or most other p53 E3 ligases, MSL2-mediated p53 ubiquitination does not affect the stability of p53. Moreover, the MSL2-mediated effect on p53 is Mdm2-independent. Thus, our study identifies an important ubiquitin-ligase for modulating p53 subcellular localization. MSL2 ubiquitination of p53 is required for p53 cytoplasmic localization.

SIGNOR-271774

Q14790

Q9NZS9

0

binding

down-regulates

0.37

We also demonstrate that the mitochondrial protein bar, which has been shown to simultaneously bind caspase-8 and bcl-2

SIGNOR-112585

P41594

Q05513

0

phosphorylation

up-regulates activity

0.37

Thus, we showed that it is phosphorylation of Ser-839, not Thr-840, that is absolutely required for the unique Ca2+ oscillations produced by mGluR5 activation. The Thr-840 residue is important only in that it is permissive for the PKC-dependent phosphorylation of Ser-839.

SIGNOR-249284

Q9Y251

P18146

0

transcriptional regulation

up-regulates quantity by expression

0.37

Promoter CpG hypomethylation and transcription factor EGR1 hyperactivate heparanase expression in bladder cancer.

SIGNOR-254267

Q99558

Q9UHD2

0

phosphorylation

down-regulates quantity by destabilization

0.37

TBK1 induces NIK phosphorylation and degradation.

SIGNOR-279767

Q9Y385

Q13490

0

ubiquitination

down-regulates quantity by destabilization

0.37

We also found that ubiquitin-ligase (E3), c-IAP1 preferentially interacts with phosphorylated Ube2j1. Moreover, we noticed that phosphorylated Ube2j1 is rapidly degraded by the proteasome during ER stress cell recovery. Taken together, these data suggest that Ube2j1 and its phosphorylation is important for transient ER stress cell recovery and the phosphorylated Ube2j1 is degraded by the proteasome.

SIGNOR-263092

Q9UKV8

P48729

0

phosphorylation

down-regulates activity

0.369

Our experiments demonstrated that target engagement by AGO2 stimulates its hierarchical, multi-site phosphorylation by CSNK1A1 on a series of highly conserved residues (S824-S834).Although this impairs target binding, dephosphorylation by ANKRD52-PPP6C allows AGO2 to engage new targets. Inactivation of this cycle strongly inhibits global miRNA-mediated repression.

SIGNOR-276510

P16885

P07333

0

null

up-regulates

0.369

Studies with multipotent precursor cell lines (Fig. 4A) indicate that CSF-1R Tyr-807 and Tyr-721 promote macrophage differentiation via the PLC-Œ≥2 pathway

SIGNOR-255570

Q01167

P24941

0

phosphorylation

up-regulates

0.369

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

SIGNOR-167834

P37231

P23769

0

null

down-regulates activity

0.369

GATA2 interacts directly with PPARG and C/EBP a , which may deplete PPARG involved in the promotion of adipogenesis

SIGNOR-132949

Q9GZQ8

Q9H2P0

0

binding

up-regulates activity

0.369

Here, we show for the first time that hippocampal ADNP deficiency paralleled reduced beclin1 expression which, in turn, parallels increased tauopathy and cell death. We now show that ADNP directly interacts with LC3B, implicating the requirement of a healthy ADNP system for the apoptotic/autophagy processes.

SIGNOR-266759

P22681

P29376

0

phosphorylation

up-regulates

0.369

Although c-cbl is found to be phosphorylated by ltk and therefore is a second candidate linking ltk with the pi3-kinase pathway along with irs-1, we found that the p85 subunit of pi3 kinase directly binds to tyrosine 753 of ltk, which is located within a yxxm motif, a consensus binding amino acid sequence for the sh2 domain of p85.

SIGNOR-49528

Q9UJ55

O00327

0

binding

down-regulates activity

0.369

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

SIGNOR-253517

P11137

Q76NI1

0

phosphorylation

up-regulates activity

0.369

V-KIND enhances Thr phosphorylation of MAP2.

SIGNOR-278950

P15559

P31749

0

phosphorylation

down-regulates quantity by destabilization

0.369

Akt phosphorylates NQO1 on S40 and T128 residues. Here we show that Akt phosphorylates NQO1 at T128 residues and triggers its polyubiquitination and proteasomal degradation, abrogating its antioxidative effects in PD. Akt binds NQO1 in a phosphorylation-dependent manner. Interestingly, Akt, but not PINK1, provokes NQO1 phosphorylation and polyubiquitination with Parkin as an E3 ligase.

SIGNOR-276868

P11831

Q9UQM7

0

phosphorylation

up-regulates activity

0.369

Skeletal muscle CaMKII enriches in nuclei and phosphorylates myogenic factor SRF at multiple sites. | Microsequencing of these phosphorylated peptides identified that both Ser-103 and a novel residue, Thr-160 in the MADS box of SRF, were sites of phosphorylation. | The location of Thr-160 in the 3-D structure of SRF suggests that its phosphorylation by nuclear CaMKII may directly influence DNA binding of SRF and other MADS box factors.

SIGNOR-250639

P42702

P28482

0

phosphorylation

down-regulates

0.369

Indeed, phosphorylation of the cytoplasmic domain of the low-affinity lif receptor alpha-subunit (lifr) in mono q-fractionated, lif-stimulated 3t3-l1 extracts occurred only in those fractions containing activated mapk;ser-1044 served as the major phosphorylation site in the human lifr for mapk both in agonist-stimulated 3t3-l1 lysates and by recombinant extracellular signal-regulated kinase 2 in vitro

SIGNOR-32753

Q14934

Q00526

0

phosphorylation

up-regulates activity

0.369

CDK3 enhances the transactivation and transcription activity of NFAT3.|NFAT3 can be phosphorylated by CDK3 at Ser259, which is critical for its transactivation activity and cell transformation.

SIGNOR-278511

P05412

Q9H4B4

0

phosphorylation

up-regulates

0.369

Stress-induced c-jun activation mediated by polo-like kinase 3 in corneal epithelial cells. Hypoxia/reoxygenation activated plk3 in hce cells to directly phosphorylate c-jun proteins at phosphorylation sites ser-63 and ser-73, and to increase dna binding activity of c-jun.

SIGNOR-157721

P35568

O14733

0

phosphorylation

down-regulates activity

0.369

Tyrosine phosphorylation of IRS-1 initiates insulin signaling, whereas serine/threonine phosphorylation alters the ability of IRS-1 to transduce the insulin signalInsulin increased the phosphorylation of Ser312, Ser616, Ser636, Ser892, Ser1101, and Ser1223 Ser312 can be phosphorylated by kinases, such as c-jun NH2-terminal kinase and inhibitor of _B kinase

SIGNOR-217920

Q96P20

P45983

0

phosphorylation

up-regulates activity

0.369

Ethanol induced JNK1 phosphorylation activated the NLRP3 inflammasome that induced caspase-1 dependent mitophagy inhibition, thereby exacerbating ROS accumulation and causing cell death.|However, recent studies suggested that Ser 194 phosphorylation of NLRP3 was essential for the control of inflammasome activation and that JNK1 directly phosphorylates NLRP3, which stimulates the self-association and oligomerization of NLRP3 [ xref , xref ].

SIGNOR-280034

Q15653

Q15418

0

phosphorylation

down-regulates quantity by destabilization

0.369

By using recombinant wild-type and mutant IkappaBbeta proteins, both active ERK2 and RSK1 were found to directly phosphorylate IkappaBbeta, but only active RSK1 phosphorylated IkappaBbeta on Ser19 and Ser23, two sites known to mediate the subsequent ubiquitination and degradation.

SIGNOR-280114

P68400

P28482

0

phosphorylation

up-regulates

0.369

Erk2, which is activated by egfr signaling, directly binds to ck2alpha via the erk2 docking groove and phosphorylates ck2alpha primarily at t360/s362, subsequently enhancing ck2alpha activity

SIGNOR-161855

Q14790

P51812

0

phosphorylation

down-regulates quantity by destabilization

0.369

The ribosomal S6 kinase 2 (RSK2) is a member of the p90 ribosomal S6 kinase (p90RSK) family of proteins and plays a critical role in proliferation, cell cycle, and cell transformation. Here, we report that RSK2 phosphorylates caspase-8, and Thr-263 was identified as a novel caspase-8 phosphorylation site. In addition, we showed that EGF induces caspase-8 ubiquitination and degradation through the proteasome pathway, and phosphorylation of Thr-263 is associated with caspase-8 stability.

SIGNOR-272997

P38398

Q9H4M3

0

binding

down-regulates quantity by destabilization

0.369

The F-box protein FBXO44 mediates BRCA1 ubiquitination and degradation. The Skp1-Cul1-F-box-protein44 (SCF(FBXO44)) complex ubiquitinates full-length BRCA1 in vitro.

SIGNOR-272037

P19174

Q12913

0

dephosphorylation

down-regulates

0.369

Cd148 can dephosphorylate lat and plc?1 In vitro. / plc?1 Undergoes inducible tyrosine phosphorylation following tcr stimulation (46), and this phosphorylation is required to stimulate its catalytic activity

SIGNOR-105790

Q13469

Q86Y07

0

phosphorylation

up-regulates

0.369

We demonstrate that vrk2 directly interacts and phosphorylates nfat1 in ser-32 within its n-terminal transactivation domain.

SIGNOR-199263

Q13547

Q99801

0

binding

down-regulates activity

0.369

NKX3.1 also binds HDAC1 and releases p53 from p53-MDM2-HDAC1 complex, promoting p53 acetylation and activity.

SIGNOR-251549