GleghornLab/Signor_2class · Datasets at Hugging Face

IdA string	IdB string	labels int64	mechanism string	effect string	score float64	sentence string	signor_id string
Q00535	Q9UQB3	1	phosphorylation	up-regulates activity	0.327	Cdk5 mediated delta-catenin phosphorylation regulates delta-catenin subcellular localization into two distinct pools : a cytoplasmic or intraneurite state as well as a pool that is localized to the membrane.\|Cdk5 phosphorylates delta-catenin on serines 300 and 357.	SIGNOR-279323
O60729	Q13309	1	dephosphorylation	down-regulates quantity by destabilization	0.357	The activity of SCF(Skp2) is regulated by the Cyclin-dependent kinase (CDK)2-mediated phosphorylation of Skp2 on Ser64 allows its expression in mid-G1 phase, even in the presence of active APC(Cdh1). Reciprocally, dephosphorylation of Skp2 by the mitotic phosphatase Cdc14B at the M --> G1 transition promotes its degradation by APC(Cdh1).	SIGNOR-248333
P48736	P05771	0	phosphorylation	up-regulates activity	0.501	Remarkably we find that PKCβ phosphorylates Ser582 in the helical domain of the PI3Kγ catalytic subunit p110γ in response to clustering of the high-affinity IgE receptor (FcεRI) and/or store-operated Ca²⁺- influx in mast cells. Phosphorylation of p110γ correlates with the release of the p84 PI3Kγ adapter subunit from the p84-p110γ complex.As functional p84-p110γ is key to GPCR-mediated p110γ signaling, this suggests that PKCβ-mediated p110γ phosphorylation disconnects PI3Kγ from its canonical inputs from trimeric G proteins, and enables p110γ to operate downstream of Ca²⁺ and PKCβ.	SIGNOR-276496
P01236	Q13177	0	phosphorylation	up-regulates	0.337	Phosphorylated form of prolactin has a higher affinity for heparin.	SIGNOR-186211
Q5S007	Q99961	1	phosphorylation	down-regulates	0.467	We show that lrrk2 affects synaptic endocytosis by phosphorylating endoa at s75, a residue in the bar domain / our work uncovers a regulatory mechanism that indicates that reduced lrrk2 kinase activity facilitates endoa membrane association, while increased kinase activity inhibits membrane association.	SIGNOR-192068
P33076	P14316	0	transcriptional regulation	up-regulates quantity by expression	0.525	In addition to IRF-1, IRF-2, another member of the IRF family, also activates the human CIITA type IV promoter, and IRF-2 cooperates with IRF-1 to activate the promoter in transient transfection assays.	SIGNOR-271681
P12814	Q9UPX8	0	relocalization	up-regulates activity	0.297	SHANK proteins are ‘master’ scaffolding proteins that tether and organize intermediate scaffolding proteins. They are located at excitatory synapses, where they are crucial for proper synaptic development and function. SAPAP proteins subsequently bind to the PDZ domain of members of the SHANK protein family. SHANK proteins then bind to the actin cytoskeleton and to Homer protein, which in turn interacts with mGluRs. Through these extended links, PSD95, SAPAP, SHANK and Homer proteins form a quaternary complex that brings together mGluR and NMDAR complexes in the PSD (FIG. 3).	SIGNOR-264584
Q92934	Q9P286	0	phosphorylation	down-regulates activity	0.2	P21-Activated kinase 5 (Pak5) localizes to mitochondria and inhibits apoptosis by phosphorylating BAD. Pak5 phosphorylates BAD Ser-112	SIGNOR-250247
P49459	P24941	0	phosphorylation	up-regulates	0.374	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-116508
P01100	P14921	0	transcriptional regulation	up-regulates quantity	0.718	Furthermore, the possible involvement of an Ets protein in the control of c-fos has interesting implications for proto-oncogene cooperation in cellular growth control.	SIGNOR-256495
Q5JVS0	P05129	0	phosphorylation	down-regulates activity	0.293	We found a strong phosphorylation of Ki-1/57 by PKCalphabeta, PKCdelta, PKClambda/zeta, and especially by PKCsigma, however not by PKCmi. These data show that Ki-1/57 can serve in principal as a substrate for a wide variety of different PKC isoforms but also that its phosphorylation is strongest with PKCsigma. \| This suggests that the two threonine residues present in this fragment (Thr354 and Thr375) might be the main target residues for phosphorylation by PKC in vitro. \| Ki-1/57 Exits the Nucleus upon PMA Activation	SIGNOR-249255
Q13976	P31645	1	phosphorylation	up-regulates	0.382	These results are consistent with the hypothesis that pkg phosphorylates hsert at thr-276 and increases its activity by modifying the substrate permeation pathway formed, in part, by tm5.	SIGNOR-158186
Q12770	Q12772	1	relocalization	up-regulates activity	0.901	SCAP contains two domains: an NH2-terminal membrane attachment domain with eight membrane-spanning helices (Nohturfft et al., 1998b) and a long COOH-terminal extension that contains multiple copies of a WD40 repeat sequence, which forms a propeller-like structure that binds to the COOH-terminal domains of the SREBPs, thereby permitting the escort function	SIGNOR-267502
P35240	P62140	0	dephosphorylation	up-regulates	0.378	When serine 518 is dephosphorylated by the myosin phosphatase mypt-1-pp1?, The tumor suppressor function of merlin is activated, inhibiting the ras signaling pathway and leading to growth arrest	SIGNOR-159836
Q16581	P35626	0	phosphorylation	down-regulates activity	0.2	These findings suggest that in agonist-stimulated mast cells GRK2 and GRK3 may phosphorylate C3aR at the same or distinct sites to promote receptor desensitization.	SIGNOR-279781
P30305	Q16549	0	phosphorylation	down-regulates	0.2	We propose that regulation of cdc25b phosphorylation by p38 is a critical event for initiating the g2/m checkpoint after ultraviolet radiation	SIGNOR-107423
P31749	Q96EB6	0	deacetylation	up-regulates activity	0.6	We show that Akt and PDK1 are acetylated at lysine residues in their pleckstrin homology domains, which mediate PIP(3) binding. Acetylation blocked binding of Akt and PDK1 to PIP(3), thereby preventing membrane localization and phosphorylation of Akt. Deacetylation by SIRT1 enhanced binding of Akt and PDK1 to PIP(3) and promoted their activation.	SIGNOR-252445
Q00535	P08670	1	phosphorylation	up-regulates activity	0.27	Cdk5 mediates vimentin Ser56 phosphorylation during GTP-induced secretion by neutrophils.	SIGNOR-278922
P06493	O43280	1	phosphorylation	up-regulates activity	0.268	Ewald et al. reported that at the G1/S transition, cyclin-dependent kinase 1 (CDK1) phosphorylates and activates the neutral trehalase (NTH1) to funnel trehalose into glycolysis (Ewald et al. xref ).	SIGNOR-280206
Q14258	Q13887	1	polyubiquitination	down-regulates quantity by destabilization	0.482	The oestrogen-inducible E3 ligase EFP (oestrogen-responsive finger protein) was identified as a key player in oestrogen-mediated degradation of KLF5, as knockdown and overexpression of EFP increased and decreased KLF5 protein levels respectively, and the decrease continued even when protein synthesis was blocked.	SIGNOR-271908
Q9UQM7	Q05397	1	phosphorylation	up-regulates	0.272	Furthermore, activated camkii directly phosphorylated the recombinant cooh-terminal region of fak at a residue equivalent to ser-843.	SIGNOR-135631
O96017	P21127	1	phosphorylation	up-regulates activity	0.2	CHK2 kinase promotes pre-mRNA splicing via phosphorylating CDK11p110\|Unexpectedly, CHK2 kinase constitutively phosphorylated CDK11(p110) in a DNA damage-independent manner.	SIGNOR-279458
Q00613	P31749	0	phosphorylation	up-regulates activity	0.405	Mass spectrometry showed that AKT1 also phosphorylated HSF1 at T142, S230 and T527 in addition to S326, whereas the other kinases did not. Subsequent investigation revealed that phosphorylation at T142 is necessary for HSF1 trimerization and that S230, S326 and T527 are required for HSF1 gene transactivation and recruitment of TFIIB and CDK9.	SIGNOR-277579
P15692	P40763	0	transcriptional regulation	up-regulates quantity by expression	0.786	Stat3 directly regulated the promoter of the VEGF gene. Blockade of activated Stat3 by ectopic expression of dominant-negative Stat3 significantly inhibited VEGF expression, and the growth and metastasis of human pancreatic cancer cells.	SIGNOR-259456
P42574	Q9UKV3	1	cleavage	up-regulates	0.628	Induces apoptotic chromatin condensation after activation by casp3	SIGNOR-70800
Q13153	Q96T58	1	phosphorylation	down-regulates activity	0.2	Pak1 phosphorylation sites in SHARP were mapped to Ser3486 and Thr3568 within the SHARP repression domain.	SIGNOR-278968
P49760	P31749	0	phosphorylation	up-regulates	0.39	Akt directly binds to and phosphorylates clk2 on serine 34 and threonine 127, in vitro and in vivo.Our results suggest that akt activation controls cell survival to ionizing radiation by phosphorylating clk2, revealing an important regulatory mechanism required for promoting cell surviva	SIGNOR-167340
P13639	Q9H2P9	0	methylation	down-regulates activity	0.747	Analysis of EF2 in the mutant cells revealed a novel form of diphthamide with an additional methyl group that prevented ADP-ribosylation and inactivation of EF2. The abnormal methylation appeared to be catalyzed by DPH5.	SIGNOR-261146
P16591	P16284	1	phosphorylation	up-regulates activity	0.322	PECAM-1 Is Phosphorylated by Fer and, To a Lesser Extent, by Fes. These results suggest that Fer not only functions as a tyrosine kinase for PECAM-1 but also that Fer modulates the downstream signaling of PECAM-1 by inducing phosphorylation of SHP-2 and Gab1.	SIGNOR-262866
P01106	P12268	1	transcriptional regulation	up-regulates quantity by expression	0.294	Analysis of in vivo C-MYC interactions with TS, IMPDH2 and PRPS2 genes confirmed that they are direct C-MYC targets. C-MYC depletion did not significantly affect levels of E2F1 protein reported to regulate expression of many S-phase specific genes, but resulted in the repression of several genes encoding enzymes rate-limiting for dNTP metabolism. These included thymidylate synthase (TS), inosine monophosphate dehydrogenase 2 (IMPDH2) and phosphoribosyl pyrophosphate synthetase 2 (PRPS2). C-MYC depletion also resulted in reduction in the amounts of deoxyribonucleoside triphosphates (dNTPs) and inhibition of proliferation.	SIGNOR-267375
P61586	Q5T5U3	0	gtpase-activating protein	down-regulates activity	0.628	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)\|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs\| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260475
P27361	Q9UBS5	1	phosphorylation	down-regulates quantity by destabilization	0.276	We found that, in addition to CaMKIIβ, also ERK1/2 is involved in the degradation pathway of GABAB receptors under physiological and ischemic conditions. In contrast to our previous view, CaMKIIβ does not appear to directly phosphorylate S867. Instead, the data support a mechanism in which CaMKIIβ activates ERK1/2, which then phosphorylates S867 and T872 in GABAB1.	SIGNOR-277854
P08709	P38435	0	carboxylation	up-regulates activity	0.688	Thus, vitamin K acts as a cofactor for GGCX via the vitamin K cycle and exerts physiological effects through its regulation of VKDPs [29]. More than 20 VKDPs have been found. Osteocalcin promotes bone formation, and blood coagulation factors II, VII, IX, and X activate blood coagulation. Matrix Gla protein suppresses cardiovascular calcification, and brain-expressed Gas 6 promotes neural differentiation [29]. GGCX is an enzyme that converts glutamic acid (Glu) residues to Gla residues, so that the Gla-containing proteins can exert various physiological actions such as blood coagulation and bone formation.	SIGNOR-265919
P42336	Q9Y4K3	0	ubiquitination	up-regulates activity	0.458	In contrast to NEDD4L, overexpression of TRAF6 increases the stability of PIK3CA protein and promotes PI3K activation.\|TRAF6 ubiquitinates PIK3CA in vivo.	SIGNOR-278727
Q53EZ4	P28482	0	phosphorylation	down-regulates	0.367	Upon mitotic entry, centrosome dissociation of cep55 is triggered by erk2/cdk1-dependent phosphorylation at s425 and s428. S425/428 phosphorylation is required for interaction with plk1, enabling phosphorylation of cep55 at s436. enabling it to relocate to the midbody to function in mitotic exit and cytokinesis.	SIGNOR-140890
Q14160	Q05086	0	polyubiquitination	down-regulates quantity by destabilization	0.552	Human scribble (Vartul) is targeted for ubiquitin-mediated degradation by the high-risk papillomavirus E6 proteins and the E6AP ubiquitin-protein ligase	SIGNOR-272573
Q5SQI0	Q9H853	1	acetylation	up-regulates quantity by stabilization	0.2	Alpha-Tubulin acetyltransferase (alphaTAT1) is the major α-tubulin lysine-40 (K40) acetyltransferase in mammals, nematodes, and protozoa, and its activity plays a conserved role in several microtubule-based processes.\|The tubulin subunits of microtubules are acetylated, and lysine-40 (K40) of the alpha-tubulin subunit has been identified as an important conserved site of microtubule acetylation (6–8). This modification is considered a hallmark of stable, long-lived microtubules	SIGNOR-272252
P29350	P52333	1	dephosphorylation	up-regulates	0.688	The expression of shp-1 protein was associated with dephosphorylation of the jak3 kinase.	SIGNOR-82764
Q01860	O00308	0	ubiquitination	down-regulates quantity	0.453	WWP2 promotes degradation of transcription factor OCT4 in human embryonic stem cells\|Here, we report that human WWP2, an E3 ubiquitin (Ub)-protein ligase, interacts with OCT4 specifically through its WW domain and enhances Ub modification of OCT4 both in vitro and in vivo.	SIGNOR-268850
P27361	P67775	0	dephosphorylation	down-regulates	0.647	P-erk1/2 proteins were efficiently dephosphorylated in vitro by protein phosphatases 1 and 2a (pp1/2a) and mapk phosphatase 3 (mkp3).	SIGNOR-103162
P42226	O15524	1	transcriptional regulation	up-regulates quantity by expression	0.638	We found that IL-4, like IFN-gamma, induces rapid de novo expression of SOCS-1 in primary macrophages. Induction of SOCS-1 gene expression by IL-4 is STAT6-dependent.	SIGNOR-249570
Q02535	Q14938	0	transcriptional regulation	down-regulates quantity	0.2	By integrating transcriptomic profiling (RNA-seq) of Nfia- and Nfix-deficient GNPs with epigenomic profiling (ChIP-seq against NFIA, NFIB and NFIX, and DNase I hypersensitivity assays), we reveal that these transcription factors share a large set of potential transcriptional targets, suggestive of complementary roles for these NFI family members in promoting neural development	SIGNOR-268885
P54274	Q8NA31	0	relocalization	up-regulates activity	0.2	The shelterin complex has six proteins, containing TRF1, TRF2, POT1, RAP1, TIN2, and TPP1. The shelterin complex is localized to the chromosome end and protects telomeric DNA (Palm and de Lange, 2008). The TTM complex acts as a “linker” and bridges the LINC and shelterin complexes together. The connection between TTM and shelterin complexes is well-known, which is mediated by TERB1 and TRF1	SIGNOR-263315
Q14669	Q13564	1	ubiquitination	down-regulates quantity by destabilization	0.432	Our data suggest that that TRIP12 promotes degradation of APP-BP1 by catalyzing its ubiquitination, which in turn modulates the neddylation pathway.	SIGNOR-266780
P28482	Q13485	1	phosphorylation	up-regulates	0.511	Phosphorylation of thr276 is shown to be important for tgf-?-Induced nuclear accumulation and, as a consequence, transcriptional activity of smad4. these results suggest that smad4 can be phosphorylated by erk2 at thr276.	SIGNOR-101660
Q9UQL6	Q13131	0	phosphorylation	down-regulates	0.341	Another recently described set of transcriptional regulators targeted by ampk and its related family members across a range of eukaryotes are the class iia family of histone deacetylases (hdacs)	SIGNOR-176479
P32927	Q06124	0	dephosphorylation	up-regulates	0.511	Shp2 is thought to act as a positive mediator of growth factor signals.. Hp2 could act as an adaptor between the activated c and grb2, thus leading to activation of the ras/mitogen-activated protein kinase pathway, known to be activated by il-3	SIGNOR-48557
Q92813	Q9Y385	0	ubiquitination	down-regulates quantity by destabilization	0.379	ER residency places D2 physically close to an array of proteins that interact and modify the D2 molecule via ubiquitination and targeting to the proteasomal system, explaining its relatively short half-life. Both ubiquitin conjugases UBC6 and or UBC7 interact with D2 and support D2 ubiquitination. Two Lys residues in D2 are involved in this process, K237 and K244.	SIGNOR-267481
P12004	Q9NS91	0	ubiquitination	up-regulates activity	0.846	Second, these findings suggest the following model (XREF_FIG) : upon replication fork stalling at cisplatin induced DNA lesions, the RAD18 and RAD6 complex ubiquitylates PCNA on Lys164.\|The DNA damage-activated E3 ubiquitin ligase RAD18 promotes repair of interstrand DNA cross-links by ubiquitylating PCNA and recruiting FANCL to chromatin.	SIGNOR-278612
P31751	P03372	1	phosphorylation	up-regulates activity	0.509	AKT activate ERalpha in the absence of estrogen. The consensus AKT phosphorylation site Ser-167 of ERalpha is required for phosphorylation and activation by AKT.	SIGNOR-251490
Q9Y6H5	Q9NV58	0	ubiquitination	up-regulates quantity	0.453	Ubiquitylation of synphilin-1 by Dorfin. A, synphilin-1 is ubiquitylated in HEK293 cells. Several lines of evidence have suggested that derangements in the ubiquitin-proteasome protein degradation pathway may have a prominent role in the pathogenesis of PD (5). Our present study shows that Dorfin, an E3 ubiquityl ligase, is colocalized with ubiquitin in LBs of PD and physically binds to ubiquitylate synphilin-1, which is known to be a major component of LBs	SIGNOR-271455
Q3KRB8	P61586	1	gtpase-activating protein	down-regulates activity	0.502	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)\|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs\| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260467
Q99988	P18847	0	transcriptional regulation	up-regulates quantity by expression	0.426	In addition, DIM increased the expression of NAG-1 as well as activating transcription factor 3 (ATF3), and the induction of ATF3 was earlier than that of NAG-1. The DIM treatment increased luciferase activity of NAG-1 in HCT-116 cells transfected with NAG-1 promoter construct. The results suggest that I3C represses cell proliferation through up-regulation of NAG-1 and that ATF3 may play a pivotal role in DIM-induced NAG-1 expression in human colorectal cancer cells.	SIGNOR-253725
Q9NZQ7	Q9Y4X5	0	polyubiquitination	down-regulates quantity by destabilization	0.2	We find EGFR inhibitors promote PD-L1 ubiquitination and proteasomal degradation following GSK3α-mediated phosphorylation of Ser279/Ser283. We identify ARIH1 as the E3 ubiquitin ligase responsible for targeting PD-L1 to degradation.	SIGNOR-277553
Q00535	O14939	1	phosphorylation	up-regulates activity	0.368	In this study, we suggest that the phosphorylation and activation of PLD2 by cyclin-dependent kinase 5 (Cdk5) is critical for EGF-dependent insulin secretion.\|We determined that Cdk5 phosphorylates PLD2 at Ser 134 of PLD2 and that this phosphorylation was suggested to be important for EGF-dependent insulin secretion.	SIGNOR-278395
O15169	O75197	0	relocalization	down-regulates quantity	0.83	Axin is a protein that interacts with the intracellular domain of LRP-5. LRP-5 active form bind Axin and induce LEF-1 activation by destabilizing Axin and stabilizing beta-catenin.	SIGNOR-236997
P25490	O15379	0	deacetylation	down-regulates activity	0.6	Previous studies have established that YY1 interacts with histone acetyltransferases p300 and CREB-binding protein (CBP) and histone deacetylase 1 (HDAC1), HDAC2, and HDAC3. Here, we present evidence that the activity of YY1 is regulated through acetylation by p300 and PCAF and through deacetylation by HDACs. YY1 was acetylated in two regions: both p300 and PCAF acetylated the central glycine-lysine-rich domain of residues 170 to 200, and PCAF also acetylated YY1 at the C-terminal DNA-binding zinc finger domain. Acetylation of the central region was required for the full transcriptional repressor activity of YY1 and targeted YY1 for active deacetylation by HDACs.	SIGNOR-268837
Q9GZM8	O14965	0	phosphorylation	down-regulates quantity by destabilization	0.603	Here, we show that Aurora-A phosphorylates NDEL1 at Ser251 at the beginning of mitotic entry. Interestingly, NDEL1 phosphorylated by Aurora-A was rapidly downregulated thereafter by ubiquitination-mediated protein degradation.	SIGNOR-263159
P63010	P12931	0	phosphorylation	down-regulates	0.272	The phosphorylation of beta2-adaptin on tyrosine residue 737 (y737) negatively regulates its interaction with betaarrestin.	SIGNOR-181743
P39019	P11309	0	phosphorylation	up-regulates	0.438	The pim-1/rps19 interaction was demonstrated both in vitro and in living cells and led to phosphorylation of rps19 in an in vitro kinase assay.	SIGNOR-141411
P24928	P50613	0	phosphorylation	down-regulates	0.789	Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination.	SIGNOR-120024
Q9HD90	O00712	0	transcriptional regulation	up-regulates quantity	0.2	For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8)	SIGNOR-268898
P08581	P40763	1	phosphorylation	up-regulates activity	0.706	It has been reported that c-Met can activate STAT3 at the endosome and phosphorylated STAT3 induced by c-Met is colocalized with EEA1, an early endosome marker.	SIGNOR-280041
Q93009	Q96EP1	1	deubiquitination	up-regulates quantity by stabilization	0.432	In this study, we identified USP7 (also known as HAUSP), which is a member of a family of proteins that cleave polyubiquitin chains and/or ubiquitin precursors, as an interacting protein with Chfr by immunoaffinity purification and mass spectrometry, and their interaction greatly increases the stability of Chfr. In fact, USP7 can remove ubiquitin moiety from the autoubiquitinated Chfr both in vivo and in vitro, which results in the accumulation of Chfr in the cell. USP7 mediates deubiquitination of Chfr.	SIGNOR-271462
P06213	P27986	1	phosphorylation	up-regulates activity	0.67	The alpha-type 85-kDa subunit of phosphatidylinositol 3-kinase is phosphorylated at tyrosines 368, 580, and 607 by the insulin receptor.	SIGNOR-251321
P04150	P27361	0	phosphorylation	down-regulates	0.542	Cyclin-dependent kinase (CDK) and mitogen-activated protein kinase (MAPK) phosphorylate the rat glucocorticoid receptor in vitro at distinct sites that together correspond to the major phosphorylated receptor residues observed in vivo; MAPK phosphorylates receptor residues threonine 171 and serine 246, whereas multiple CDK complexes modify serines 224 and 232.\|MAPKs and CDKs exert opposite effects on receptor transcriptional enhancement. From our results, we speculate that activators of the MAPK pathway, such as growth factors, insulin, and certain oncoproteins, or inhibitors of CDK function, such as tumor growth factor beta (TGF_), p21, and p27, might attenuate receptor-induced transcrip- tional responses. In contrast, negative regulators of MAPK, such as pKA, as well as activators of CDK, such as the cyclins or CAKs, should potentiate receptor action.	SIGNOR-154409
Q16539	Q13115	0	dephosphorylation	down-regulates	0.665	This result suggests that dusp4 represses gluconeogenesis through dephosphorylation of p38	SIGNOR-147958
A8MYZ6	O75874	1	transcriptional regulation	up-regulates quantity by expression	0.2	We identify FOXOs as transcriptional activators of IDH1. FOXOs promote IDH1 expression and thereby maintain the cytosolic levels of α-ketoglutarate and NADPH.	SIGNOR-260092
O60343	P31749	0	phosphorylation	down-regulates	0.764	Recently, we identified a 160-kda protein in adipocytes, designated as160, that is phosphorylated by the insulin-activated kinase akt	SIGNOR-252594
P61586	Q9H8V3	0	guanine nucleotide exchange factor	up-regulates activity	0.712	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)\|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs\| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260550
P45983	Q12904	1	phosphorylation	down-regulates	0.473	We further demonstrated that serine-140 residue of aimp1 was phosphorylated by jnk and alanine mutation of serine-140 suppressed lps-induced cell surface altogether, these results suggest that aimp1 is phosphorylated by jnk through tlr-myd88 pathway and lose the regulatory activity for er retention of gp96expression of gp96.	SIGNOR-165763
P07333	O60716	1	phosphorylation	up-regulates quantity by stabilization	0.27	In our study, CSF-1R induced the tyrosine phosphorylation of p120 Y904 and Y228 in a SRC-dependent manner ( xref ).	SIGNOR-278929
P06241	Q04759	1	phosphorylation	up-regulates	0.344	Further indications of direct interaction are that p59fyn potentiates ?PKC Catalytic activity and that ?PKC Is a substrate for tyrosine phosphorylation by p59fyn.	SIGNOR-68798
P17612	P63252	1	phosphorylation	down-regulates activity	0.2	PKA consensus site S425 required for PKA-mediated effects on Kir2.1 channels. PKA activation reduced outward IK1 for heteromeric Kir2.1 WT+V227F channels after 2 hours of PKA activation.	SIGNOR-276267
P37275	P52954	0	transcriptional regulation	up-regulates quantity by expression	0.326	Compared with the empty vector, LBX1 induced increased promoter activity of threefold to fourfold and fivefold to sixfold for ZEB1 and Snail1, respectively	SIGNOR-266054
Q8IYA7	P35711	1	transcriptional regulation	up-regulates quantity by expression	0.295	MKX is a meniscus-enriched transcription factor. In human meniscus cells, MKX regulates the expression of meniscus marker genes, OA-related genes, and other transcription factors, including Scleraxis (SCX), SRY Box 5 (SOX5), and Runt domain-related transcription factor 2 (RUNX2).	SIGNOR-267214
P68400	Q13371	1	phosphorylation	up-regulates	0.387	Phosducin-like protein (phlp) is a widely expressed binding partner of the g protein betagamma subunit complex (gbetagamma) that has been recently shown to catalyze the formation of the gbetagamma dimer from its nascent polypeptides. Phosphorylation of phlp at one or more of three consecutive serines (ser-18, ser-19, and ser-20) is necessary for gbetagamma dimer formation and is believed to be mediated by the protein kinase ck2.	SIGNOR-146833
Q01196	P24941	0	phosphorylation	up-regulates activity	0.2	We have identified four phosphorylation sites on aml1c that are necessary for transcriptional activity of aml1c in k562 and 293t cells (27).4 mutation of these four sites (serine 276, serine 293, serine 303, and threonine 300) to alanine abolishes transcriptional activation, whereas mutation of these sites to aspartic acid (which mimics phosphorylation) results in a hyperactive protein.	SIGNOR-138932
Q2M385	O96017	0	phosphorylation	up-regulates activity	0.2	Chk2 phosphorylates Mps1-T288 after DNA damage.\|In the present study, we show that Chk2 stabilizes Mps1 protein and phosphorylates Aurora B-B-serine 331 to prevent mitotic exit in vertebrate cells when the majority of kinetochores are unattached.	SIGNOR-279160
P07948	P33993	1	phosphorylation	up-regulates activity	0.453	Lyn phosphorylates MCM7 at Y600.\|These evidences suggest that Lyn mediated Y600 phosphorylation may regulate MCM7 function in DNA replication licensing.	SIGNOR-278407
P35813	Q14653	1	dephosphorylation	down-regulates activity	0.247	In contrast, coexpression of wild-type PPM1A, but not its D239N or R174G mutant, abolished IRF3 activation (XREF_FIG).\|We found that PPM1A abolished the C-terminal phosphorylation of IRF3 (XREF_FIG), whereas depletion of PPM1A expression improved virus induced pIRF3 level (XREF_FIG and XREF_FIG).	SIGNOR-277152
Q9Y219	Q96AX9	0	ubiquitination	up-regulates	0.809	Skeletrophin bound the intracellular regions of the notch ligand jagged-2, but not to those of delta-1, -3, -4, or jagged-1. Skeletrophin, but not its ring-mutated form, ubiquitinized the intracellular region of jagged-2.	SIGNOR-137922
P21731-2	P35626	0	phosphorylation	down-regulates activity	0.2	These data suggest a model whereby agonist-induced PKC phosphorylation of Ser(145) partially impairs TPbeta signalling while GRK2/3 phosphorylation at both Ser(239) and Ser(357) within its IC(3) and C-tail domains, respectively, sterically inhibits G-protein coupling, profoundly desensitizing signalling, and promotes beta-arrestin association and, in turn, facilitates TPbeta internalization.	SIGNOR-274091
P17612	P62834	1	phosphorylation	down-regulates activity	0.521	Phosphorylation of Rap1A by PKA abolished its binding activity to CRR. a mutant Rap1A(S180E), whose sole PKA phosphorylation residue, Ser-180, was substituted by an acidic residue, Glu, to mimic its phosphorylated form, failed to suppress Ras-dependent Raf-1 activation in COS-7 cells.	SIGNOR-250042
P51812	O14649	1	phosphorylation	up-regulates activity	0.2	The chaperone protein, 14-3-3, binds to a critical phosphorylated serine in the channel c termini of k2p3.1 and k2p9.1 (ser(393) and ser(373), respectively) and overcomes retention in the endoplasmic reticulum by ?COP. We sought to identify the kinase responsible for phosphorylation of the terminal serine in human and rat variants of k2p3.1 and k2p9.1. Adopting a bioinformatic approach, three candidate protein kinases were identified: camp-dependent protein kinase, ribosomal s6 kinase, and protein kinase c.	SIGNOR-172470
Q15119	P29803	1	phosphorylation	down-regulates	0.548	Kinetic and regulatory properties of recombinant human pdh2 and pdh1 were compared in this study. Site-specific phosphorylation/dephosphorylation of the three phosphorylation sites by four pdh kinases (pdk1-4) and two pdh phosphatases (pdp1-2) were investigated by substituting serines with alanine or glutamate in pdhs.	SIGNOR-143970
P12931	O75955	1	phosphorylation	up-regulates activity	0.335	Taken together, we conclude that mitochondrial c-Src phosphorylates flotillin-1 at Tyr56 and Tyr149, and that these phosphorylations are required for its interaction with CxII and the prevention of ROS production.	SIGNOR-273805
Q9H300	Q9BXM7	1	cleavage	down-regulates quantity by destabilization	0.613	Using an unbiased RNA-mediated interference (RNAi)-based screen, we identified four mitochondrial proteases, mitochondrial processing peptidase (MPP), presenilin-associated rhomboid-like protease (PARL), m-AAA and ClpXP, involved in PINK1 degradation. We find that PINK1 turnover is particularly sensitive to even modest reductions in MPP levels. Moreover, PINK1 cleavage by MPP is coupled to import such that reducing MPP activity induces PINK1 accumulation at the mitochondrial surface, leading to Parkin recruitment and mitophagy.	SIGNOR-261364
Q13216	Q03468	1	ubiquitination	down-regulates quantity by destabilization	0.582	We have previously shown that CSA is a subunit of an E3 ubiquitin ligase complex. Here we demonstrate that CSB is a substrate of this ligase: Following UV irradiation, CSB is degraded at a late stage of the repair process in a proteasome- and CSA-dependent manner.	SIGNOR-271406
P36952	Q13547	0	transcriptional regulation	down-regulates quantity by repression	0.413	We found that maspin is selectively upregulated in IFIXα-expressing cells and involved in anti-invasive activity of IFIXα. We also present evidence indicating that IFIXα downregulates histone deacetylase 1 (HDAC1), which is possibly involved in the silencing of the maspin gene in human breast cancer cells. To confirm these results, we performed a luciferase assay using a maspin-promoter-luciferase plasmid. The results showed that HDAC1 overexpression suppressed the activity of the maspin promoter (Figure 3C). Therefore, our results suggest that IFIXα enhances maspin expression through the downregulation of HDAC1.	SIGNOR-268494
Q14654	Q13557	0	phosphorylation	down-regulates	0.2	Results showed that activation of camkii triggered dynamin-dependent internalization of k(atp) channels. This process required phosphorylation of threonine at 180 and 224 and an intact (330)yskf(333) endocytosis motif of the k(atp) channel kir6.2 pore-forming subunit.	SIGNOR-200027
Q13153	P35813	0	dephosphorylation	down-regulates activity	0.337	Purified PP2Cα protein efficiently dephosphorylated PAK1 in vitro (Fig. 1, D and E). We previously assessed the time course of phospho-PAK1 dephosphorylation assessed using specific antibodies against either Ser(P)198/203 or Thr(P)422 sites in the PAK1 activation loop.	SIGNOR-248492
P04629	O14492	1	phosphorylation	up-regulates	0.547	Two substrates of trk kinases, raps and sh2-b. raps and sh2-b mediate trk signaling in developing neurons	SIGNOR-62619
Q9BV47	P04629	1	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
P30408	Q9H190	1	relocalization	up-regulates activity	0.402	TM4SF1 functions as a membrane adaptor connecting DDR1 to syntenin2.	SIGNOR-272401
P68400	Q13563	1	phosphorylation	up-regulates	0.421	Ser(812) can be phosphorylated by ck2 in vitro and substitution s812a results in failure to incorporate phosphate in cultured epithelial cells.	SIGNOR-121572
Q15075	Q16539	0	phosphorylation	up-regulates activity	0.458	We found that p38alpha can phosphorylate the rab5 effectors eea1 and rabenosyn-5 on thr-1392 and ser-215, respectively, and these phosphorylation events regulate the recruitment of eea1 and rabenosyn-5 to membranes	SIGNOR-140082
P48730	O75581	1	phosphorylation	up-regulates activity	0.2	Central to WNT signalosome formation is phosphorylation of LRP6 at multiple sites, with GSK3β phosphorylating LRP6 at S1490 and CK1 family members phosphorylating LRP6 at T1479 and T1493	SIGNOR-275402
Q06210	P17252	0	phosphorylation	down-regulates activity	0.307	Phosphorylation of human glutamine:fructose-6-phosphate amidotransferase by cAMP-dependent protein kinase at serine 205 blocks the enzyme activity.	SIGNOR-249040
P45985	P31749	0	phosphorylation	down-regulates	0.594	Akt phosphorylated sek1 on serine 78.	SIGNOR-236494

Q00535

Q9UQB3

1

phosphorylation

up-regulates activity

0.327

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

SIGNOR-279323

O60729

Q13309

1

dephosphorylation

down-regulates quantity by destabilization

0.357

The activity of SCF(Skp2) is regulated by the Cyclin-dependent kinase (CDK)2-mediated phosphorylation of Skp2 on Ser64 allows its expression in mid-G1 phase, even in the presence of active APC(Cdh1). Reciprocally, dephosphorylation of Skp2 by the mitotic phosphatase Cdc14B at the M --> G1 transition promotes its degradation by APC(Cdh1).

SIGNOR-248333

P48736

P05771

0

phosphorylation

up-regulates activity

0.501

Remarkably we find that PKCβ phosphorylates Ser582 in the helical domain of the PI3Kγ catalytic subunit p110γ in response to clustering of the high-affinity IgE receptor (FcεRI) and/or store-operated Ca²⁺- influx in mast cells. Phosphorylation of p110γ correlates with the release of the p84 PI3Kγ adapter subunit from the p84-p110γ complex.As functional p84-p110γ is key to GPCR-mediated p110γ signaling, this suggests that PKCβ-mediated p110γ phosphorylation disconnects PI3Kγ from its canonical inputs from trimeric G proteins, and enables p110γ to operate downstream of Ca²⁺ and PKCβ.

SIGNOR-276496

P01236

Q13177

0

phosphorylation

up-regulates

0.337

Phosphorylated form of prolactin has a higher affinity for heparin.

SIGNOR-186211

Q5S007

Q99961

1

phosphorylation

down-regulates

0.467

We show that lrrk2 affects synaptic endocytosis by phosphorylating endoa at s75, a residue in the bar domain / our work uncovers a regulatory mechanism that indicates that reduced lrrk2 kinase activity facilitates endoa membrane association, while increased kinase activity inhibits membrane association.

SIGNOR-192068

P33076

P14316

0

transcriptional regulation

up-regulates quantity by expression

0.525

In addition to IRF-1, IRF-2, another member of the IRF family, also activates the human CIITA type IV promoter, and IRF-2 cooperates with IRF-1 to activate the promoter in transient transfection assays.

SIGNOR-271681

P12814

Q9UPX8

0

relocalization

up-regulates activity

0.297

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

SIGNOR-264584

Q92934

Q9P286

0

phosphorylation

down-regulates activity

0.2

P21-Activated kinase 5 (Pak5) localizes to mitochondria and inhibits apoptosis by phosphorylating BAD. Pak5 phosphorylates BAD Ser-112

SIGNOR-250247

P49459

P24941

0

phosphorylation

up-regulates

0.374

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-116508

P01100

P14921

0

transcriptional regulation

up-regulates quantity

0.718

Furthermore, the possible involvement of an Ets protein in the control of c-fos has interesting implications for proto-oncogene cooperation in cellular growth control.

SIGNOR-256495

Q5JVS0

P05129

0

phosphorylation

down-regulates activity

0.293

We found a strong phosphorylation of Ki-1/57 by PKCalphabeta, PKCdelta, PKClambda/zeta, and especially by PKCsigma, however not by PKCmi. These data show that Ki-1/57 can serve in principal as a substrate for a wide variety of different PKC isoforms but also that its phosphorylation is strongest with PKCsigma. | This suggests that the two threonine residues present in this fragment (Thr354 and Thr375) might be the main target residues for phosphorylation by PKC in vitro. | Ki-1/57 Exits the Nucleus upon PMA Activation

SIGNOR-249255

Q13976

P31645

1

phosphorylation

up-regulates

0.382

These results are consistent with the hypothesis that pkg phosphorylates hsert at thr-276 and increases its activity by modifying the substrate permeation pathway formed, in part, by tm5.

SIGNOR-158186

Q12770

Q12772

1

relocalization

up-regulates activity

0.901

SCAP contains two domains: an NH2-terminal membrane attachment domain with eight membrane-spanning helices (Nohturfft et al., 1998b) and a long COOH-terminal extension that contains multiple copies of a WD40 repeat sequence, which forms a propeller-like structure that binds to the COOH-terminal domains of the SREBPs, thereby permitting the escort function

SIGNOR-267502

P35240

P62140

0

dephosphorylation

up-regulates

0.378

When serine 518 is dephosphorylated by the myosin phosphatase mypt-1-pp1?, The tumor suppressor function of merlin is activated, inhibiting the ras signaling pathway and leading to growth arrest

SIGNOR-159836

Q16581

P35626

0

phosphorylation

down-regulates activity

0.2

These findings suggest that in agonist-stimulated mast cells GRK2 and GRK3 may phosphorylate C3aR at the same or distinct sites to promote receptor desensitization.

SIGNOR-279781

P30305

Q16549

0

phosphorylation

down-regulates

0.2

We propose that regulation of cdc25b phosphorylation by p38 is a critical event for initiating the g2/m checkpoint after ultraviolet radiation

SIGNOR-107423

P31749

Q96EB6

0

deacetylation

up-regulates activity

0.6

We show that Akt and PDK1 are acetylated at lysine residues in their pleckstrin homology domains, which mediate PIP(3) binding. Acetylation blocked binding of Akt and PDK1 to PIP(3), thereby preventing membrane localization and phosphorylation of Akt. Deacetylation by SIRT1 enhanced binding of Akt and PDK1 to PIP(3) and promoted their activation.

SIGNOR-252445

Q00535

P08670

1

phosphorylation

up-regulates activity

0.27

Cdk5 mediates vimentin Ser56 phosphorylation during GTP-induced secretion by neutrophils.

SIGNOR-278922

P06493

O43280

1

phosphorylation

up-regulates activity

0.268

Ewald et al. reported that at the G1/S transition, cyclin-dependent kinase 1 (CDK1) phosphorylates and activates the neutral trehalase (NTH1) to funnel trehalose into glycolysis (Ewald et al. xref ).

SIGNOR-280206

Q14258

Q13887

1

polyubiquitination

down-regulates quantity by destabilization

0.482

The oestrogen-inducible E3 ligase EFP (oestrogen-responsive finger protein) was identified as a key player in oestrogen-mediated degradation of KLF5, as knockdown and overexpression of EFP increased and decreased KLF5 protein levels respectively, and the decrease continued even when protein synthesis was blocked.

SIGNOR-271908

Q9UQM7

Q05397

1

phosphorylation

up-regulates

0.272

Furthermore, activated camkii directly phosphorylated the recombinant cooh-terminal region of fak at a residue equivalent to ser-843.

SIGNOR-135631

O96017

P21127

1

phosphorylation

up-regulates activity

0.2

CHK2 kinase promotes pre-mRNA splicing via phosphorylating CDK11p110|Unexpectedly, CHK2 kinase constitutively phosphorylated CDK11(p110) in a DNA damage-independent manner.

SIGNOR-279458

Q00613

P31749

0

phosphorylation

up-regulates activity

0.405

Mass spectrometry showed that AKT1 also phosphorylated HSF1 at T142, S230 and T527 in addition to S326, whereas the other kinases did not. Subsequent investigation revealed that phosphorylation at T142 is necessary for HSF1 trimerization and that S230, S326 and T527 are required for HSF1 gene transactivation and recruitment of TFIIB and CDK9.

SIGNOR-277579

P15692

P40763

0

transcriptional regulation

up-regulates quantity by expression

0.786

Stat3 directly regulated the promoter of the VEGF gene. Blockade of activated Stat3 by ectopic expression of dominant-negative Stat3 significantly inhibited VEGF expression, and the growth and metastasis of human pancreatic cancer cells.

SIGNOR-259456

P42574

Q9UKV3

1

cleavage

up-regulates

0.628

Induces apoptotic chromatin condensation after activation by casp3

SIGNOR-70800

Q13153

Q96T58

1

phosphorylation

down-regulates activity

0.2

Pak1 phosphorylation sites in SHARP were mapped to Ser3486 and Thr3568 within the SHARP repression domain.

SIGNOR-278968

P49760

P31749

0

phosphorylation

up-regulates

0.39

Akt directly binds to and phosphorylates clk2 on serine 34 and threonine 127, in vitro and in vivo.Our results suggest that akt activation controls cell survival to ionizing radiation by phosphorylating clk2, revealing an important regulatory mechanism required for promoting cell surviva

SIGNOR-167340

P13639

Q9H2P9

0

methylation

down-regulates activity

0.747

Analysis of EF2 in the mutant cells revealed a novel form of diphthamide with an additional methyl group that prevented ADP-ribosylation and inactivation of EF2. The abnormal methylation appeared to be catalyzed by DPH5.

SIGNOR-261146

P16591

P16284

1

phosphorylation

up-regulates activity

0.322

PECAM-1 Is Phosphorylated by Fer and, To a Lesser Extent, by Fes. These results suggest that Fer not only functions as a tyrosine kinase for PECAM-1 but also that Fer modulates the downstream signaling of PECAM-1 by inducing phosphorylation of SHP-2 and Gab1.

SIGNOR-262866

P01106

P12268

1

transcriptional regulation

up-regulates quantity by expression

0.294

Analysis of in vivo C-MYC interactions with TS, IMPDH2 and PRPS2 genes confirmed that they are direct C-MYC targets. C-MYC depletion did not significantly affect levels of E2F1 protein reported to regulate expression of many S-phase specific genes, but resulted in the repression of several genes encoding enzymes rate-limiting for dNTP metabolism. These included thymidylate synthase (TS), inosine monophosphate dehydrogenase 2 (IMPDH2) and phosphoribosyl pyrophosphate synthetase 2 (PRPS2). C-MYC depletion also resulted in reduction in the amounts of deoxyribonucleoside triphosphates (dNTPs) and inhibition of proliferation.

SIGNOR-267375

P61586

Q5T5U3

0

gtpase-activating protein

down-regulates activity

0.628

We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).

SIGNOR-260475

P27361

Q9UBS5

1

phosphorylation

down-regulates quantity by destabilization

0.276

We found that, in addition to CaMKIIβ, also ERK1/2 is involved in the degradation pathway of GABAB receptors under physiological and ischemic conditions. In contrast to our previous view, CaMKIIβ does not appear to directly phosphorylate S867. Instead, the data support a mechanism in which CaMKIIβ activates ERK1/2, which then phosphorylates S867 and T872 in GABAB1.

SIGNOR-277854

P08709

P38435

0

carboxylation

up-regulates activity

0.688

Thus, vitamin K acts as a cofactor for GGCX via the vitamin K cycle and exerts physiological effects through its regulation of VKDPs [29]. More than 20 VKDPs have been found. Osteocalcin promotes bone formation, and blood coagulation factors II, VII, IX, and X activate blood coagulation. Matrix Gla protein suppresses cardiovascular calcification, and brain-expressed Gas 6 promotes neural differentiation [29]. GGCX is an enzyme that converts glutamic acid (Glu) residues to Gla residues, so that the Gla-containing proteins can exert various physiological actions such as blood coagulation and bone formation.

SIGNOR-265919

P42336

Q9Y4K3

0

ubiquitination

up-regulates activity

0.458

In contrast to NEDD4L, overexpression of TRAF6 increases the stability of PIK3CA protein and promotes PI3K activation.|TRAF6 ubiquitinates PIK3CA in vivo.

SIGNOR-278727

Q53EZ4

P28482

0

phosphorylation

down-regulates

0.367

Upon mitotic entry, centrosome dissociation of cep55 is triggered by erk2/cdk1-dependent phosphorylation at s425 and s428. S425/428 phosphorylation is required for interaction with plk1, enabling phosphorylation of cep55 at s436. enabling it to relocate to the midbody to function in mitotic exit and cytokinesis.

SIGNOR-140890

Q14160

Q05086

0

polyubiquitination

down-regulates quantity by destabilization

0.552

Human scribble (Vartul) is targeted for ubiquitin-mediated degradation by the high-risk papillomavirus E6 proteins and the E6AP ubiquitin-protein ligase

SIGNOR-272573

Q5SQI0

Q9H853

1

acetylation

up-regulates quantity by stabilization

0.2

Alpha-Tubulin acetyltransferase (alphaTAT1) is the major α-tubulin lysine-40 (K40) acetyltransferase in mammals, nematodes, and protozoa, and its activity plays a conserved role in several microtubule-based processes.|The tubulin subunits of microtubules are acetylated, and lysine-40 (K40) of the alpha-tubulin subunit has been identified as an important conserved site of microtubule acetylation (6–8). This modification is considered a hallmark of stable, long-lived microtubules

SIGNOR-272252

P29350

P52333

1

dephosphorylation

up-regulates

0.688

The expression of shp-1 protein was associated with dephosphorylation of the jak3 kinase.

SIGNOR-82764

Q01860

O00308

0

ubiquitination

down-regulates quantity

0.453

WWP2 promotes degradation of transcription factor OCT4 in human embryonic stem cells|Here, we report that human WWP2, an E3 ubiquitin (Ub)-protein ligase, interacts with OCT4 specifically through its WW domain and enhances Ub modification of OCT4 both in vitro and in vivo.

SIGNOR-268850

P27361

P67775

0

dephosphorylation

down-regulates

0.647

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

SIGNOR-103162

P42226

O15524

1

transcriptional regulation

up-regulates quantity by expression

0.638

We found that IL-4, like IFN-gamma, induces rapid de novo expression of SOCS-1 in primary macrophages. Induction of SOCS-1 gene expression by IL-4 is STAT6-dependent.

SIGNOR-249570

Q02535

Q14938

0

transcriptional regulation

down-regulates quantity

0.2

By integrating transcriptomic profiling (RNA-seq) of Nfia- and Nfix-deficient GNPs with epigenomic profiling (ChIP-seq against NFIA, NFIB and NFIX, and DNase I hypersensitivity assays), we reveal that these transcription factors share a large set of potential transcriptional targets, suggestive of complementary roles for these NFI family members in promoting neural development

SIGNOR-268885

P54274

Q8NA31

0

relocalization

up-regulates activity

0.2

The shelterin complex has six proteins, containing TRF1, TRF2, POT1, RAP1, TIN2, and TPP1. The shelterin complex is localized to the chromosome end and protects telomeric DNA (Palm and de Lange, 2008). The TTM complex acts as a “linker” and bridges the LINC and shelterin complexes together. The connection between TTM and shelterin complexes is well-known, which is mediated by TERB1 and TRF1

SIGNOR-263315

Q14669

Q13564

1

ubiquitination

down-regulates quantity by destabilization

0.432

Our data suggest that that TRIP12 promotes degradation of APP-BP1 by catalyzing its ubiquitination, which in turn modulates the neddylation pathway.

SIGNOR-266780

P28482

Q13485

1

phosphorylation

up-regulates

0.511

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

SIGNOR-101660

Q9UQL6

Q13131

0

phosphorylation

down-regulates

0.341

Another recently described set of transcriptional regulators targeted by ampk and its related family members across a range of eukaryotes are the class iia family of histone deacetylases (hdacs)

SIGNOR-176479

P32927

Q06124

0

dephosphorylation

up-regulates

0.511

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

SIGNOR-48557

Q92813

Q9Y385

0

ubiquitination

down-regulates quantity by destabilization

0.379

ER residency places D2 physically close to an array of proteins that interact and modify the D2 molecule via ubiquitination and targeting to the proteasomal system, explaining its relatively short half-life. Both ubiquitin conjugases UBC6 and or UBC7 interact with D2 and support D2 ubiquitination. Two Lys residues in D2 are involved in this process, K237 and K244.

SIGNOR-267481

P12004

Q9NS91

0

ubiquitination

up-regulates activity

0.846

Second, these findings suggest the following model (XREF_FIG) : upon replication fork stalling at cisplatin induced DNA lesions, the RAD18 and RAD6 complex ubiquitylates PCNA on Lys164.|The DNA damage-activated E3 ubiquitin ligase RAD18 promotes repair of interstrand DNA cross-links by ubiquitylating PCNA and recruiting FANCL to chromatin.

SIGNOR-278612

P31751

P03372

1

phosphorylation

up-regulates activity

0.509

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

SIGNOR-251490

Q9Y6H5

Q9NV58

0

ubiquitination

up-regulates quantity

0.453

Ubiquitylation of synphilin-1 by Dorfin. A, synphilin-1 is ubiquitylated in HEK293 cells. Several lines of evidence have suggested that derangements in the ubiquitin-proteasome protein degradation pathway may have a prominent role in the pathogenesis of PD (5). Our present study shows that Dorfin, an E3 ubiquityl ligase, is colocalized with ubiquitin in LBs of PD and physically binds to ubiquitylate synphilin-1, which is known to be a major component of LBs

SIGNOR-271455

Q3KRB8

P61586

1

gtpase-activating protein

down-regulates activity

0.502

We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).

SIGNOR-260467

Q99988

P18847

0

transcriptional regulation

up-regulates quantity by expression

0.426

In addition, DIM increased the expression of NAG-1 as well as activating transcription factor 3 (ATF3), and the induction of ATF3 was earlier than that of NAG-1. The DIM treatment increased luciferase activity of NAG-1 in HCT-116 cells transfected with NAG-1 promoter construct. The results suggest that I3C represses cell proliferation through up-regulation of NAG-1 and that ATF3 may play a pivotal role in DIM-induced NAG-1 expression in human colorectal cancer cells.

SIGNOR-253725

Q9NZQ7

Q9Y4X5

0

polyubiquitination

down-regulates quantity by destabilization

0.2

We find EGFR inhibitors promote PD-L1 ubiquitination and proteasomal degradation following GSK3α-mediated phosphorylation of Ser279/Ser283. We identify ARIH1 as the E3 ubiquitin ligase responsible for targeting PD-L1 to degradation.

SIGNOR-277553

Q00535

O14939

1

phosphorylation

up-regulates activity

0.368

In this study, we suggest that the phosphorylation and activation of PLD2 by cyclin-dependent kinase 5 (Cdk5) is critical for EGF-dependent insulin secretion.|We determined that Cdk5 phosphorylates PLD2 at Ser 134 of PLD2 and that this phosphorylation was suggested to be important for EGF-dependent insulin secretion.

SIGNOR-278395

O15169

O75197

0

relocalization

down-regulates quantity

0.83

Axin is a protein that interacts with the intracellular domain of LRP-5. LRP-5 active form bind Axin and induce LEF-1 activation by destabilizing Axin and stabilizing beta-catenin.

SIGNOR-236997

P25490

O15379

0

deacetylation

down-regulates activity

0.6

Previous studies have established that YY1 interacts with histone acetyltransferases p300 and CREB-binding protein (CBP) and histone deacetylase 1 (HDAC1), HDAC2, and HDAC3. Here, we present evidence that the activity of YY1 is regulated through acetylation by p300 and PCAF and through deacetylation by HDACs. YY1 was acetylated in two regions: both p300 and PCAF acetylated the central glycine-lysine-rich domain of residues 170 to 200, and PCAF also acetylated YY1 at the C-terminal DNA-binding zinc finger domain. Acetylation of the central region was required for the full transcriptional repressor activity of YY1 and targeted YY1 for active deacetylation by HDACs.

SIGNOR-268837

Q9GZM8

O14965

0

phosphorylation

down-regulates quantity by destabilization

0.603

Here, we show that Aurora-A phosphorylates NDEL1 at Ser251 at the beginning of mitotic entry. Interestingly, NDEL1 phosphorylated by Aurora-A was rapidly downregulated thereafter by ubiquitination-mediated protein degradation.

SIGNOR-263159

P63010

P12931

0

phosphorylation

down-regulates

0.272

The phosphorylation of beta2-adaptin on tyrosine residue 737 (y737) negatively regulates its interaction with betaarrestin.

SIGNOR-181743

P39019

P11309

0

phosphorylation

up-regulates

0.438

The pim-1/rps19 interaction was demonstrated both in vitro and in living cells and led to phosphorylation of rps19 in an in vitro kinase assay.

SIGNOR-141411

P24928

P50613

0

phosphorylation

down-regulates

0.789

Although there is some inconsistency in the literature, it is generally thought that cdk7, a component of the transcription factor (tf) iih, is a major ser-5 kinase, whereas cdk9, a component of positive transcription elongation factor (p-tef) b, is a major ser-2 kinase within cells. These results suggest that subsequent to h2o2 treatment, the ser-5-phosphorylated form, but not the ser-2-phosphorylated form or the unphosphorylated form, is targeted for rapid proteasomal degradation through its ubiquitination.

SIGNOR-120024

Q9HD90

O00712

0

transcriptional regulation

up-regulates quantity

0.2

For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8)

SIGNOR-268898

P08581

P40763

1

phosphorylation

up-regulates activity

0.706

It has been reported that c-Met can activate STAT3 at the endosome and phosphorylated STAT3 induced by c-Met is colocalized with EEA1, an early endosome marker.

SIGNOR-280041

Q93009

Q96EP1

1

deubiquitination

up-regulates quantity by stabilization

0.432

In this study, we identified USP7 (also known as HAUSP), which is a member of a family of proteins that cleave polyubiquitin chains and/or ubiquitin precursors, as an interacting protein with Chfr by immunoaffinity purification and mass spectrometry, and their interaction greatly increases the stability of Chfr. In fact, USP7 can remove ubiquitin moiety from the autoubiquitinated Chfr both in vivo and in vitro, which results in the accumulation of Chfr in the cell. USP7 mediates deubiquitination of Chfr.

SIGNOR-271462

P06213

P27986

1

phosphorylation

up-regulates activity

0.67

The alpha-type 85-kDa subunit of phosphatidylinositol 3-kinase is phosphorylated at tyrosines 368, 580, and 607 by the insulin receptor.

SIGNOR-251321

P04150

P27361

0

phosphorylation

down-regulates

0.542

Cyclin-dependent kinase (CDK) and mitogen-activated protein kinase (MAPK) phosphorylate the rat glucocorticoid receptor in vitro at distinct sites that together correspond to the major phosphorylated receptor residues observed in vivo; MAPK phosphorylates receptor residues threonine 171 and serine 246, whereas multiple CDK complexes modify serines 224 and 232.|MAPKs and CDKs exert opposite effects on receptor transcriptional enhancement. From our results, we speculate that activators of the MAPK pathway, such as growth factors, insulin, and certain oncoproteins, or inhibitors of CDK function, such as tumor growth factor beta (TGF_), p21, and p27, might attenuate receptor-induced transcrip- tional responses. In contrast, negative regulators of MAPK, such as pKA, as well as activators of CDK, such as the cyclins or CAKs, should potentiate receptor action.

SIGNOR-154409

Q16539

Q13115

0

dephosphorylation

down-regulates

0.665

This result suggests that dusp4 represses gluconeogenesis through dephosphorylation of p38

SIGNOR-147958

A8MYZ6

O75874

1

transcriptional regulation

up-regulates quantity by expression

0.2

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

SIGNOR-260092

O60343

P31749

0

phosphorylation

down-regulates

0.764

Recently, we identified a 160-kda protein in adipocytes, designated as160, that is phosphorylated by the insulin-activated kinase akt

SIGNOR-252594

P61586

Q9H8V3

0

guanine nucleotide exchange factor

up-regulates activity

0.712

We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).

SIGNOR-260550

P45983

Q12904

1

phosphorylation

down-regulates

0.473

We further demonstrated that serine-140 residue of aimp1 was phosphorylated by jnk and alanine mutation of serine-140 suppressed lps-induced cell surface altogether, these results suggest that aimp1 is phosphorylated by jnk through tlr-myd88 pathway and lose the regulatory activity for er retention of gp96expression of gp96.

SIGNOR-165763

P07333

O60716

1

phosphorylation

up-regulates quantity by stabilization

0.27

In our study, CSF-1R induced the tyrosine phosphorylation of p120 Y904 and Y228 in a SRC-dependent manner ( xref ).

SIGNOR-278929

P06241

Q04759

1

phosphorylation

up-regulates

0.344

Further indications of direct interaction are that p59fyn potentiates ?PKC Catalytic activity and that ?PKC Is a substrate for tyrosine phosphorylation by p59fyn.

SIGNOR-68798

P17612

P63252

1

phosphorylation

down-regulates activity

0.2

PKA consensus site S425 required for PKA-mediated effects on Kir2.1 channels. PKA activation reduced outward IK1 for heteromeric Kir2.1 WT+V227F channels after 2 hours of PKA activation.

SIGNOR-276267

P37275

P52954

0

transcriptional regulation

up-regulates quantity by expression

0.326

Compared with the empty vector, LBX1 induced increased promoter activity of threefold to fourfold and fivefold to sixfold for ZEB1 and Snail1, respectively

SIGNOR-266054

Q8IYA7

P35711

1

transcriptional regulation

up-regulates quantity by expression

0.295

MKX is a meniscus-enriched transcription factor. In human meniscus cells, MKX regulates the expression of meniscus marker genes, OA-related genes, and other transcription factors, including Scleraxis (SCX), SRY Box 5 (SOX5), and Runt domain-related transcription factor 2 (RUNX2).

SIGNOR-267214

P68400

Q13371

1

phosphorylation

up-regulates

0.387

Phosducin-like protein (phlp) is a widely expressed binding partner of the g protein betagamma subunit complex (gbetagamma) that has been recently shown to catalyze the formation of the gbetagamma dimer from its nascent polypeptides. Phosphorylation of phlp at one or more of three consecutive serines (ser-18, ser-19, and ser-20) is necessary for gbetagamma dimer formation and is believed to be mediated by the protein kinase ck2.

SIGNOR-146833

Q01196

P24941

0

phosphorylation

up-regulates activity

0.2

We have identified four phosphorylation sites on aml1c that are necessary for transcriptional activity of aml1c in k562 and 293t cells (27).4 mutation of these four sites (serine 276, serine 293, serine 303, and threonine 300) to alanine abolishes transcriptional activation, whereas mutation of these sites to aspartic acid (which mimics phosphorylation) results in a hyperactive protein.

SIGNOR-138932

Q2M385

O96017

0

phosphorylation

up-regulates activity

0.2

Chk2 phosphorylates Mps1-T288 after DNA damage.|In the present study, we show that Chk2 stabilizes Mps1 protein and phosphorylates Aurora B-B-serine 331 to prevent mitotic exit in vertebrate cells when the majority of kinetochores are unattached.

SIGNOR-279160

P07948

P33993

1

phosphorylation

up-regulates activity

0.453

Lyn phosphorylates MCM7 at Y600.|These evidences suggest that Lyn mediated Y600 phosphorylation may regulate MCM7 function in DNA replication licensing.

SIGNOR-278407

P35813

Q14653

1

dephosphorylation

down-regulates activity

0.247

In contrast, coexpression of wild-type PPM1A, but not its D239N or R174G mutant, abolished IRF3 activation (XREF_FIG).|We found that PPM1A abolished the C-terminal phosphorylation of IRF3 (XREF_FIG), whereas depletion of PPM1A expression improved virus induced pIRF3 level (XREF_FIG and XREF_FIG).

SIGNOR-277152

Q9Y219

Q96AX9

0

ubiquitination

up-regulates

0.809

Skeletrophin bound the intracellular regions of the notch ligand jagged-2, but not to those of delta-1, -3, -4, or jagged-1. Skeletrophin, but not its ring-mutated form, ubiquitinized the intracellular region of jagged-2.

SIGNOR-137922

P21731-2

P35626

0

phosphorylation

down-regulates activity

0.2

These data suggest a model whereby agonist-induced PKC phosphorylation of Ser(145) partially impairs TPbeta signalling while GRK2/3 phosphorylation at both Ser(239) and Ser(357) within its IC(3) and C-tail domains, respectively, sterically inhibits G-protein coupling, profoundly desensitizing signalling, and promotes beta-arrestin association and, in turn, facilitates TPbeta internalization.

SIGNOR-274091

P17612

P62834

1

phosphorylation

down-regulates activity

0.521

Phosphorylation of Rap1A by PKA abolished its binding activity to CRR. a mutant Rap1A(S180E), whose sole PKA phosphorylation residue, Ser-180, was substituted by an acidic residue, Glu, to mimic its phosphorylated form, failed to suppress Ras-dependent Raf-1 activation in COS-7 cells.

SIGNOR-250042

P51812

O14649

1

phosphorylation

up-regulates activity

0.2

The chaperone protein, 14-3-3, binds to a critical phosphorylated serine in the channel c termini of k2p3.1 and k2p9.1 (ser(393) and ser(373), respectively) and overcomes retention in the endoplasmic reticulum by ?COP. We sought to identify the kinase responsible for phosphorylation of the terminal serine in human and rat variants of k2p3.1 and k2p9.1. Adopting a bioinformatic approach, three candidate protein kinases were identified: camp-dependent protein kinase, ribosomal s6 kinase, and protein kinase c.

SIGNOR-172470

Q15119

P29803

1

phosphorylation

down-regulates

0.548

Kinetic and regulatory properties of recombinant human pdh2 and pdh1 were compared in this study. Site-specific phosphorylation/dephosphorylation of the three phosphorylation sites by four pdh kinases (pdk1-4) and two pdh phosphatases (pdp1-2) were investigated by substituting serines with alanine or glutamate in pdhs.

SIGNOR-143970

P12931

O75955

1

phosphorylation

up-regulates activity

0.335

Taken together, we conclude that mitochondrial c-Src phosphorylates flotillin-1 at Tyr56 and Tyr149, and that these phosphorylations are required for its interaction with CxII and the prevention of ROS production.

SIGNOR-273805

Q9H300

Q9BXM7

1

cleavage

down-regulates quantity by destabilization

0.613

Using an unbiased RNA-mediated interference (RNAi)-based screen, we identified four mitochondrial proteases, mitochondrial processing peptidase (MPP), presenilin-associated rhomboid-like protease (PARL), m-AAA and ClpXP, involved in PINK1 degradation. We find that PINK1 turnover is particularly sensitive to even modest reductions in MPP levels. Moreover, PINK1 cleavage by MPP is coupled to import such that reducing MPP activity induces PINK1 accumulation at the mitochondrial surface, leading to Parkin recruitment and mitophagy.

SIGNOR-261364

Q13216

Q03468

1

ubiquitination

down-regulates quantity by destabilization

0.582

We have previously shown that CSA is a subunit of an E3 ubiquitin ligase complex. Here we demonstrate that CSB is a substrate of this ligase: Following UV irradiation, CSB is degraded at a late stage of the repair process in a proteasome- and CSA-dependent manner.

SIGNOR-271406

P36952

Q13547

0

transcriptional regulation

down-regulates quantity by repression

0.413

We found that maspin is selectively upregulated in IFIXα-expressing cells and involved in anti-invasive activity of IFIXα. We also present evidence indicating that IFIXα downregulates histone deacetylase 1 (HDAC1), which is possibly involved in the silencing of the maspin gene in human breast cancer cells. To confirm these results, we performed a luciferase assay using a maspin-promoter-luciferase plasmid. The results showed that HDAC1 overexpression suppressed the activity of the maspin promoter (Figure 3C). Therefore, our results suggest that IFIXα enhances maspin expression through the downregulation of HDAC1.

SIGNOR-268494

Q14654

Q13557

0

phosphorylation

down-regulates

0.2

Results showed that activation of camkii triggered dynamin-dependent internalization of k(atp) channels. This process required phosphorylation of threonine at 180 and 224 and an intact (330)yskf(333) endocytosis motif of the k(atp) channel kir6.2 pore-forming subunit.

SIGNOR-200027

Q13153

P35813

0

dephosphorylation

down-regulates activity

0.337

Purified PP2Cα protein efficiently dephosphorylated PAK1 in vitro (Fig. 1, D and E). We previously assessed the time course of phospho-PAK1 dephosphorylation assessed using specific antibodies against either Ser(P)198/203 or Thr(P)422 sites in the PAK1 activation loop.

SIGNOR-248492

P04629

O14492

1

phosphorylation

up-regulates

0.547

Two substrates of trk kinases, raps and sh2-b. raps and sh2-b mediate trk signaling in developing neurons

SIGNOR-62619

Q9BV47

P04629

1

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

P30408

Q9H190

1

relocalization

up-regulates activity

0.402

TM4SF1 functions as a membrane adaptor connecting DDR1 to syntenin2.

SIGNOR-272401

P68400

Q13563

1

phosphorylation

up-regulates

0.421

Ser(812) can be phosphorylated by ck2 in vitro and substitution s812a results in failure to incorporate phosphate in cultured epithelial cells.

SIGNOR-121572

Q15075

Q16539

0

phosphorylation

up-regulates activity

0.458

We found that p38alpha can phosphorylate the rab5 effectors eea1 and rabenosyn-5 on thr-1392 and ser-215, respectively, and these phosphorylation events regulate the recruitment of eea1 and rabenosyn-5 to membranes

SIGNOR-140082

P48730

O75581

1

phosphorylation

up-regulates activity

0.2

Central to WNT signalosome formation is phosphorylation of LRP6 at multiple sites, with GSK3β phosphorylating LRP6 at S1490 and CK1 family members phosphorylating LRP6 at T1479 and T1493

SIGNOR-275402

Q06210

P17252

0

phosphorylation

down-regulates activity

0.307

Phosphorylation of human glutamine:fructose-6-phosphate amidotransferase by cAMP-dependent protein kinase at serine 205 blocks the enzyme activity.

SIGNOR-249040

P45985

P31749

0

phosphorylation

down-regulates

0.594

Akt phosphorylated sek1 on serine 78.

SIGNOR-236494