GleghornLab/Signor_2class · Datasets at Hugging Face

IdA string	IdB string	labels int64	mechanism string	effect string	score float64	sentence string	signor_id string
P23409	Q02078	0	transcriptional regulation	up-regulates quantity by expression	0.589	Myogenin and MEF2 function synergistically to activate the MRF4 promoter during myogenesis.	SIGNOR-238709
P17706	P35968	1	dephosphorylation	down-regulates activity	0.566	We show that a TCPTP substrate-trapping mutant interacts with VEGFR2. Moreover, TCPTP dephosphorylates VEGFR2 in a phosphosite-specific manner, inhibits its kinase activity and prevents its internalization from the cell surface. \|The autophosphorylation sites Tyr1054/1059 and Tyr1214 were dephosphorylated by TCPTP (Fig. 4B). Tyr996, the functional significance of which is currently uncertain (Olsson et al., 2006), was a TCPTP target as well.	SIGNOR-248399
Q9UQB3	P12931	0	phosphorylation	up-regulates activity	0.329	Furthermore, according to our data from immunoprecipitation to py20 antibody, c-Src can phosphorylate delta-catenin on Y1073, Y1176, Y1179 and Y1112, with the predominant sites being Y1073, Y1112 and Y1176.\|Interestingly, we found that c-Src can increase the stability of delta-catenin in MEF cells.	SIGNOR-278327
P17612	O75581	1	phosphorylation	up-regulates activity	0.2	These results suggest that camppka activation is involved in activation of lrp6(...) our results demonstrate that lrp6 can be directly phosphorylated by pka catalytic subunit.	SIGNOR-181979
Q9UNE7	P17542	1	ubiquitination	down-regulates quantity by destabilization	0.356	Ubiquitination and degradation of Tal1/SCL are induced by notch signaling and depend on Skp2 and CHIP. CHIP promoted Tal1 degradation with both chaperone binding and ubiquitin ligase activities, which are mediated by its TPR domain and U box, respectively.	SIGNOR-271393
P53667	Q9Y252	0	polyubiquitination	down-regulates quantity by destabilization	0.432	Consistent with a role in axonal growth, we found that Rnf6 binds to, polyubiquitinates, and targets LIMK1 for proteasomal degradation in growth cones of primary hippocampal neurons.	SIGNOR-271481
Q02750	Q16584	0	phosphorylation	up-regulates activity	0.335	Here we report that MLK3 can phosphorylate and activate MEK-1 directly in vitro and also can induce MEK phosphorylation on its activation sites in vivo in COS-7 cells.	SIGNOR-280019
Q9UJY5	P68400	0	phosphorylation	down-regulates activity	0.504	Serine-355 of GGA1 is phosphorylated in vivo and in vitro. This inhibition is caused by the binding of an AC-LL sequence present in the hinge segment to the ligand-binding site in the VHS domain. The inhibition depends on the phosphorylation of a serine located three residues upstream of the AC-LL motif. The serine is phosphorylated by casein kinase 2 in in vitro assays.	SIGNOR-273623
P52732	P06493	0	phosphorylation	up-regulates activity	0.638	Nek6 phosphorylated Eg5 at several sites in vitro and one of these sites, Ser1033, is phosphorylated in vivo during mitosis. Whereas CDK1 phosphorylates nearly all Eg5 at Thr926 during mitosis, Nek6 phosphorylates approximately 3% of Eg5, primarily at the spindle poles.	SIGNOR-273887
Q15208	P30304	1	phosphorylation	down-regulates quantity	0.247	Here, we demonstrate that the depletion of serine-threonine kinase 38 (STK38) prevents the DNA-damage-induced degradation of CDC25A and subsequent G2 arrest, and that STK38 directly phosphorylates CDC25A at Ser-76, resulting in CDC25A's degradation.	SIGNOR-279488
Q13489	O43353	1	polyubiquitination	up-regulates activity	0.787	CIAP1/2 are direct E3 ligases conjugating diverse types of ubiquitin chains to receptor interacting proteins kinases 1 to 4 (RIP1-4).Together, our results demonstrate that depleting cIAP1/2 inhibits RIP1-4 mediated NF-kB activation without affecting RIP auto-phosphorylation.	SIGNOR-272715
O95644	Q9Y625	1	transcriptional regulation	up-regulates quantity by expression	0.251	NFAT transcriptionally regulates GPC6 induction in breast cancer cells and binds to three regulatory elements in the GPC6 proximal promoter. Expression of GPC6 in response to NFAT signalling promotes invasive migration, whereas GPC6 silencing with shRNA (small-hairpin RNA) potently blocks this phenotype.	SIGNOR-264022
P11802	P38398	1	phosphorylation	down-regulates	0.665	In particular, we have identified ser 632 of brca1 as a cyclin d1/cdk4 phosphorylation site in vitro. Using chromatin immunoprecipitation assays, we observed that the inhibition of cyclin d1/cdk4 activity resulted in increased brca1 dna binding at particular promoters in vivo.	SIGNOR-153450
P00519	O75122	1	phosphorylation	up-regulates quantity	0.502	We find that Abl binds to and phosphorylates CLASP2 in response to extracellular signals such as serum or PDGF.	SIGNOR-279580
Q15418	Q8IX03	1	phosphorylation	up-regulates	0.335	Moreover, we found that rsk1/2 specifically phosphorylates kibra at two highly conserved sites (thr(929) and ser(947)) in vitro and in cells. Rsk-mediated phosphorylation is required for kibra binding to rsk1, but not rsk2.	SIGNOR-203298
P00533	Q8IVM0	1	phosphorylation	down-regulates activity	0.415	We also detected tyrosine phosphorylation of Ymer by EGF stimulation as previously reported (Fig. 1A). Furthermore, we verified that EGF receptor-mediated tyrosine phosphorylation of Ymer is inhibited by AG1478, which is known as an EGF receptor tyrosine kinase inhibitor (Fig. 1B). A luciferase reporter assay showed that mutation of tyrosines on Ymer (YmerY217/279/304F) results in loss of the inhibitory activity for NF-kappaB signaling.	SIGNOR-262851
P53350	P60484	1	phosphorylation	down-regulates activity	0.534	Subsequently, Plk1 phosphorylation of PTEN was shown to be responsible for its inactivation.	SIGNOR-280070
P31751	P15311	1	phosphorylation	up-regulates	0.375	Purified akt directly phosphorylates recombinant ezrin at threonine 567 in vitro in an atp-dependent manner. ezrin activation after initiation of na+-glucose cotransport requires akt2 expression	SIGNOR-130260
P17600	Q14012	0	phosphorylation	down-regulates activity	0.561	Synapsin phosphorylation in the A domain, at the only phosphorylation site shared by all synapsins, dissociates synapsins from synaptic vesicles.This site is located in the N-terminal A domain and is a substrate for both PKA and CaM Kinase I	SIGNOR-250615
Q9ULG1	Q9UNE7	0	ubiquitination	up-regulates activity	0.2	Then, by an in vivo ubiquitination assay under denaturing conditions (hereafter, all in vivo ubiquitination assays were carried out under denaturing conditions), we determined whether CHIP ubiquitinates Ino80.\|We also show that CHIP works together with BAP1 to enhance the stabilization of Ino80, leading to its chromatin binding.	SIGNOR-278646
P02818	P07339	0	cleavage	down-regulates quantity by destabilization	0.314	This study has been undertaken to compare the degradation of BGP by the cysteine proteinases cathepsins L, B, H, S, and the aspartic proteinase cathepsin D. Cathepsins B, L, H, and S readily cleave BGP at the G7-A8 bond; cathepsin L also cleaves at R43-R44; cathepsin B also cleaves at R44-F45; and cathepsin D cleaves only at A41-Y42.	SIGNOR-256319
P24941	P29374	1	phosphorylation	down-regulates	0.426	In the present study we identified rbp1 as a novel cdk substrate. Rbp1 is phosphorylated by cdk2 on serines 864 and 1007, which are n- and c-terminal to the lxcxe motif, respectively. Cdk2-mediated phosphorylation of rbp1 or prb destabilizes their interaction in vitro, with concurrent phosphorylation of both proteins leading to their dissociation	SIGNOR-170455
P12755	P31749	0	phosphorylation	down-regulates	0.337	The phosphorylation of ski at threonine 458 is induced by akt pathway activators including insulin, insulin-like growth factor-1, and hepatocyte growth factor. The phosphorylation of ski causes its destabilization and reduces ski-mediated inhibition of expression of another negative regulator of tgf-beta, smad7	SIGNOR-252527
O00401	P00519	0	phosphorylation	up-regulates activity	0.55	Abl phosphorylates N-WASP on tyrosines 175 and 256. Phosphorylation at this site stabilizes the active conformation of N-WASP, resulting in comet tail elongation.	SIGNOR-251437
P12931	P15941	1	phosphorylation	up-regulates	0.444	The c-src tyrosine kinase regulates signaling of the human df3/muc1 carcinoma-associated antigen with gsk3 beta and betBeta-catenin c-src phosphorylates the muc1 cytoplasmic domain at a yekv motif c-src-mediated phosphorylation of muc1 increases binding of muc1 and betBeta-catenin	SIGNOR-85938
P15172	P30281	1	transcriptional regulation	up-regulates quantity by expression	0.374	Here we report that, at the onset of differentiation, activation by MyoD of the Rb, p21, and cyclin D3 genes occurs in the absence of new protein synthesis and with the requirement of the p300 transcriptional coactivator.	SIGNOR-238526
P31749	Q15119	0	phosphorylation	up-regulates activity	0.749	PIP3 recruits PDK1 and AKT to the plasma membrane, where PDK1 phosphorylates AKT on Thr308 in the activation loop of the kinase domain. The phosphorylation of AKT on Ser473 by PDK2 acts as a gain control for AKT and regulates its degree of activation. The sirolimus-insensitive mTORC2 complex exhibits PDK2 activity	SIGNOR-249630
Q99759	P53805	1	phosphorylation	up-regulates	0.448	Essential role of mekk3 signaling in angiotensin ii-induced calcineurin/nuclear factor of activated t-cells activation	SIGNOR-102294
Q9H2X6	Q08050	1	phosphorylation	up-regulates activity	0.2	In conclusion, the phosphorylation of FOXM1 by HIPK2 can promote FOXM1 transcription activity and cell proliferation in RCC, thus, indicating a potential mechanism for the treatment of human RCC in the future.	SIGNOR-278944
P50591	P19838	1	post transcriptional regulation	up-regulates quantity by expression	0.302	Treatment with TRAIL increased the NF-κB transcriptional activity by approximately twofold in MDA-MB-231 cells compared to the control.	SIGNOR-277936
O15297	Q16539	1	dephosphorylation	down-regulates activity	0.444	Wip1 selectively inactivates p38 by specific dephosphorylation of its conserved threonine residue	SIGNOR-84793
Q05086	Q13200	1	ubiquitination	down-regulates quantity by destabilization	0.277	Our experiments collectively suggest that UBE3A stimulates Wnt pathway activation by interacting with, ubiquitinating, and reducing the levels of multiple (PSMB1, PSMC2, PSMD2, and PSMD7) proteasome subunits.	SIGNOR-265133
Q8IW41	Q15382	1	phosphorylation	down-regulates activity	0.401	Phosphorylation of Rheb at Ser 130 by PRAK impairs the nucleotide-binding ability of Rheb and inhibits Rheb-mediated mTORC1 activation.	SIGNOR-276313
Q05513	Q07812	1	phosphorylation	down-regulates activity	0.2	Protein kinase czeta abrogates the proapoptotic function of bax through phosphorylation. Overexpression of wild type or the constitutively active a119d but not the dominant negative k281w pkczeta mutant results in bax phosphorylation at serine 184.	SIGNOR-155111
Q99558	P40763	1	phosphorylation	up-regulates activity	0.26	Activation of Stat3 by NIK requires NIK kinase activity as showed by kinase assays.\|When we transfected NIK into LNCaP cells, NIK was able to phosphorylate Stat3 at both tyrosine 705 and serine 727 residues ( Fig. 3 A).	SIGNOR-279341
Q9UGL1	Q16665	0	transcriptional regulation	up-regulates quantity by expression	0.271	To this end, we confirm that KDM3A, KDM4B, KDM4C, KDM5B, KDM5C, and KDM62 are direct targets of HIF-1a while extent the list of known targets to KDM2A, KDM2B, KDM4D, KDM5A, and KDM6A. The results demonstrated that majority of the KDMs were similarly induced (KDM2A, KDM2B, KDM3A, KDM4B, KDM4C, KDM4D, KDM5A, KDM5B, KDM5C, KDM6B, and KDM7A) or repressed (KDM NO66 and KDM1A) by both HIF-1a and HIF-2a.	SIGNOR-271563
Q9HBY8	O15530	0	phosphorylation	up-regulates activity	0.596	SGK2 and SGK3 are activated in vitro by PDK1, albeit more slowly than SGK1, and their activation is accompanied by the phosphorylation of Thr(193) and Thr(253) respectively. The PDK1-catalysed phosphorylation and activation of SGK2 and SGK3, like SGK1, is greatly potentiated by mutating Ser(356) and Ser(419) respectively to Asp, these residues being equivalent to the C-terminal phosphorylation site of PKB.	SIGNOR-250277
P53567	P35247	1	transcriptional regulation	up-regulates quantity by expression	0.2	Cotransfection of C/EBPalpha, C/EBPbeta, or C/EBPdelta cDNA in H441 lung adenocarcinoma cells significantly increased the luciferase activity of a wild-type SP-D promoter construct containing 698 bp of upstream sequence (SS698). Transfection of C/EBP also increased the level of endogenous SP-D mRNA in H441 cells\| Thus, interactions among C/EBP elements in the near-distal promoter can modulate the promoter activity of SP-D.	SIGNOR-254058
Q92786	P54646	0	phosphorylation	down-regulates quantity by destabilization	0.2	Furthermore, the Ser79 phosphorylation of PROX1 by AMPK enhances the recruitment of CUL4-DDB1 ubiquitin ligase to promote PROX1 degradation.	SIGNOR-277608
P17612	Q92777	1	phosphorylation	down-regulates activity	0.326	Synapsin phosphorylation in the A domain, at the only phosphorylation site shared by all synapsins, dissociates synapsins from synaptic vesicles.This site is located in the N-terminal A domain and is a substrate for both PKA and CaM Kinase I	SIGNOR-250059
P50570	P12931	0	phosphorylation	down-regulates activity	0.557	We used cSrc-transformed NIH 3T3 fibroblasts to examine the effect of mutant Dyn2Y597. Similar to its effect in myotubes, Dyn2Y597F presented reduced enrichment at podosomes, whereas Dyn2Y597E clearly targeted podosome rosettes (Figures S9B and S9C). Moreover, Dyn2Y597F significantly reduced the podosome area, ECM degradation ability, and lifespan of the podosome in cSrc-transformed NIH 3T3 fibroblasts, whereas Dyn2Y597E displayed contradictory effects (Figures S9D–S9G).	SIGNOR-277539
P06493	P49792	1	phosphorylation	up-regulates activity	0.474	Cdk1 phosphorylates conserved sites within RanBP2 and activates BicD2 binding and early dynein recruitment.	SIGNOR-259118
P01135	P12931	0	cleavage	up-regulates	0.3	Ep2 can also promote the transactivation of epidermal growth factor receptor (egfr) expressed in colon cancer cells through src, which activates the proteolytic release of the egfr ligands amphiregulin (ar) and transforming growth factor-alfa (tgfalfa)125, thereby stimulating the egfr- network.	SIGNOR-235888
Q9BUB5	P67775	0	dephosphorylation	down-regulates	0.514	Moreover, a dephosphorylation assay revealed that pp2a could directly dephosphorylate mnk1 and eif4e.	SIGNOR-168314
P04637	P52789	1	transcriptional regulation	down-regulates quantity by repression	0.412	P53 regulates basal expression of AIF and SCO2 and facilitates oxidative phosphorylation. The expression of GLUT1, GLUT4, and HK2 is negatively regulated by p53, whereas TIGAR expression is induced by p53. The net result of p53-mediated regulation of these glycolytic enzymes is the suppression of glycolysis. In addition, p53 directly binds and inhibits G6PD activity and downregulates the pentose phosphate pathway.	SIGNOR-267466
O75460	P17861	1	phosphorylation	up-regulates activity	0.647	IRE1\u03b1 phosphorylates and activates the XBP1 transcription factor XBP1 via its kinase activity.	SIGNOR-279712
P68400	Q13530	1	phosphorylation	up-regulates activity	0.2	The two serines within the PSAC of Serinc3 are phosphorylated by casein kinase II and mediate interaction with the μ subunits in vitro.	SIGNOR-273631
P46934	Q9HC16	1	ubiquitination	up-regulates activity	0.284	APOBEC3G ubiquitination by Nedd4-1 favors its packaging into HIV-1 particles\|This could be explained in at least two ways : first, endogenous Nedd4 is naturally expressed at a level largely sufficient to target APOBEC3G into the VLP or virions.	SIGNOR-278635
O95155	Q99689	1	polyubiquitination	up-regulates activity	0.391	E4B mediated the polyubiquitylation of FEZ1 but did not affect its intracellular stability, suggesting that such modification of FEZ1 is not a signal for its proteolysis. Polyubiquitylation of FEZ1 by E4B required Lys(27) of ubiquitin. Expression of a dominant-negative mutant of E4B in rat pheochromocytoma PC12 cells resulted in inhibition of neurite extension induced either by nerve growth factor or by coexpression of FEZ1 and constitutively active PKCzeta. These findings indicate that E4B serves as a ubiquitin ligase for FEZ1 and thereby regulates its function but not its degradation. The polyubiquitin chain attached by E4B to FEZ1 might therefore facilitate the interaction of FEZ1 with an unidentified target that functions in neuritogenesis.	SIGNOR-271510
O60858	Q00987	1	polyubiquitination	down-regulates quantity by destabilization	0.374	Here, we demonstrate that overexpression of RFP2 in cells induced apoptosis through proteasomal degradation of MDM2 and AKT. We observed that RFP2 formed a complex with MDM2, a negative regulator of the p53 tumor suppressor, and AKT, a regulator of apoptosis inhibition at the cellular level. Additionally, we found that the interaction of RFP2 with MDM2 and AKT resulted in ubiquitination and proteasomal degradation of MDM2 and AKT in vivo and in vitro.	SIGNOR-271851
P51608	O00141	1	transcriptional regulation	down-regulates quantity by repression	0.292	These results are compatible with the hypothesis that MeCP2 associates with the Sgk and Fkbp5 promoters and has a repressive effect that is over-ridden by elevated glucocorticoids in response to stress.	SIGNOR-264543
O75398	P08908	1	transcriptional regulation	down-regulates quantity by repression	0.437	The human 5-HT1A gene (HTR1A) rs6295 risk allele prevents Deaf1 binding to HTR1A, resulting in increased 5-HT1A autoreceptor transcription	SIGNOR-269064
P78347	Q13976	0	phosphorylation	up-regulates	0.569	G-kinase phosphorylated tfii-i in vitro and in vivo on ser(371) and ser(743) outside of the interaction domain. G-kinase strongly enhanced tfii-i transactivation of a serum-response element-containing promoter in cos7 cells	SIGNOR-89849
P63279	P41161	1	sumoylation	down-regulates	0.266	Here we show that erm interacts with the sumo-conjugating enzyme ubc9 and is modified by sumo. We further show that sumo modification of this ets transcription factor affects its ability to activate transcription.	SIGNOR-135850
P45983	P42226	1	phosphorylation	down-regulates	0.353	Deactivation of stat6 through serine 707 phosphorylation by jnk.	SIGNOR-170153
P07858	P0DTC2	1	cleavage	up-regulates activity	0.2	SARS-2-S can use both CatB/L as well as TMPRSS2 for priming in these cell lines.	SIGNOR-260738
Q00987	O60858	0	polyubiquitination	down-regulates quantity by destabilization	0.374	Here, we demonstrate that overexpression of RFP2 in cells induced apoptosis through proteasomal degradation of MDM2 and AKT. We observed that RFP2 formed a complex with MDM2, a negative regulator of the p53 tumor suppressor, and AKT, a regulator of apoptosis inhibition at the cellular level. Additionally, we found that the interaction of RFP2 with MDM2 and AKT resulted in ubiquitination and proteasomal degradation of MDM2 and AKT in vivo and in vitro.	SIGNOR-271851
Q9NRF2	P43405	1	dephosphorylation	down-regulates activity	0.2	SHP-1 is recruited by the phosphorylated ITIM-bearing receptors such as CD22 and it dephosphorylates proximal BCR signaling molecules such as CD79, SYK, BLNK.	SIGNOR-268445
O00401	P12931	0	phosphorylation	up-regulates activity	0.759	An Src family tyrosine kinase, v-Src, phosphorylates and activates N-WASP.	SIGNOR-279487
Q13546	Q9NWF9	0	ubiquitination	down-regulates quantity by destabilization	0.503	Triad3A promotes proteolytic degradation of adapter proteins. Triad3A promotes down-regulation of TIRAP, TRIF, and RIP1 proteins.	SIGNOR-271608
P16220	Q9Y2T3	1	transcriptional regulation	up-regulates quantity by expression	0.2	In addition, exposure of the neurons to BDNF increased CREB binding to the cypin promoter and, in line with these data, expression of a dominant negative form of CREB blocked BDNF-promoted increases in cypin protein levels and proximal dendrite branches.	SIGNOR-268968
Q9H4A6	P78527	0	phosphorylation	up-regulates activity	0.318	In response to DNA damage, DNA-PK phosphorylates GOLPH3, resulting in increased interaction with MYO18A, which applies a tensile force to the Golgi. Interference with the Golgi DNA damage response by depletion of DNA-PK, GOLPH3, or MYO18A reduces survival after DNA damage, whereas overexpression of GOLPH3, as is observed frequently in human cancers, confers resistance to killing by DNA-damaging agents	SIGNOR-253558
P12931	P60953	1	phosphorylation	up-regulates	0.695	Epidermal growth factor-dependent regulation of cdc42 is mediated by the src tyrosine kinaseegf signaling through src appears to have dual regulatory effects on cdc42: 1). it leads to the activation of cdc42 as mediated by the vav2 guanine nucleotide exchange factor, and 2). it results in the phosphorylation of cdc42, which stimulates the binding of rhogdi, perhaps to direct the movement of cdc42 to a specific cellular site to trigger a signaling response, because cdc42-rhogdi interactions are essential for cdc42-induced cellular transformation.	SIGNOR-118206
P14780	P51684	0	null	up-regulates activity	0.2	We hypothesized that MIP-3alpha promotes pancreatic cancer invasion through the up-regulation of MMP-9, a Type 4 collagenase.	SIGNOR-278042
Q6DN90	O95819	0	phosphorylation	up-regulates activity	0.2	Together, our results provide compelling evidence that MAP4K4 promotes FA dynamics by regulating IQSEC1 and Arf6 pathway and controlling endocytosis of integrin.\|Upon targeting to FAs via MTs, MAP4K4 can bind and phosphorylate IQSEC1, which in turn activates Arf6 and endocytosis, leading to turnover of FAs.	SIGNOR-280020
P50219	P49841	0	phosphorylation	down-regulates	0.295	Here we show that gsk-3_ inactivates the proapoptotic activity of hlxb9 by phosphorylating hlxb9 at ser-78/ser-80 (phlxb9).	SIGNOR-203657
Q9Y463	Q99801	1	phosphorylation	down-regulates quantity by destabilization	0.332	In addition, an in vitro kinase assay showed that DYRK1B phosphorylated NKX3.1 at serine 185, a residue critical for NKX3.1 steady-state turnover.	SIGNOR-279610
Q15572	O60729	0	dephosphorylation	up-regulates activity	0.2	Consistent with prior studies showing that the phosphatase hCdc14B regulates progression through mitosis by counteracting mitotic phosphorylation by Cdk1/cyclin B [ ], hCdc14B dephosphorylates TAFI110, thus promoting its reactivation as cells exit mitosis.\|Here we show that hCdc14B, the phosphatase that regulates Cdk1/cyclin B activity and progression through mitosis, promotes reactivation of rDNA transcription by dephosphorylating TAFI110.	SIGNOR-277135
Q9UKI8	Q99638	1	phosphorylation	up-regulates	0.448	Tlk1b phosphorylates hrad9 at s328 after the induction of dsb, occupancy of rad9 adjacent to the break increased during repair while that of asf1 decreased, and the effect was more pronounced in tlk1b-overexpressing cells. We propose that following genotoxic stress, tlk1/1b is first recruited to the dsb in a complex with rad9. It then exchanges with asf1 to promote nucleosomes eviction at the dsb and access of the repair machinery to unencumbered dna.	SIGNOR-181748
P46527	O15111	0	phosphorylation	down-regulates activity	0.372	Reduced nuclear p27 was also found in MCF7 human breast cancer cells that were transiently transfected with an IKKalpha expression vector; increased IKKalpha expression resulted in a dose dependent decrease in nuclear p27 and increased cytoplasmic p27 (XREF_FIG).\|We found that IKKalpha phosphorylates p27 at S183 to cause its nuclear export.	SIGNOR-278438
Q06787	Q9Y566	1	post transcriptional regulation	up-regulates quantity	0.4	These results point toward a novel mechanism by which FUS targets neuronal mRNA and given that these PSD-95 and Shank1 3'-UTR G quadruplex structures are also targeted by the fragile X mental retardation protein (FMRP), they raise the possibility that FUS and FMRP might work together to regulate the translation of these neuronal mRNA targets.	SIGNOR-262109
Q8N726	Q9HCX3	0	transcriptional regulation	down-regulates quantity by repression	0.302	Finally, we show that ZNF304 also directs transcriptional silencing of INK4-ARF in human embryonic stem cells.	SIGNOR-266098
Q13627	P24385	1	phosphorylation	down-regulates	0.395	Dyrk1a controls the rate of cycd1 degradation by directly phosphorylating cycd1 at thr 286 and thereby regulates the fraction of cycling cells.	SIGNOR-202838
P45983	Q9NRA8	1	phosphorylation	up-regulates	0.322	Identification of 4e-t phosphorylation sites regulated by jnk. identification of these residues as phosphorylation sites (ser301, ser374, ser513, ser587, ser693, and ser752) was obtained by ms/ms sequencing, these results demonstrate that jnk activity is required to stimulate the assembly of pbs in response to oxidative stress.	SIGNOR-199004
P17612	Q9NS28	1	phosphorylation	up-regulates activity	0.2	Cyclic AMP- and cyclic GMP-dependent kinases (PKA, PKG) inhibit the interaction of RGS18 and 14-3-3 by phosphorylating S216.	SIGNOR-273786
P78536	P12931	0	phosphorylation	up-regulates activity	0.458	These data suggests that Src mediates TACE activation in mechanically stressed cardiomyocytes and this mechanism could be exploited for specific blockade of TNFalpha secretion and its detrimental effects in congestive heart failure.\|We found that the non receptor tyrosine kinase Src mediates TACE activation in mechanically stretched rat cardiomyocytes by phosphorylating the Tyr 702 residue within the intracellular tail of TACE.	SIGNOR-279115
P40763	P54762	0	phosphorylation	up-regulates activity	0.353	By integrating mouse in vivo and in vitro models with human iPSC derived astrocytes, we provide direct evidence that EphB1 can induce early astrocytic STAT3 activation via ephrin-B1 signalling.\|We confirmed that EphB1 activates astrocytes by inducing ephrin-B1 dependent STAT3 phosphorylation.	SIGNOR-279709
P62136	P51955	1	dephosphorylation	down-regulates	0.374	Nek2 is activated by autophosphorylation, and its dephosphorylation is catalyzed by pp1	SIGNOR-152949
P11309	O43524	1	phosphorylation	down-regulates activity	0.387	Pim1s expression induced the phosphorylation of foxo3a (fig. 5a and b) and inactivated its transcriptional activity (fig. 5c). A previous report showed that phosphorylation at t32, s253, and s315 residues in foxo3a induced 14-3-3 binding, nuclear export, and proteasomemediated degradation (42).	SIGNOR-179308
P55064	P17612	0	phosphorylation	up-regulates activity	0.2	AQP5 can be directly phosphorylated by PKA at Ser 156 \|Our data hint at a mechanism whereby phosphorylation of Ser 156 in AQP5 increases its membrane localization, thereby enhancing cancer cell proliferation.	SIGNOR-272088
P84022	Q6ZNA4	0	ubiquitination	down-regulates activity	0.654	Arkadia represses the expression of myoblast differentiation markers through degradation of ski and the ski-bound smad complex in c2c12 myoblasts. Arkadia bound smad2/3 via ski to induce the ubiquitination of smad2/3. These results suggest that arkadia targets ski-bound, inactive phospho-smad2/3 to regulate positively myostatin/tgf-beta signaling.	SIGNOR-235388
Q9UQM7	Q00613	1	phosphorylation	up-regulates activity	0.513	Ser230 is located in the regulatory domain of HSF1, and promotes the magnitude of the inducible transcriptional activity. Ser230 lies within a consensus site for calcium/calmodulin-dependent protein kinase II (CaMKII), and CaMKII overexpression enhances both the level of in vivo Ser230 phosphorylation and transactivation of HSF1. The importance of Ser230 was further established by the S230A HSF1 mutant showing markedly reduced activity relative to wild-type HSF1 when expressed in hsf1(-/-) cells.	SIGNOR-250631
P49841	Q9UQD0	1	phosphorylation	up-regulates activity	0.2	In vivo genetic manipulations demonstrate that GSK3β and Nav1.6 are molecular determinants of MSN excitability and that silencing of GSK3β prevents maladaptive plasticity of IC MSNs. In vitro studies reveal direct interaction of GSK3β with Nav1.6 and phosphorylation at Nav1.6T1936 by GSK3β. A GSK3β-Nav1.6T1936 competing peptide reduces MSNs excitability in IC, but not EC rats. These results identify GSK3β regulation of Nav1.6 as a biosignature of MSNs maladaptive plasticity.	SIGNOR-275763
P61764	Q02156	0	phosphorylation	down-regulates quantity	0.273	These results show that nPKC\u03b5 induces Munc18-1 phosphorylation during synaptic activity and reinforce the idea that nPKC\u03b5 downregulates Munc18-1 levels, induced by the nerve stimulation.\|These results show that nPKCepsilon induces Munc18-1 phosphorylation during synaptic activity and reinforce the idea that nPKCepsilon downregulates Munc18-1 levels, induced by the nerve stimulation.	SIGNOR-279479
O43524	Q08999	1	transcriptional regulation	up-regulates quantity	0.291	Here we show that the Forkheads AFX (FOXO4) and FKHR-L1 (FOXO3a) also directly control transcription of the retinoblastoma-like p130 protein and cause upregulation of p130 protein expression.	SIGNOR-238606
A1Z1Q3	Q13315	0	phosphorylation	down-regulates activity	0.2	We found that MacroD2 is exported from the nucleus upon DNA damage and that this depends on the ATM-induced phosphorylation of the MacroD2 C-terminal IDR.\|ATM activation leads to phosphorylation of the MacroD2 C-terminal region.	SIGNOR-279792
Q13464	P19105	1	phosphorylation	up-regulates activity	0.561	Phosphorylation of myosin II regulatory light chain (MRLC) is important for cell motility and cytokinesis in nonmuscle cells. Although the regulation of monophosphorylated MRLC at serine 19 throughout the cell cycle was examined in detail, MRLC diphosphorylation at both threonine 18 and serine 19 is still unclear. Here we found that Rho-kinase has an activity for MRLC diphosphorylation in nonmuscle cells using sequential column chromatographies.	SIGNOR-263074
P11308	O00501	1	transcriptional regulation	up-regulates quantity by expression	0.224	ETS-related gene (ERG) controls endothelial cell permeability via transcriptional regulation of the claudin 5 (CLDN5) gene.	SIGNOR-261596
Q14457	Q6J9G0	0	phosphorylation	up-regulates activity	0.2	We also demonstrated that STYK1 elevated the serine phosphorylation of BECN1, thereby decreasing the interaction between BECN1 and BCL2. \|The results indicated that the level of BECN1 S90 phosphorylation significantly increased after STYK1 overexpression, but not STYK1K147R mutant.\|STYK1 promotes autophagy through enhancing the assembly of autophagy-specific class III phosphatidylinositol 3-kinase complex I	SIGNOR-264568
Q8IYU2	Q13153	0	phosphorylation	down-regulates activity	0.2	Using a proteomic approach, we identified serine 385 as a target of group-I PAK kinases […] We have established in vitro that HACE1 is a direct target of PAK1 kinase activity.	SIGNOR-255537
P26358	P31749	0	phosphorylation	up-regulates	0.527	Akt1 kinase colocalizes and directly interacts with dnmt1 and phosphorylates ser143. Phosphorylated dnmt1 peaks during dna synthesis, before dnmt1 methylation. Depletion of akt1 or overexpression of dominant-negative akt1 increases methylated dnmt1, resulting in a decrease in dnmt1 abundance. In mammalian cells, phosphorylated dnmt1 is more stable than methylated dnmt1.	SIGNOR-170530
P04040	P42684	0	phosphorylation	up-regulates activity	0.34	C-abl and arg phosphorylated catalase at tyr231 and tyr386 in vitrocatalase is a major effector in the defense of aerobic cells against oxidative stress. Recent studies have shown that catalase activity is stimulated by the c-abl and arg tyrosine kinases	SIGNOR-101306
Q06609	P42574	0	cleavage	down-regulates quantity by destabilization	0.466	The RAD51 protein has been shown to be a substrate for caspase-3\|he activated caspase-3 fragments (19 kDa and 17 kDa) and caspase-3 cleaved RAD51 fragment (∼23 kDa) was detected by Western analysis (Figure 3E). Activation of caspase-3 and the signature proteolytic degradation product of RAD51 only occurred in parental 32Dcl3 cells after treatment with cisplatin	SIGNOR-271709
Q9H334	O75364	1	transcriptional regulation	up-regulates quantity by expression	0.292	We identified FoxP1 as a novel marker for midbrain dopamine neurons. Enforced expression of FoxP1 in embryonic stem cells actuates the expression of Pitx3, a homeobox protein that is exclusively expressed in midbrain dopaminergic neurons and is required for their differentiation and survival during development and from embryonic stem cells in vitro. We show that FoxP1 can be recruited to the Pitx3 locus in embryonic stem cells and regulate Pitx3 promoter activity in a dual-luciferase assay.	SIGNOR-269049
Q13131	P98177	1	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
O75582	Q15759	0	phosphorylation	up-regulates	0.615	Mitogen- and stress-activated protein kinase-1 (msk1) is directly activated by mapk and sapk2/p38, and may mediate activation of crebactivated by phosphorylation at ser-360, thr-581 and thr-700 by mapk1/erk2, mapk3/erk1 and mapk14/p38-alpha	SIGNOR-59443
Q13315	P53350	1	phosphorylation	down-regulates activity	0.429	Indeed Chk2 mediates the degradation of Cdc25A to activate the S-phase checkpoint [5\u20137,18] , whereas ATM phosphorylates and inactivates Plk1, consolidating the delay in the entry into M phase [5\u201319] .\|Indeed Chk2 mediates the degradation of Cdc25A to activate the S-phase checkpoint [5-7,18], whereas ATM phosphorylates and inactivates Plk1, consolidating the delay in the entry into M phase [5-19].	SIGNOR-279793
P29350	Q14790	1	dephosphorylation	up-regulates activity	0.354	Caspase-8 is tyrosine-phosphorylated in freshly isolated neutrophils but spontaneously dephosphorylates in culture, in association with the progression of constitutive apoptosis. Phosphorylation of caspase-8 on Tyr-310 facilitates its interaction with the Src-homology domain 2 containing tyrosine phosphatase-1 (SHP-1) and enables SHP-1 to dephosphorylate caspase-8, permitting apoptosis to proceed. The non-receptor tyrosine kinase, Lyn, can phosphorylate caspase-8 on Tyr-397 and Tyr-465, rendering it resistant to activational cleavage and inhibiting apoptosis. Exposure to lipopolysaccharide reduces SHP-1 activity and binding to caspase-8, caspase-8 activity, and rates of spontaneous apoptosis.	SIGNOR-248478
P17252	Q99801	1	phosphorylation	up-regulates	0.2	Phosphorylation of wild-type nkx3.1 decreased the apparent binding affinity of the protein for the consensus sequence by 3-fold relative to the nonphosphorylated protein (fig. 3) _ .	SIGNOR-86723
Q99618	O60729	0	dephosphorylation	up-regulates	0.281	The phosphatase cdc14b translocates from the nucleolus to the nucleoplasm and induces the activation of the ubiquitin ligase apc/ccdh1	SIGNOR-179664

P23409

Q02078

0

transcriptional regulation

up-regulates quantity by expression

0.589

Myogenin and MEF2 function synergistically to activate the MRF4 promoter during myogenesis.

SIGNOR-238709

P17706

P35968

1

dephosphorylation

down-regulates activity

0.566

We show that a TCPTP substrate-trapping mutant interacts with VEGFR2. Moreover, TCPTP dephosphorylates VEGFR2 in a phosphosite-specific manner, inhibits its kinase activity and prevents its internalization from the cell surface. |The autophosphorylation sites Tyr1054/1059 and Tyr1214 were dephosphorylated by TCPTP (Fig. 4B). Tyr996, the functional significance of which is currently uncertain (Olsson et al., 2006), was a TCPTP target as well.

SIGNOR-248399

Q9UQB3

P12931

0

phosphorylation

up-regulates activity

0.329

Furthermore, according to our data from immunoprecipitation to py20 antibody, c-Src can phosphorylate delta-catenin on Y1073, Y1176, Y1179 and Y1112, with the predominant sites being Y1073, Y1112 and Y1176.|Interestingly, we found that c-Src can increase the stability of delta-catenin in MEF cells.

SIGNOR-278327

P17612

O75581

1

phosphorylation

up-regulates activity

0.2

These results suggest that camppka activation is involved in activation of lrp6(...) our results demonstrate that lrp6 can be directly phosphorylated by pka catalytic subunit.

SIGNOR-181979

Q9UNE7

P17542

1

ubiquitination

down-regulates quantity by destabilization

0.356

Ubiquitination and degradation of Tal1/SCL are induced by notch signaling and depend on Skp2 and CHIP. CHIP promoted Tal1 degradation with both chaperone binding and ubiquitin ligase activities, which are mediated by its TPR domain and U box, respectively.

SIGNOR-271393

P53667

Q9Y252

0

polyubiquitination

down-regulates quantity by destabilization

0.432

Consistent with a role in axonal growth, we found that Rnf6 binds to, polyubiquitinates, and targets LIMK1 for proteasomal degradation in growth cones of primary hippocampal neurons.

SIGNOR-271481

Q02750

Q16584

0

phosphorylation

up-regulates activity

0.335

Here we report that MLK3 can phosphorylate and activate MEK-1 directly in vitro and also can induce MEK phosphorylation on its activation sites in vivo in COS-7 cells.

SIGNOR-280019

Q9UJY5

P68400

0

phosphorylation

down-regulates activity

0.504

Serine-355 of GGA1 is phosphorylated in vivo and in vitro. This inhibition is caused by the binding of an AC-LL sequence present in the hinge segment to the ligand-binding site in the VHS domain. The inhibition depends on the phosphorylation of a serine located three residues upstream of the AC-LL motif. The serine is phosphorylated by casein kinase 2 in in vitro assays.

SIGNOR-273623

P52732

P06493

0

phosphorylation

up-regulates activity

0.638

Nek6 phosphorylated Eg5 at several sites in vitro and one of these sites, Ser1033, is phosphorylated in vivo during mitosis. Whereas CDK1 phosphorylates nearly all Eg5 at Thr926 during mitosis, Nek6 phosphorylates approximately 3% of Eg5, primarily at the spindle poles.

SIGNOR-273887

Q15208

P30304

1

phosphorylation

down-regulates quantity

0.247

Here, we demonstrate that the depletion of serine-threonine kinase 38 (STK38) prevents the DNA-damage-induced degradation of CDC25A and subsequent G2 arrest, and that STK38 directly phosphorylates CDC25A at Ser-76, resulting in CDC25A's degradation.

SIGNOR-279488

Q13489

O43353

1

polyubiquitination

up-regulates activity

0.787

CIAP1/2 are direct E3 ligases conjugating diverse types of ubiquitin chains to receptor interacting proteins kinases 1 to 4 (RIP1-4).Together, our results demonstrate that depleting cIAP1/2 inhibits RIP1-4 mediated NF-kB activation without affecting RIP auto-phosphorylation.

SIGNOR-272715

O95644

Q9Y625

1

transcriptional regulation

up-regulates quantity by expression

0.251

NFAT transcriptionally regulates GPC6 induction in breast cancer cells and binds to three regulatory elements in the GPC6 proximal promoter. Expression of GPC6 in response to NFAT signalling promotes invasive migration, whereas GPC6 silencing with shRNA (small-hairpin RNA) potently blocks this phenotype.

SIGNOR-264022

P11802

P38398

1

phosphorylation

down-regulates

0.665

In particular, we have identified ser 632 of brca1 as a cyclin d1/cdk4 phosphorylation site in vitro. Using chromatin immunoprecipitation assays, we observed that the inhibition of cyclin d1/cdk4 activity resulted in increased brca1 dna binding at particular promoters in vivo.

SIGNOR-153450

P00519

O75122

1

phosphorylation

up-regulates quantity

0.502

We find that Abl binds to and phosphorylates CLASP2 in response to extracellular signals such as serum or PDGF.

SIGNOR-279580

Q15418

Q8IX03

1

phosphorylation

up-regulates

0.335

Moreover, we found that rsk1/2 specifically phosphorylates kibra at two highly conserved sites (thr(929) and ser(947)) in vitro and in cells. Rsk-mediated phosphorylation is required for kibra binding to rsk1, but not rsk2.

SIGNOR-203298

P00533

Q8IVM0

1

phosphorylation

down-regulates activity

0.415

We also detected tyrosine phosphorylation of Ymer by EGF stimulation as previously reported (Fig. 1A). Furthermore, we verified that EGF receptor-mediated tyrosine phosphorylation of Ymer is inhibited by AG1478, which is known as an EGF receptor tyrosine kinase inhibitor (Fig. 1B). A luciferase reporter assay showed that mutation of tyrosines on Ymer (YmerY217/279/304F) results in loss of the inhibitory activity for NF-kappaB signaling.

SIGNOR-262851

P53350

P60484

1

phosphorylation

down-regulates activity

0.534

Subsequently, Plk1 phosphorylation of PTEN was shown to be responsible for its inactivation.

SIGNOR-280070

P31751

P15311

1

phosphorylation

up-regulates

0.375

Purified akt directly phosphorylates recombinant ezrin at threonine 567 in vitro in an atp-dependent manner. ezrin activation after initiation of na+-glucose cotransport requires akt2 expression

SIGNOR-130260

P17600

Q14012

0

phosphorylation

down-regulates activity

0.561

Synapsin phosphorylation in the A domain, at the only phosphorylation site shared by all synapsins, dissociates synapsins from synaptic vesicles.This site is located in the N-terminal A domain and is a substrate for both PKA and CaM Kinase I

SIGNOR-250615

Q9ULG1

Q9UNE7

0

ubiquitination

up-regulates activity

0.2

Then, by an in vivo ubiquitination assay under denaturing conditions (hereafter, all in vivo ubiquitination assays were carried out under denaturing conditions), we determined whether CHIP ubiquitinates Ino80.|We also show that CHIP works together with BAP1 to enhance the stabilization of Ino80, leading to its chromatin binding.

SIGNOR-278646

P02818

P07339

0

cleavage

down-regulates quantity by destabilization

0.314

This study has been undertaken to compare the degradation of BGP by the cysteine proteinases cathepsins L, B, H, S, and the aspartic proteinase cathepsin D. Cathepsins B, L, H, and S readily cleave BGP at the G7-A8 bond; cathepsin L also cleaves at R43-R44; cathepsin B also cleaves at R44-F45; and cathepsin D cleaves only at A41-Y42.

SIGNOR-256319

P24941

P29374

1

phosphorylation

down-regulates

0.426

In the present study we identified rbp1 as a novel cdk substrate. Rbp1 is phosphorylated by cdk2 on serines 864 and 1007, which are n- and c-terminal to the lxcxe motif, respectively. Cdk2-mediated phosphorylation of rbp1 or prb destabilizes their interaction in vitro, with concurrent phosphorylation of both proteins leading to their dissociation

SIGNOR-170455

P12755

P31749

0

phosphorylation

down-regulates

0.337

The phosphorylation of ski at threonine 458 is induced by akt pathway activators including insulin, insulin-like growth factor-1, and hepatocyte growth factor. The phosphorylation of ski causes its destabilization and reduces ski-mediated inhibition of expression of another negative regulator of tgf-beta, smad7

SIGNOR-252527

O00401

P00519

0

phosphorylation

up-regulates activity

0.55

Abl phosphorylates N-WASP on tyrosines 175 and 256. Phosphorylation at this site stabilizes the active conformation of N-WASP, resulting in comet tail elongation.

SIGNOR-251437

P12931

P15941

1

phosphorylation

up-regulates

0.444

The c-src tyrosine kinase regulates signaling of the human df3/muc1 carcinoma-associated antigen with gsk3 beta and betBeta-catenin c-src phosphorylates the muc1 cytoplasmic domain at a yekv motif c-src-mediated phosphorylation of muc1 increases binding of muc1 and betBeta-catenin

SIGNOR-85938

P15172

P30281

1

transcriptional regulation

up-regulates quantity by expression

0.374

Here we report that, at the onset of differentiation, activation by MyoD of the Rb, p21, and cyclin D3 genes occurs in the absence of new protein synthesis and with the requirement of the p300 transcriptional coactivator.

SIGNOR-238526

P31749

Q15119

0

phosphorylation

up-regulates activity

0.749

PIP3 recruits PDK1 and AKT to the plasma membrane, where PDK1 phosphorylates AKT on Thr308 in the activation loop of the kinase domain. The phosphorylation of AKT on Ser473 by PDK2 acts as a gain control for AKT and regulates its degree of activation. The sirolimus-insensitive mTORC2 complex exhibits PDK2 activity

SIGNOR-249630

Q99759

P53805

1

phosphorylation

up-regulates

0.448

Essential role of mekk3 signaling in angiotensin ii-induced calcineurin/nuclear factor of activated t-cells activation

SIGNOR-102294

Q9H2X6

Q08050

1

phosphorylation

up-regulates activity

0.2

In conclusion, the phosphorylation of FOXM1 by HIPK2 can promote FOXM1 transcription activity and cell proliferation in RCC, thus, indicating a potential mechanism for the treatment of human RCC in the future.

SIGNOR-278944

P50591

P19838

1

post transcriptional regulation

up-regulates quantity by expression

0.302

Treatment with TRAIL increased the NF-κB transcriptional activity by approximately twofold in MDA-MB-231 cells compared to the control.

SIGNOR-277936

O15297

Q16539

1

dephosphorylation

down-regulates activity

0.444

Wip1 selectively inactivates p38 by specific dephosphorylation of its conserved threonine residue

SIGNOR-84793

Q05086

Q13200

1

ubiquitination

down-regulates quantity by destabilization

0.277

Our experiments collectively suggest that UBE3A stimulates Wnt pathway activation by interacting with, ubiquitinating, and reducing the levels of multiple (PSMB1, PSMC2, PSMD2, and PSMD7) proteasome subunits.

SIGNOR-265133

Q8IW41

Q15382

1

phosphorylation

down-regulates activity

0.401

Phosphorylation of Rheb at Ser 130 by PRAK impairs the nucleotide-binding ability of Rheb and inhibits Rheb-mediated mTORC1 activation.

SIGNOR-276313

Q05513

Q07812

1

phosphorylation

down-regulates activity

0.2

Protein kinase czeta abrogates the proapoptotic function of bax through phosphorylation. Overexpression of wild type or the constitutively active a119d but not the dominant negative k281w pkczeta mutant results in bax phosphorylation at serine 184.

SIGNOR-155111

Q99558

P40763

1

phosphorylation

up-regulates activity

0.26

Activation of Stat3 by NIK requires NIK kinase activity as showed by kinase assays.|When we transfected NIK into LNCaP cells, NIK was able to phosphorylate Stat3 at both tyrosine 705 and serine 727 residues ( Fig. 3 A).

SIGNOR-279341

Q9UGL1

Q16665

0

transcriptional regulation

up-regulates quantity by expression

0.271

To this end, we confirm that KDM3A, KDM4B, KDM4C, KDM5B, KDM5C, and KDM62 are direct targets of HIF-1a while extent the list of known targets to KDM2A, KDM2B, KDM4D, KDM5A, and KDM6A. The results demonstrated that majority of the KDMs were similarly induced (KDM2A, KDM2B, KDM3A, KDM4B, KDM4C, KDM4D, KDM5A, KDM5B, KDM5C, KDM6B, and KDM7A) or repressed (KDM NO66 and KDM1A) by both HIF-1a and HIF-2a.

SIGNOR-271563

Q9HBY8

O15530

0

phosphorylation

up-regulates activity

0.596

SGK2 and SGK3 are activated in vitro by PDK1, albeit more slowly than SGK1, and their activation is accompanied by the phosphorylation of Thr(193) and Thr(253) respectively. The PDK1-catalysed phosphorylation and activation of SGK2 and SGK3, like SGK1, is greatly potentiated by mutating Ser(356) and Ser(419) respectively to Asp, these residues being equivalent to the C-terminal phosphorylation site of PKB.

SIGNOR-250277

P53567

P35247

1

transcriptional regulation

up-regulates quantity by expression

0.2

Cotransfection of C/EBPalpha, C/EBPbeta, or C/EBPdelta cDNA in H441 lung adenocarcinoma cells significantly increased the luciferase activity of a wild-type SP-D promoter construct containing 698 bp of upstream sequence (SS698). Transfection of C/EBP also increased the level of endogenous SP-D mRNA in H441 cells| Thus, interactions among C/EBP elements in the near-distal promoter can modulate the promoter activity of SP-D.

SIGNOR-254058

Q92786

P54646

0

phosphorylation

down-regulates quantity by destabilization

0.2

Furthermore, the Ser79 phosphorylation of PROX1 by AMPK enhances the recruitment of CUL4-DDB1 ubiquitin ligase to promote PROX1 degradation.

SIGNOR-277608

P17612

Q92777

1

phosphorylation

down-regulates activity

0.326

Synapsin phosphorylation in the A domain, at the only phosphorylation site shared by all synapsins, dissociates synapsins from synaptic vesicles.This site is located in the N-terminal A domain and is a substrate for both PKA and CaM Kinase I

SIGNOR-250059

P50570

P12931

0

phosphorylation

down-regulates activity

0.557

We used cSrc-transformed NIH 3T3 fibroblasts to examine the effect of mutant Dyn2Y597. Similar to its effect in myotubes, Dyn2Y597F presented reduced enrichment at podosomes, whereas Dyn2Y597E clearly targeted podosome rosettes (Figures S9B and S9C). Moreover, Dyn2Y597F significantly reduced the podosome area, ECM degradation ability, and lifespan of the podosome in cSrc-transformed NIH 3T3 fibroblasts, whereas Dyn2Y597E displayed contradictory effects (Figures S9D–S9G).

SIGNOR-277539

P06493

P49792

1

phosphorylation

up-regulates activity

0.474

Cdk1 phosphorylates conserved sites within RanBP2 and activates BicD2 binding and early dynein recruitment.

SIGNOR-259118

P01135

P12931

0

cleavage

up-regulates

0.3

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

SIGNOR-235888

Q9BUB5

P67775

0

dephosphorylation

down-regulates

0.514

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

SIGNOR-168314

P04637

P52789

1

transcriptional regulation

down-regulates quantity by repression

0.412

P53 regulates basal expression of AIF and SCO2 and facilitates oxidative phosphorylation. The expression of GLUT1, GLUT4, and HK2 is negatively regulated by p53, whereas TIGAR expression is induced by p53. The net result of p53-mediated regulation of these glycolytic enzymes is the suppression of glycolysis. In addition, p53 directly binds and inhibits G6PD activity and downregulates the pentose phosphate pathway.

SIGNOR-267466

O75460

P17861

1

phosphorylation

up-regulates activity

0.647

IRE1\u03b1 phosphorylates and activates the XBP1 transcription factor XBP1 via its kinase activity.

SIGNOR-279712

P68400

Q13530

1

phosphorylation

up-regulates activity

0.2

The two serines within the PSAC of Serinc3 are phosphorylated by casein kinase II and mediate interaction with the μ subunits in vitro.

SIGNOR-273631

P46934

Q9HC16

1

ubiquitination

up-regulates activity

0.284

APOBEC3G ubiquitination by Nedd4-1 favors its packaging into HIV-1 particles|This could be explained in at least two ways : first, endogenous Nedd4 is naturally expressed at a level largely sufficient to target APOBEC3G into the VLP or virions.

SIGNOR-278635

O95155

Q99689

1

polyubiquitination

up-regulates activity

0.391

E4B mediated the polyubiquitylation of FEZ1 but did not affect its intracellular stability, suggesting that such modification of FEZ1 is not a signal for its proteolysis. Polyubiquitylation of FEZ1 by E4B required Lys(27) of ubiquitin. Expression of a dominant-negative mutant of E4B in rat pheochromocytoma PC12 cells resulted in inhibition of neurite extension induced either by nerve growth factor or by coexpression of FEZ1 and constitutively active PKCzeta. These findings indicate that E4B serves as a ubiquitin ligase for FEZ1 and thereby regulates its function but not its degradation. The polyubiquitin chain attached by E4B to FEZ1 might therefore facilitate the interaction of FEZ1 with an unidentified target that functions in neuritogenesis.

SIGNOR-271510

O60858

Q00987

1

polyubiquitination

down-regulates quantity by destabilization

0.374

Here, we demonstrate that overexpression of RFP2 in cells induced apoptosis through proteasomal degradation of MDM2 and AKT. We observed that RFP2 formed a complex with MDM2, a negative regulator of the p53 tumor suppressor, and AKT, a regulator of apoptosis inhibition at the cellular level. Additionally, we found that the interaction of RFP2 with MDM2 and AKT resulted in ubiquitination and proteasomal degradation of MDM2 and AKT in vivo and in vitro.

SIGNOR-271851

P51608

O00141

1

transcriptional regulation

down-regulates quantity by repression

0.292

These results are compatible with the hypothesis that MeCP2 associates with the Sgk and Fkbp5 promoters and has a repressive effect that is over-ridden by elevated glucocorticoids in response to stress.

SIGNOR-264543

O75398

P08908

1

transcriptional regulation

down-regulates quantity by repression

0.437

The human 5-HT1A gene (HTR1A) rs6295 risk allele prevents Deaf1 binding to HTR1A, resulting in increased 5-HT1A autoreceptor transcription

SIGNOR-269064

P78347

Q13976

0

phosphorylation

up-regulates

0.569

G-kinase phosphorylated tfii-i in vitro and in vivo on ser(371) and ser(743) outside of the interaction domain. G-kinase strongly enhanced tfii-i transactivation of a serum-response element-containing promoter in cos7 cells

SIGNOR-89849

P63279

P41161

1

sumoylation

down-regulates

0.266

Here we show that erm interacts with the sumo-conjugating enzyme ubc9 and is modified by sumo. We further show that sumo modification of this ets transcription factor affects its ability to activate transcription.

SIGNOR-135850

P45983

P42226

1

phosphorylation

down-regulates

0.353

Deactivation of stat6 through serine 707 phosphorylation by jnk.

SIGNOR-170153

P07858

P0DTC2

1

cleavage

up-regulates activity

0.2

SARS-2-S can use both CatB/L as well as TMPRSS2 for priming in these cell lines.

SIGNOR-260738

Q00987

O60858

0

polyubiquitination

down-regulates quantity by destabilization

0.374

Here, we demonstrate that overexpression of RFP2 in cells induced apoptosis through proteasomal degradation of MDM2 and AKT. We observed that RFP2 formed a complex with MDM2, a negative regulator of the p53 tumor suppressor, and AKT, a regulator of apoptosis inhibition at the cellular level. Additionally, we found that the interaction of RFP2 with MDM2 and AKT resulted in ubiquitination and proteasomal degradation of MDM2 and AKT in vivo and in vitro.

SIGNOR-271851

Q9NRF2

P43405

1

dephosphorylation

down-regulates activity

0.2

SHP-1 is recruited by the phosphorylated ITIM-bearing receptors such as CD22 and it dephosphorylates proximal BCR signaling molecules such as CD79, SYK, BLNK.

SIGNOR-268445

O00401

P12931

0

phosphorylation

up-regulates activity

0.759

An Src family tyrosine kinase, v-Src, phosphorylates and activates N-WASP.

SIGNOR-279487

Q13546

Q9NWF9

0

ubiquitination

down-regulates quantity by destabilization

0.503

Triad3A promotes proteolytic degradation of adapter proteins. Triad3A promotes down-regulation of TIRAP, TRIF, and RIP1 proteins.

SIGNOR-271608

P16220

Q9Y2T3

1

transcriptional regulation

up-regulates quantity by expression

0.2

In addition, exposure of the neurons to BDNF increased CREB binding to the cypin promoter and, in line with these data, expression of a dominant negative form of CREB blocked BDNF-promoted increases in cypin protein levels and proximal dendrite branches.

SIGNOR-268968

Q9H4A6

P78527

0

phosphorylation

up-regulates activity

0.318

In response to DNA damage, DNA-PK phosphorylates GOLPH3, resulting in increased interaction with MYO18A, which applies a tensile force to the Golgi. Interference with the Golgi DNA damage response by depletion of DNA-PK, GOLPH3, or MYO18A reduces survival after DNA damage, whereas overexpression of GOLPH3, as is observed frequently in human cancers, confers resistance to killing by DNA-damaging agents

SIGNOR-253558

P12931

P60953

1

phosphorylation

up-regulates

0.695

Epidermal growth factor-dependent regulation of cdc42 is mediated by the src tyrosine kinaseegf signaling through src appears to have dual regulatory effects on cdc42: 1). it leads to the activation of cdc42 as mediated by the vav2 guanine nucleotide exchange factor, and 2). it results in the phosphorylation of cdc42, which stimulates the binding of rhogdi, perhaps to direct the movement of cdc42 to a specific cellular site to trigger a signaling response, because cdc42-rhogdi interactions are essential for cdc42-induced cellular transformation.

SIGNOR-118206

P14780

P51684

0

null

up-regulates activity

0.2

We hypothesized that MIP-3alpha promotes pancreatic cancer invasion through the up-regulation of MMP-9, a Type 4 collagenase.

SIGNOR-278042

Q6DN90

O95819

0

phosphorylation

up-regulates activity

0.2

Together, our results provide compelling evidence that MAP4K4 promotes FA dynamics by regulating IQSEC1 and Arf6 pathway and controlling endocytosis of integrin.|Upon targeting to FAs via MTs, MAP4K4 can bind and phosphorylate IQSEC1, which in turn activates Arf6 and endocytosis, leading to turnover of FAs.

SIGNOR-280020

P50219

P49841

0

phosphorylation

down-regulates

0.295

Here we show that gsk-3_ inactivates the proapoptotic activity of hlxb9 by phosphorylating hlxb9 at ser-78/ser-80 (phlxb9).

SIGNOR-203657

Q9Y463

Q99801

1

phosphorylation

down-regulates quantity by destabilization

0.332

In addition, an in vitro kinase assay showed that DYRK1B phosphorylated NKX3.1 at serine 185, a residue critical for NKX3.1 steady-state turnover.

SIGNOR-279610

Q15572

O60729

0

dephosphorylation

up-regulates activity

0.2

Consistent with prior studies showing that the phosphatase hCdc14B regulates progression through mitosis by counteracting mitotic phosphorylation by Cdk1/cyclin B [ ], hCdc14B dephosphorylates TAFI110, thus promoting its reactivation as cells exit mitosis.|Here we show that hCdc14B, the phosphatase that regulates Cdk1/cyclin B activity and progression through mitosis, promotes reactivation of rDNA transcription by dephosphorylating TAFI110.

SIGNOR-277135

Q9UKI8

Q99638

1

phosphorylation

up-regulates

0.448

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

SIGNOR-181748

P46527

O15111

0

phosphorylation

down-regulates activity

0.372

Reduced nuclear p27 was also found in MCF7 human breast cancer cells that were transiently transfected with an IKKalpha expression vector; increased IKKalpha expression resulted in a dose dependent decrease in nuclear p27 and increased cytoplasmic p27 (XREF_FIG).|We found that IKKalpha phosphorylates p27 at S183 to cause its nuclear export.

SIGNOR-278438

Q06787

Q9Y566

1

post transcriptional regulation

up-regulates quantity

0.4

These results point toward a novel mechanism by which FUS targets neuronal mRNA and given that these PSD-95 and Shank1 3'-UTR G quadruplex structures are also targeted by the fragile X mental retardation protein (FMRP), they raise the possibility that FUS and FMRP might work together to regulate the translation of these neuronal mRNA targets.

SIGNOR-262109

Q8N726

Q9HCX3

0

transcriptional regulation

down-regulates quantity by repression

0.302

Finally, we show that ZNF304 also directs transcriptional silencing of INK4-ARF in human embryonic stem cells.

SIGNOR-266098

Q13627

P24385

1

phosphorylation

down-regulates

0.395

Dyrk1a controls the rate of cycd1 degradation by directly phosphorylating cycd1 at thr 286 and thereby regulates the fraction of cycling cells.

SIGNOR-202838

P45983

Q9NRA8

1

phosphorylation

up-regulates

0.322

Identification of 4e-t phosphorylation sites regulated by jnk. identification of these residues as phosphorylation sites (ser301, ser374, ser513, ser587, ser693, and ser752) was obtained by ms/ms sequencing, these results demonstrate that jnk activity is required to stimulate the assembly of pbs in response to oxidative stress.

SIGNOR-199004

P17612

Q9NS28

1

phosphorylation

up-regulates activity

0.2

Cyclic AMP- and cyclic GMP-dependent kinases (PKA, PKG) inhibit the interaction of RGS18 and 14-3-3 by phosphorylating S216.

SIGNOR-273786

P78536

P12931

0

phosphorylation

up-regulates activity

0.458

These data suggests that Src mediates TACE activation in mechanically stressed cardiomyocytes and this mechanism could be exploited for specific blockade of TNFalpha secretion and its detrimental effects in congestive heart failure.|We found that the non receptor tyrosine kinase Src mediates TACE activation in mechanically stretched rat cardiomyocytes by phosphorylating the Tyr 702 residue within the intracellular tail of TACE.

SIGNOR-279115

P40763

P54762

0

phosphorylation

up-regulates activity

0.353

By integrating mouse in vivo and in vitro models with human iPSC derived astrocytes, we provide direct evidence that EphB1 can induce early astrocytic STAT3 activation via ephrin-B1 signalling.|We confirmed that EphB1 activates astrocytes by inducing ephrin-B1 dependent STAT3 phosphorylation.

SIGNOR-279709

P62136

P51955

1

dephosphorylation

down-regulates

0.374

Nek2 is activated by autophosphorylation, and its dephosphorylation is catalyzed by pp1

SIGNOR-152949

P11309

O43524

1

phosphorylation

down-regulates activity

0.387

Pim1s expression induced the phosphorylation of foxo3a (fig. 5a and b) and inactivated its transcriptional activity (fig. 5c). A previous report showed that phosphorylation at t32, s253, and s315 residues in foxo3a induced 14-3-3 binding, nuclear export, and proteasomemediated degradation (42).

SIGNOR-179308

P55064

P17612

0

phosphorylation

up-regulates activity

0.2

AQP5 can be directly phosphorylated by PKA at Ser 156 |Our data hint at a mechanism whereby phosphorylation of Ser 156 in AQP5 increases its membrane localization, thereby enhancing cancer cell proliferation.

SIGNOR-272088

P84022

Q6ZNA4

0

ubiquitination

down-regulates activity

0.654

Arkadia represses the expression of myoblast differentiation markers through degradation of ski and the ski-bound smad complex in c2c12 myoblasts. Arkadia bound smad2/3 via ski to induce the ubiquitination of smad2/3. These results suggest that arkadia targets ski-bound, inactive phospho-smad2/3 to regulate positively myostatin/tgf-beta signaling.

SIGNOR-235388

Q9UQM7

Q00613

1

phosphorylation

up-regulates activity

0.513

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

SIGNOR-250631

P49841

Q9UQD0

1

phosphorylation

up-regulates activity

0.2

In vivo genetic manipulations demonstrate that GSK3β and Nav1.6 are molecular determinants of MSN excitability and that silencing of GSK3β prevents maladaptive plasticity of IC MSNs. In vitro studies reveal direct interaction of GSK3β with Nav1.6 and phosphorylation at Nav1.6T1936 by GSK3β. A GSK3β-Nav1.6T1936 competing peptide reduces MSNs excitability in IC, but not EC rats. These results identify GSK3β regulation of Nav1.6 as a biosignature of MSNs maladaptive plasticity.

SIGNOR-275763

P61764

Q02156

0

phosphorylation

down-regulates quantity

0.273

These results show that nPKC\u03b5 induces Munc18-1 phosphorylation during synaptic activity and reinforce the idea that nPKC\u03b5 downregulates Munc18-1 levels, induced by the nerve stimulation.|These results show that nPKCepsilon induces Munc18-1 phosphorylation during synaptic activity and reinforce the idea that nPKCepsilon downregulates Munc18-1 levels, induced by the nerve stimulation.

SIGNOR-279479

O43524

Q08999

1

transcriptional regulation

up-regulates quantity

0.291

Here we show that the Forkheads AFX (FOXO4) and FKHR-L1 (FOXO3a) also directly control transcription of the retinoblastoma-like p130 protein and cause upregulation of p130 protein expression.

SIGNOR-238606

A1Z1Q3

Q13315

0

phosphorylation

down-regulates activity

0.2

We found that MacroD2 is exported from the nucleus upon DNA damage and that this depends on the ATM-induced phosphorylation of the MacroD2 C-terminal IDR.|ATM activation leads to phosphorylation of the MacroD2 C-terminal region.

SIGNOR-279792

Q13464

P19105

1

phosphorylation

up-regulates activity

0.561

Phosphorylation of myosin II regulatory light chain (MRLC) is important for cell motility and cytokinesis in nonmuscle cells. Although the regulation of monophosphorylated MRLC at serine 19 throughout the cell cycle was examined in detail, MRLC diphosphorylation at both threonine 18 and serine 19 is still unclear. Here we found that Rho-kinase has an activity for MRLC diphosphorylation in nonmuscle cells using sequential column chromatographies.

SIGNOR-263074

P11308

O00501

1

transcriptional regulation

up-regulates quantity by expression

0.224

ETS-related gene (ERG) controls endothelial cell permeability via transcriptional regulation of the claudin 5 (CLDN5) gene.

SIGNOR-261596

Q14457

Q6J9G0

0

phosphorylation

up-regulates activity

0.2

We also demonstrated that STYK1 elevated the serine phosphorylation of BECN1, thereby decreasing the interaction between BECN1 and BCL2. |The results indicated that the level of BECN1 S90 phosphorylation significantly increased after STYK1 overexpression, but not STYK1K147R mutant.|STYK1 promotes autophagy through enhancing the assembly of autophagy-specific class III phosphatidylinositol 3-kinase complex I

SIGNOR-264568

Q8IYU2

Q13153

0

phosphorylation

down-regulates activity

0.2

Using a proteomic approach, we identified serine 385 as a target of group-I PAK kinases […] We have established in vitro that HACE1 is a direct target of PAK1 kinase activity.

SIGNOR-255537

P26358

P31749

0

phosphorylation

up-regulates

0.527

Akt1 kinase colocalizes and directly interacts with dnmt1 and phosphorylates ser143. Phosphorylated dnmt1 peaks during dna synthesis, before dnmt1 methylation. Depletion of akt1 or overexpression of dominant-negative akt1 increases methylated dnmt1, resulting in a decrease in dnmt1 abundance. In mammalian cells, phosphorylated dnmt1 is more stable than methylated dnmt1.

SIGNOR-170530

P04040

P42684

0

phosphorylation

up-regulates activity

0.34

C-abl and arg phosphorylated catalase at tyr231 and tyr386 in vitrocatalase is a major effector in the defense of aerobic cells against oxidative stress. Recent studies have shown that catalase activity is stimulated by the c-abl and arg tyrosine kinases

SIGNOR-101306

Q06609

P42574

0

cleavage

down-regulates quantity by destabilization

0.466

The RAD51 protein has been shown to be a substrate for caspase-3|he activated caspase-3 fragments (19 kDa and 17 kDa) and caspase-3 cleaved RAD51 fragment (∼23 kDa) was detected by Western analysis (Figure 3E). Activation of caspase-3 and the signature proteolytic degradation product of RAD51 only occurred in parental 32Dcl3 cells after treatment with cisplatin

SIGNOR-271709

Q9H334

O75364

1

transcriptional regulation

up-regulates quantity by expression

0.292

We identified FoxP1 as a novel marker for midbrain dopamine neurons. Enforced expression of FoxP1 in embryonic stem cells actuates the expression of Pitx3, a homeobox protein that is exclusively expressed in midbrain dopaminergic neurons and is required for their differentiation and survival during development and from embryonic stem cells in vitro. We show that FoxP1 can be recruited to the Pitx3 locus in embryonic stem cells and regulate Pitx3 promoter activity in a dual-luciferase assay.

SIGNOR-269049

Q13131

P98177

1

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

O75582

Q15759

0

phosphorylation

up-regulates

0.615

Mitogen- and stress-activated protein kinase-1 (msk1) is directly activated by mapk and sapk2/p38, and may mediate activation of crebactivated by phosphorylation at ser-360, thr-581 and thr-700 by mapk1/erk2, mapk3/erk1 and mapk14/p38-alpha

SIGNOR-59443

Q13315

P53350

1

phosphorylation

down-regulates activity

0.429

Indeed Chk2 mediates the degradation of Cdc25A to activate the S-phase checkpoint [5\u20137,18] , whereas ATM phosphorylates and inactivates Plk1, consolidating the delay in the entry into M phase [5\u201319] .|Indeed Chk2 mediates the degradation of Cdc25A to activate the S-phase checkpoint [5-7,18], whereas ATM phosphorylates and inactivates Plk1, consolidating the delay in the entry into M phase [5-19].

SIGNOR-279793

P29350

Q14790

1

dephosphorylation

up-regulates activity

0.354

Caspase-8 is tyrosine-phosphorylated in freshly isolated neutrophils but spontaneously dephosphorylates in culture, in association with the progression of constitutive apoptosis. Phosphorylation of caspase-8 on Tyr-310 facilitates its interaction with the Src-homology domain 2 containing tyrosine phosphatase-1 (SHP-1) and enables SHP-1 to dephosphorylate caspase-8, permitting apoptosis to proceed. The non-receptor tyrosine kinase, Lyn, can phosphorylate caspase-8 on Tyr-397 and Tyr-465, rendering it resistant to activational cleavage and inhibiting apoptosis. Exposure to lipopolysaccharide reduces SHP-1 activity and binding to caspase-8, caspase-8 activity, and rates of spontaneous apoptosis.

SIGNOR-248478

P17252

Q99801

1

phosphorylation

up-regulates

0.2

Phosphorylation of wild-type nkx3.1 decreased the apparent binding affinity of the protein for the consensus sequence by 3-fold relative to the nonphosphorylated protein (fig. 3) _ .

SIGNOR-86723

Q99618

O60729

0

dephosphorylation

up-regulates

0.281

The phosphatase cdc14b translocates from the nucleolus to the nucleoplasm and induces the activation of the ubiquitin ligase apc/ccdh1

SIGNOR-179664