GleghornLab/Signor_2class · Datasets at Hugging Face

IdA string	IdB string	labels int64	mechanism string	effect string	score float64	sentence string	signor_id string
Q9H2G2	P68400	0	phosphorylation	down-regulates	0.2	Slk down-regulation by v-src is indirect and is accompanied by slk hyperphosphorylation on serine residues. Deletion analysis revealed that casein kinase ii (ck2) sites at position 347/348 are critical for v-src-dependent modulation of slk activity.	SIGNOR-147879
P28482	Q01860	1	phosphorylation	down-regulates	0.38	We demonstrate that oct4a interacts with erk1/2 by using both in vitro gst pulldown and in vivo co-immunoprecipitation assays. Ms analysis identified phosphorylation of oct4a at ser-111. / serine 111 phosphorylation regulates oct4a protein subcellular distribution and degradation.	SIGNOR-192097
Q96F46	P49841	0	phosphorylation	down-regulates quantity by destabilization	0.2	Glycogen synthase kinase 3 (GSK3) constitutively bound to and phosphorylated IL-17RA at T780, leading to ubiquitination and proteasome-mediated degradation of IL-17RA, thus inhibiting IL-17-mediated inflammation.	SIGNOR-277205
O15550	P31273	1	transcriptional regulation	up-regulates quantity by expression	0.307	Evidence for direct involvement of UTX in regulation of HOX gene activity was demonstrated through UTX knockdown experiments in HEK293T cells in which loss of UTX induced transcriptional repression of HOXA and HOXC clusters.	SIGNOR-260029
P10915	P08254	0	cleavage	down-regulates quantity by destabilization	0.384	Matrix metalloproteinases cleave at two distinct sites on human cartilage link protein. Sequencing studies of modified link protein components revealed that stromelysins-1 and -2, gelatinases A and B and collagenase cleaved specifically between His16 and Ile17, and matrilysin, stromelysin-2 and gelatinase A cleaved between Leu25 and Leu26. Based on previously determined in situ cleavage sites it is evident that matrix metalloproteinases are not solely responsible for the accumulation of link protein degradation products in adult human cartilage, indicating that additional proteolytic agents are involved in the normal catabolism of human cartilage matrix.	SIGNOR-256330
Q9NQB0	Q9UBE8	0	phosphorylation	down-regulates quantity	0.772	NLK Augments the Ubiquitylation Activity of NARF against TCF/LEF. ctivation of NLK induced by unknown ligands leads to the phosphorylation of TCF/LEF. NARF then acts on TCF/LEF as an E3 ubiquitin-ligase and, together with E1 and E2 ubiquitylation enzymes, catalyze the ubiquitylation of TCF/LEF. Finally, ubiquitylated TCF/LEF is degraded by the 26 S proteasome.	SIGNOR-271597
P12931	P01112	1	phosphorylation	down-regulates activity	0.775	Src binds to and phosphorylates GTP-, but not GDP-, loaded Ras on a conserved Y32 residue within the switch I region in vitro and that in vivo, Ras-Y32 phosphorylation markedly reduces the binding to effector Raf and concomitantly increases binding to GTPase-activating proteins and the rate of GTP hydrolysis	SIGNOR-252093
P49841	P42338	0	phosphorylation	down-regulates activity	0.48	In our cultures, both p110alpha and p110beta phosphorylated GSK-3beta at Ser9 confirming previous data.\|Whereas p110alpha reduced the protein levels of the CDK2-inhibitor p27 Kip1, p110beta phosphorylated and inactivated GSK-3beta.	SIGNOR-279089
Q5S007	O95295	1	phosphorylation	down-regulates	0.514	Lrrk2 phosphorylates snapin and inhibits interaction of snapin with snap-25. these data suggest that lrrk2 may regulate neurotransmitter release via control of snapin function by inhibitory phosphorylation. hreonine 117 of snapin is one of the sites phosphorylated by lrrk2	SIGNOR-202436
P53671	Q05655	0	phosphorylation	down-regulates	0.256	Activation of pkc by phorbol ester treatment of endothelial cells stimulated limk2 phosphorylation at ser-283 and inhibited nuclear import of limk2	SIGNOR-137927
P24941	P62136	1	phosphorylation	down-regulates activity	0.377	Both of these pp1 isoforms contain an arg-pro-ile/val-thr-pro-pro-arg sequence near the c terminus, a known site of phosphorylation by cdc/cdk kinases, and phosphorylation attenuates phosphatase activity	SIGNOR-92265
Q9Y4P1	Q9BXW4	1	cleavage	up-regulates activity	0.757	Human atg4 homologues cleave the carboxyl termini of the three human atg8 homologues, microtubule-associated protein light chain 3 (lc3), gabarap, and gate-16.	SIGNOR-125489
Q01860	P31751	0	phosphorylation	up-regulates quantity by stabilization	0.255	Here we show that in ECCs, Akt phosphorylated the master pluripotency factor Oct4 at threonine 235, and that the levels of phosphorylated Oct4 in ECCs correlated with resistance to apoptosis and tumorigenic potential. Phosphorylation of Oct4 increased its stability and facilitated its nuclear localization and its interaction with Sox2, which promoted the transcription of the core stemness genes POU5F1 and NANOG.	SIGNOR-242097
O60674	P05107	1	phosphorylation	up-regulates activity	0.265	PTKs of the JAK and SRC families have a regulatory role in LFA-1 affinity triggering, with JAKs showing a positive role (3), whereas SRCs possibly have a negative role.	SIGNOR-254738
O60729	Q93008	1	dephosphorylation	down-regulates quantity by destabilization	0.2	Here, we find that CDC14B antagonizes CDK1-mediated activating mitotic phosphorylation of the deubiquitinase USP9X at serine residue 2563, which we show to be essential for USP9X to mediate mitotic survival. Starting from an unbiased proteome-wide screening approach, we specify Wilms' tumor protein 1 (WT1) as the relevant substrate that becomes deubiquitylated and stabilized by serine 2563-phosphorylated USP9X in mitosis.	SIGNOR-275613
P45983	P31749	1	phosphorylation	up-regulates activity	0.427	We report that JNKs are necessary for the reactivation of Akt after ischemic injury. We identified Thr450 of Akt as a residue that is phosphorylated by JNKs, and the phosphorylation status of Thr450 regulates reactivation of Akt after hypoxia, apparently by priming Akt for subsequent phosphorylation by 3-phosphoinositide-dependent protein kinase.	SIGNOR-252426
Q13621	Q9BYP7	0	phosphorylation	up-regulates activity	0.498	We have shown that with-no-lysine kinase 3 (WNK3) possesses several properties that suggest it could be the Cl−/volume-sensitive regulatory kinase that, in association with protein phosphatases, reciprocally modifies the phosphorylation/dephosphorylation states of the SLC12 proteins and thus their activities\|WNK3 activates NKCC1/2 and NCC and inhibits the KCCs	SIGNOR-264626
P03372	P31749	0	phosphorylation	up-regulates	0.765	Studies using mutants of er-alpha demonstrated that akt increased estrogen receptor activity through the amino-terminal activation function-1 (af-1). Serines s104 s106, s118, and s167 appear to play a role in the activation of er-alpha by akt.	SIGNOR-84963
P01213	P35372	1	chemical activation	up-regulates activity	0.674	Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors.	SIGNOR-258414
P24941	P55273	1	phosphorylation	up-regulates	0.526	Cdk2 and pka were found to participate in p19ink4d phosphorylation process and that they would mediate serine 76 and threonine 141 modifications respectively. Nuclear translocation of p19ink4d induced by dna damage was shown to be dependent on serine 76 phosphorylation.	SIGNOR-197270
P63000	Q8WZ64	0	gtpase-activating protein	down-regulates activity	0.463	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-260454
Q5VT25	P24844	1	phosphorylation	up-regulates	0.516	More than a dozen kinases have been reported to phosphorylate the rlcs of nm ii (fig. 2), including myosin light chain kinase (mlck;also known as mylk), rho-associated, coiled coil-containing kinase (rock), citron kinase, leucine zipper interacting kinase (zipk;also known as dapk3) and myotonic dystrophy kinase-related cdc42-binding kinase (mrck;also known as cdc42bp)6,34,45,46. These kinases phosphorylate rlcs on ser19, thr18 or both, to relieve the inhibition imposed on the myosin molecule by unphosphorylated rlcs and the head_head interaction outlined above.	SIGNOR-188781
P31751	Q92900	1	phosphorylation	up-regulates activity	0.2	AKT-Mediated UPF1 Phosphorylation at T151 Promotes UPF1 Helicase Activity	SIGNOR-277595
Q14493	Q8IUE6	1	translation regulation	up-regulates quantity by expression	0.2	Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA\|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control.	SIGNOR-265406
Q2TAL8	O95363	1	transcriptional regulation	up-regulates quantity by expression	0.2	QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress.	SIGNOR-269403
P18084	O96013	0	phosphorylation	up-regulates	0.451	Pak4 specifically phosphorylated the integrin beta5 subunit at ser-759 and ser-762 within the beta5-sers-motif. Point mutation of these two serine residues abolished the pak4-induced cell migration, indicating a functional role for these phosphorylations in migration.	SIGNOR-165702
P50552	P54646	0	phosphorylation	down-regulates	0.2	Pharmacological ampk inhibitors and activators and ampk mutants revealed that the kinase specifically targets residue thr-278 but not ser-157 or ser-239. Quantitative fluorescence-activated cell sorter analysis and serum response factor transcriptional reporter assays, which quantify the cellular f-/g-actin equilibrium, indicated that ampk-mediated vasp phosphorylation impaired actin stress fiber formation and altered cell morphology.	SIGNOR-150462
P67870	Q13422	1	phosphorylation	down-regulates	0.2	We identified four novelikarosphosphorylation sites that are phosphorylated by ck2 kinase. / ck2-mediated phosphorylation inhibits ikaros' localization to pc-hc / hyperphosphorylation of ikaros promotes its degradation by the ubiquitin/proteasome pathway	SIGNOR-174844
P49841	P10415	1	phosphorylation	down-regulates quantity by destabilization	0.2	A previous study has demonstrated that GSK3B triggers the degradation of BCL2 by inducing phosphorylation of BCL2 at Ser70, which induced autophagy by interrupting the interaction between BECN1 and BCL2 [32].	SIGNOR-279784
P05129	P07900	1	phosphorylation	down-regulates	0.258	Threonine residue set, thr(115)/thr(425)/thr(603), of hsp90_ is specifically phosphorylated by pkc_phosphorylation of hsp90_ by pkc_ decreases the binding affinity of hsp90_ towards atp and co-chaperones such as cdc37 (cell-division cycle 37), thereby decreasing its chaperone activity.	SIGNOR-202812
P08294	Q04656	0	null	up-regulates activity	0.696	Copper transporter ATP7A (copper-transporting/ATPase) is required for full activation of SOD3 (extracellular superoxide dismutase), which is secreted from vascular smooth muscle cells (VSMCs) and anchors to endothelial cell surface to preserve endothelial function by scavenging extracellular superoxide.	SIGNOR-272267
P21333	Q9Y2H1	0	phosphorylation	up-regulates activity	0.2	Activated Ndr2 Promotes FLNa Release From LFA-1.\|Taken together the data depicted in Figures xref and xref indicate that Ndr2 phosphorylates FLNa at S2152 both in vitro and in vivo .	SIGNOR-278501
O14920	O75688	0	dephosphorylation	down-regulates activity	0.404	PPM1A and PPM1B act as IKKbeta phosphatases to terminate TNFalpha-induced IKKbeta-NF-kappaB activation\|Overexpression of PPM1A or PPM1B results in dephosphorylation of IKKbeta at Ser177 and Ser181 and termination of IKKbeta-induced NF-kappaB activation.	SIGNOR-248343
Q8WVD3	O75771	1	ubiquitination	down-regulates quantity by destabilization	0.39	RNF138 dependent ubiquitination of RAD51D and proteasome mediated degradation.	SIGNOR-278775
Q9H074	O00308	0	ubiquitination	down-regulates quantity by destabilization	0.332	Here, we show that the E6AP carboxyl terminus (HECT)-type ubiquitin ligase WW domain-containing protein 2 (WWP2), a homolog of the HECT-type ubiquitin ligase WWP1, interacts with and targets Paip1 for ubiquitination and proteasomal degradation.	SIGNOR-272842
Q13188	Q9Y243	0	phosphorylation	down-regulates	0.271	Akt phosphorylates mst2 at thr117 in vitro and in vivo, which leads to mst2 cleavage and kinase activity as well as nuclear translocation.	SIGNOR-164306
P10070	Q9UMX1	0	relocalization	down-regulates activity	0.909	We demonstrate here that Su(fu) prevents the nuclear accumulation of Gli1 and Gli2 through multiple mechanisms	SIGNOR-129065
P45984	P15336	1	phosphorylation	up-regulates	0.698	Phosphorylation of thr-69 by mapk14 and mapk11, and at thr-71 by mapk1/erk2, mapk3/erk1, mapk11, mapk12 and mapk14 in response to external stimulus like insulin causes increased transcriptional activity.	SIGNOR-163266
Q9UHP3	Q86Y07	0	phosphorylation	down-regulates activity	0.294	Here, we report that USP25 is a novel TRiC interacting protein that is also phosphorylated by VRK2. USP25 catalyzed deubiquitination of the TRiC protein and stabilized the chaperonin, thereby reducing accumulation of misfolded polyglutamine protein aggregates. Notably, USP25 deubiquitinating activity was suppressed when VRK2 phosphorylated the Thr(680), Thr(727), and Ser(745) residues.	SIGNOR-273579
P42345	O60516	1	phosphorylation	up-regulates	0.358	While promoting initiation of protein translation through mtor, eukaryoticinitiation factor 4e, and the ribosomal p70-s6 kinase.	SIGNOR-122035
P06493	Q53EZ4	1	phosphorylation	down-regulates	0.45	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-140882
P10275	Q9Y618	0	acetylation	down-regulates	0.562	In this study we assessed the effect of smrt and dax-1 on ar and pr activity in the presence of both agonists and partial antagonists. We show that smrt and dax-1 repress agonist-dependent activity of both receptors, and the mechanism of repression includes disruption of the receptor dimer interactions rather than recruitment of histone deacetylases.	SIGNOR-101286
P09601	O14867	0	transcriptional regulation	down-regulates quantity	0.361	These results indicate that ho-1 regulation involves a competition between the activator Nrf2 and the Bach1 repressor for interactions with the small Maf proteins.	SIGNOR-259336
P04839	P23769	0	transcriptional regulation	down-regulates quantity	0.25	These results suggest that GATA-1 is an activator and that GATA-2 is a relative competitive inhibitor of GATA-1 in the expression of the gp91(phox) gene in human eosinophils.	SIGNOR-259948
Q04760	P35916	0	phosphorylation	up-regulates activity	0.2	We show that Glo1 activity is promoted by phosphorylation on Tyrosine 136 via multiple kinases. Glo1 Y136 is phosphorylated by multiple different kinases including all members of the Src family. Depletion of multiple different kinases led to a partial reduction in Glo1(Y136) phosphorylation. These included members of the Src family (Src, Yes1, FGR, and the related Abl1), and of the FAK, EPHA, FGFR, and VEGFR families (Figure 2B), suggesting phosphorylation of Glo1 on Y136 by multiple different kinases. In vitro kinase assays revealed that all the members of the Src family, as well as Epha5 and VEGFR3, can efficiently phosphorylate recombinant Glo1 on Y136 (Figure 2C–D).	SIGNOR-276180
P14735	P01308	1	cleavage	down-regulates quantity by destabilization	0.719	IDE processively degrades insulin by stochastically cutting either chain without breaking disulfide bonds	SIGNOR-260986
P35670	Q15139	0	phosphorylation	up-regulates activity	0.296	ATP7B trafficking was markedly reduced by the Ser-478/481/1121/1453 to Ala mutation. We conclude that PKD plays a key role in copper-dependent serine phosphorylation, permitting high levels of ATP7B protein expression and trafficking.	SIGNOR-272295
Q9UHF7	P43026	0	relocalization	up-regulates activity	0.306	Treatment of cells with Gdf5 enhanced Trps1 protein levels and phosphorylation of p38 mitogen-activated protein kinase (MAPK) in a dose-dependent manner. Nuclear translocation of Trps1 was also induced by Gdf5. These effects were blocked by a dominant negative form of activin-linked kinase 6 (dn-Alk6) and by SB203580, an inhibitor of the p38 MAPK pathway. Conversely, Gdf5 expression was suppressed by the over-expression of Trps1.	SIGNOR-251867
P17252	O15350	1	phosphorylation	up-regulates activity	0.2	Here, we report that p73 is able to induce cell cycle arrest independently of its amino-terminal transactivation domain, whereas this domain is crucial for p73 proapoptotic functions. its activity is regulated throughout the cell cycle and modified by protein kinase C-dependent phosphorylation at serine residue 388.	SIGNOR-276235
P20042	Q9UI10	0	guanine nucleotide exchange factor	up-regulates activity	0.754	EIF2B converts the protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex owing to its guanine nucleotide exchange factor (GEF) activity.	SIGNOR-269132
P24941	Q03112	1	phosphorylation	up-regulates activity	0.296	The motif harbouring S436 is a target of CDK2 and CDK3 kinases, which interacted with EVI1-WT. The methyltransferase DNMT3A bound preferentially to EVI1-WT compared with EVI1-S436A, and a hypomethylated cell population associated by EVI1-WT expression in murine haematopoietic progenitors is not maintained with EVI1-S436A.	SIGNOR-273426
P10912	P43378	0	dephosphorylation	down-regulates activity	0.314	Protein tyrosine phosphatases (PTPs) play key roles in switching off tyrosine phosphorylation cascades, such as initiated by cytokine receptors. We have used substrate-trapping mutants of a large set of PTPs to identify members of the PTP family that have substrate specificity for the phosphorylated human GH receptor (GHR) intracellular domain. Among 31 PTPs tested, T cell (TC)-PTP, PTP-beta, PTP1B, stomach cancer-associated PTP 1 (SAP-1), Pyst-2, Meg-2, and PTP-H1 showed specificity for phosphorylated GHR	SIGNOR-248505
Q9UBS0	Q53EL6	1	phosphorylation	down-regulates	0.438	Both akt and p70(s6k) phosphorylate pdcd4, allowing for binding of the e3-ubiquitin ligase beta-trcp and consequently ubiquitylation.	SIGNOR-160992
Q8IUQ4	Q9Y6H5	1	ubiquitination	down-regulates	0.676	Siah proteins ubiquitylate synphilin-1 and promote its degradation through the ubiquitin proteasome system	SIGNOR-140612
Q15084	Q9NZJ5	1	null	down-regulates activity	0.2	Protein disulfide isomerase A6 (PDIA6) interacts with protein kinase RNA-like endoplasmic reticulum kinase (PERK) and inositol requiring enzyme (IRE)-1 and inhibits their unfolded protein response signaling.	SIGNOR-256537
P11309	P46527	1	phosphorylation	down-regulates activity	0.382	We show, herein, that all the pim family members (pim1, pim2, and pim3) bind to and directly phosphorylate the cyclin-dependent kinase inhibitor p27(kip1) at threonine-157 and threonine-198 residues in cells and in vitro.\|Pim kinases promote cell cycle progression and tumorigenesis by down-regulating p27(Kip1) expression at both transcriptional and posttranslational levels.	SIGNOR-179300
Q9BZL6	Q8WYL5	1	phosphorylation	down-regulates	0.291	Phosphorylation of ser 402 impedes phosphatase activity of slingshot 1.	SIGNOR-173441
O15264	P16949	1	phosphorylation	down-regulates	0.414	Serine 25 of oncoprotein 18 is a major cytosolic target for the mitogen-activated protein kinase.	SIGNOR-36362
Q5T6F2	P07355	1	ubiquitination	down-regulates quantity	0.341	UBAP2 formed a complex with Annexin A2 and promoted the degradation of Annexin A2 protein by ubiquitination	SIGNOR-261314
P01106	P11274	1	transcriptional regulation	up-regulates quantity by expression	0.362	In the present study we demonstrate that MYC and its partner MAX bind to the BCR promoter, leading to up-regulation of BCR and BCR/ABL1 at both transcriptional and protein levels.\|Here we describe a regulatory pathway modulating BCR and BCR/ABL1 expression, showing that the BCR promoter is under the transcriptional control of the MYC/MAX heterodimer.	SIGNOR-272144
P37840	Q9NYY3	0	phosphorylation	down-regulates activity	0.478	Polo-like kinase 2 (plk2) phosphorylates alpha-synuclein at serine 129 in central nervous system. The membrane association of pd-linked mutant alpha -synuclein, but not wild-type -synuclein, was increased by serine 129 phosphorylation. Pathological serine 129 phosphorylation regulates membrane accumulation of mutant alpha-synuclein.	SIGNOR-182155
P52907	P68400	0	phosphorylation	up-regulates	0.2	We demonstrate that ser9 of cpalpha is phosphorylated by protein kinase ck2 in vitro, that cpalpha is phosphorylated in vivo. Finally, we demonstrate that ckip-1 and ck2 inhibit the activity of actin capping protein at the barbed ends of actin filaments.	SIGNOR-135422
P17612	P33076	1	phosphorylation	down-regulates activity	0.309	Downregulation of ciita function by protein kinase a (pka)-mediated phosphorylation phosphorylation at ciita serines 834 and 1050 accounts for the inhibitory effects of pka on ciita-driven class ii mhc transcription.	SIGNOR-108569
P19484	P28482	0	phosphorylation	down-regulates activity	0.413	Evidence for ERK2-mediated TFEB phosphorylation came from ERK2-TFEB coimmuno-precipitation (fig. S12C) in normal but not in starved medium and from a peptide-based kinase assay showing that mutation of Ser142 to alanine abolished ERK2-mediated phosphorylation (	SIGNOR-248279
Q96PU5	P51795	1	ubiquitination	down-regulates quantity by destabilization	0.292	The presence of albumin triggers the formation of an endocytic complex that includes ClC-5. (iii) Nedd4-2 is recruited to this complex and ubiquitinates ClC-5. This ubiquitination by Nedd4-2 shunts ClC-5 into the albumin uptake/degradative pathway.	SIGNOR-272665
P12644	Q04206	0	transcriptional regulation	down-regulates quantity by repression	0.2	Co-transfection with pCMV4-RelA alone or in combination with pCMV4p50 repressed pSLA4.1 EX-Lux activity by approximately 75 percent in both H441 and A549 cells	SIGNOR-266087
P17252	P09651	1	phosphorylation	down-regulates	0.2	A survey of seven protein kinases showed that a1 was heavily phosphorylated by protein kinase c (pkc) and also was phosphorylated by casein kinase iiamino acid sequencing revealed that these sites were ser95, ser192, and ser199;phosphorylation at ser192 was more abundant than at ser95 and ser199. Phosphorylation by pkc inhibited the strand annealing activity of a1.	SIGNOR-32291
Q9UHD2	Q04864	1	phosphorylation	up-regulates	0.579	The present results demonstrate that ikkepsilon- and tbk1-mediated phosphorylation of crel in the c-terminal td leads to cytoplasmic dissociation of a crel-ikb_ complex and nuclear accumulation of crel.	SIGNOR-148623
Q9Y2H0	Q9UPX8	1	relocalization	up-regulates activity	0.744	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-264596
P29474	P12931	0	phosphorylation	up-regulates activity	0.42	Two kinases, i.e. abelson-tyrosine protein kinase (ABL)1 and Src were identified as eNOS Tyr81 kinases as their inhibition and down-regulation significantly reduced the basal and Yoda1-induced tyrosine phosphorylation and activity of eNOS.	SIGNOR-277520
P51813	P12931	0	phosphorylation	up-regulates	0.535	Coexpression of v-src and etk led to a transphosphorylation on tyrosine 566 of etk and subsequent autophosphorylation. These events correlated with a substantial increase in the kinase activity of etk.	SIGNOR-75330
P36873	P42575	1	dephosphorylation	up-regulates activity	0.2	nutrient-replete oocytes inhibit C2 via S135 phosphorylation catalyzed by calcium/calmodulin-dependent protein kinase II. We now show that C2 phosphorylated at S135 binds 14-3-3zeta, thus preventing C2 dephosphorylation. Moreover, we determined that S135 dephosphorylation is catalyzed by protein phosphatase-1 (PP1), which directly binds C2.	SIGNOR-248503
P31269	Q8NFU7	0	transcriptional regulation	up-regulates quantity by expression	0.306	Furthermore, TET1 catalytic domain possessed demethylase activity in cancer cells, being able to inhibit the CpG methylation of tumor suppressor gene (TSG) promoters and reactivate their expression, such as SLIT2, ZNF382 and HOXA9.	SIGNOR-259094
P41968	Q5JWF2	1	null	up-regulates activity	0.547	We hypothesize that XLŒ±s may be involved in this regulatory loop by coupling to melanocortin receptors 3 and 4 in the hypothalamus.	SIGNOR-253068
O43148	P06493	0	phosphorylation	up-regulates activity	0.255	We report that CDK1-cyclin B1 phosphorylates the RNMT regulatory domain on T77 during G2/M phase of the cell cycle. RNMT T77 phosphorylation activates the enzyme both directly and indirectly by inhibiting interaction with KPNA2, an RNMT inhibitor.	SIGNOR-265501
A6NI28	Q05397	0	phosphorylation	up-regulates activity	0.309	FAK and Src Mediated Phosphorylation of GRAF3 at Y376 Promotes Allosteric Activation.	SIGNOR-280097
P11309	P30307	1	phosphorylation	up-regulates activity	0.348	First, Pim-1 activates the Cdc25C phosphatase directly through phosphorylation, very probably at the N-terminal part of the protein.\|We find that phosphorylation by Pim-1 enhances the phosphatase activity of Cdc25C and in transfected cells that are arrested in G2/M by bleomycin, Pim-1 can enhance progression into G1.	SIGNOR-278298
Q7L5N1	P31749	0	phosphorylation	up-regulates	0.282	Mechanistic studies show that akt causes csn6 phosphorylation at ser 60, which, in turn, reduces ubiquitin-mediated protein degradation of csn6.	SIGNOR-252532
O60674	Q92888	1	phosphorylation	up-regulates	0.325	We found that angiotensin ii activates arhgef1 through a previously undescribed mechanism in which jak2 phosphorylates tyr738 of arhgef1	SIGNOR-163557
P62993	P22681	1	relocalization	up-regulates	0.904	The underlying mechanism seems to involve recruitment of a grb2 c-cbl complex to grb2-specific docking sites of egfr, and concurrent acceleration of receptor ubiquitylation and desensitization.	SIGNOR-114704
P46821	Q13618	0	ubiquitination	down-regulates quantity	0.254	Gigaxonin is the substrate-specific adaptor for a new Cul3-E3-ubiquitin ligase family that promotes the proteasome dependent degradation of its partners MAP1B, MAP8 and tubulin cofactor B.	SIGNOR-268946
P45983	P30307	1	phosphorylation	down-regulates	0.411	Here we show that jnk directly phosphorylates cdc25c at serine 168 during g(2) phase of the cell cycle. Cdc25c phosphorylation by jnk negatively regulates its phosphatase activity and thereby cdk1 activation, enabling a timely control of mitosis onset.	SIGNOR-164089
P49137	P04792	1	phosphorylation	down-regulates	0.809	Notably mk2 is well known to play an important role in actin filament remodellng by phosphorylating hsp27.	SIGNOR-94021
Q15418	Q8TB45	1	phosphorylation	down-regulates	0.492	We found that deptor was rapidly phosphorylated on three serines in a conserved degron, facilitating binding and ubiquitylation by the f box protein _trcp, with consequent proteasomal degradation of deptor. Phosphorylation of the _trcp degron in deptor is executed by ck1	SIGNOR-176883
P49841	O95997	1	phosphorylation	down-regulates activity	0.2	Glycogen synthase kinase-3beta (GSK3beta) negatively regulates PTTG1 and human securin protein stability, and GSK3beta inactivation correlates with securin accumulation in breast tumors.\|Here, we demonstrate that glycogen synthase kinase-3\u03b2 (GSK3\u03b2) phosphorylates securin to promote its proteolysis via SCF(\u03b2TrCP) E3 ubiquitin ligase.	SIGNOR-279188
Q15389	Q03112	0	transcriptional regulation	up-regulates quantity by expression	0.2	We finally observed that the forced expression of Evi1 induced GATA-2 expression in a hematopoietic cell line, EML C1, along with GATA-1, Ang-1, Ang-2 and Tie2	SIGNOR-266059
Q13535	P00519	0	phosphorylation	up-regulates	0.599	C-abl can phosphorylate atr on y291 and y310 and this phosphorylation appears to have a positive role in atr activation under genotoxic stress.	SIGNOR-167632
Q5JVL4	Q92949	0	transcriptional regulation	up-regulates quantity by expression	0.356	FOXJ1 expression in basal cells induced the expression of a panel of cilia-associated genes, including centrin 2 (CETN2); dynein, axonemal, heavy chain 11 (DNAH11); dynein, axonemal, intermediate chain 1 (DNAI1); dynein, axonemal, light intermediate chain 1 (DNALI1); EF-hand domain, C-terminal, containing 1 (EFHC1); sperm associated antigen 6 (SPAG6); tektin 1 (TEKT1), TEKT2 and tubulin, alpha 1a (TUBA1A; Figure 3C and Additional file 2: Table S1).	SIGNOR-266934
O43524	Q13043	0	phosphorylation	up-regulates	0.681	Bonni and coworkers demonstrated that mst1 can phosphorylate foxo3 (and subsequently, foxo1) principally ser207 (ser212 in foxo1), a conserved site in the forkhead domain. This phosphorylation interdicts 14-3-3 binding, promotes foxo nuclear residence and transcriptional activity.	SIGNOR-178190
P38936	Q99683	0	phosphorylation	up-regulates	0.589	P21cip1 is phosphorylated in vitro by both ask1 and jnk1 at s98. /phosphorylation of p21cip1 at s98, which in vivo appears to be regulated by ask1, may therefore mediate negative feedback in the ask1 signaling pathway.	SIGNOR-153440
Q13233	Q8IVH8	0	phosphorylation	up-regulates	0.453	With regard to at least mekk1, serine/threonine kinases such as nik,glkand hpk1 appear also to be important for regulation	SIGNOR-61814
O43542	Q13535	0	phosphorylation	up-regulates activity	0.464	HXRCC3 S225 phosphorylation is mediated by ATR via an ATM-dependent signaling pathway. These data clearly indicate that ATR mediates the late activation of XRCC3 following DSB accumulation.	SIGNOR-262666
P49841	O00159	1	phosphorylation	up-regulates activity	0.2	Here, we report that at early G1 the glycogen synthase kinase 3\u03b2 phosphorylates and stabilizes Nuclear myosin 1c, allowing for Nuclear myosin 1c association with the chromatin.	SIGNOR-279184
P31751	Q13835	1	phosphorylation	up-regulates quantity by stabilization	0.267	Akt2 phosphorylates PKP1 in vitro. Phosphorylated PKP1 is more resistant to degradation. PKP1 phosphorylation sites identified by peptide microarray analyses and mass spectrometry.	SIGNOR-273494
Q13489	Q7Z570	0	transcriptional regulation	down-regulates quantity by repression	0.2	ZNF804A has been implicated in susceptibility to schizophrenia by several genome-wide association studies (GWAS), follow-up association studies and meta-analyses. ZNF804A was identified as a schizophrenia-associated gene by GWAS and was predicted to play a role in DNA binding and transcription To identify the genes that are affected by ZNF804A, we manipulated the expression of the ZNF804A protein in HEK293 human embryonic kidney cell lines and performed a cDNA microarray analysis followed by qPCR. We found that ZNF804A-overexpression up-regulated four genes (ANKRD1, INHBE, PIK3AP1, and DDIT3) and down-regulated three genes (CLIC2, MGAM, and BIRC3).	SIGNOR-269467
Q9UQM7	P35367	1	phosphorylation	down-regulates	0.282	As we have shown previously, human h1r can be phosphorylated in vitro by several kinases includingpka, pkc, pkg, and camk ii in summary, these data suggest that thr140, thr142, ser396, ser398, and thr478 can be phosphorylated by the kinases described above (table 2).	SIGNOR-124348
Q15831	Q9Y2K2	1	phosphorylation	up-regulates	0.488	Lkb1 is a master kinase that activates 13 kinases of the ampk subfamily, including mark/par-1we recently demonstrated that the lkb1 tumour suppressor kinase, in complex with the pseudokinase strad and the scaffolding protein mo25, phosphorylates and activates amp-activated protein kinase (ampk). A total of 12 human kinases (nuak1, nuak2, brsk1, brsk2, qik, qsk, sik, mark1, mark2, mark3, mark4 and melk) are related to ampk. Here we demonstrate that lkb1 can phosphorylate the t-loop of all the members of this subfamily, apart from melk, increasing their activity >50-fold	SIGNOR-122835
P53350	Q8NFH5	1	phosphorylation	down-regulates activity	0.415	Collectively, these data show that mitotic hyperphosphorylation of Nup53 by CDK1 and PLK1 contributes to its removal from NPCs.\|The combined mutation of the CDK1 and PLK1 sites to phosphomimetic residues almost completely abolished NPC integration of Nup53, indicating that hyperphosphorylation of Nup53 might be incompatible with its NPC association.	SIGNOR-279252
P01189-PRO_0000024969	P16519	0	cleavage	up-regulates quantity	0.2	POMC is post-translationally cleaved by prohormone convertase enzymes 1 and 2 (PC1, PC2) into ACTH, an N-terminal glycopeptide	SIGNOR-268725
Q13049	Q86U86	1	ubiquitination	down-regulates quantity by destabilization	0.2	TRIM32 ubiquitination of PB1 leads to its protein degradation.	SIGNOR-278735

Q9H2G2

P68400

0

phosphorylation

down-regulates

0.2

Slk down-regulation by v-src is indirect and is accompanied by slk hyperphosphorylation on serine residues. Deletion analysis revealed that casein kinase ii (ck2) sites at position 347/348 are critical for v-src-dependent modulation of slk activity.

SIGNOR-147879

P28482

Q01860

1

phosphorylation

down-regulates

0.38

We demonstrate that oct4a interacts with erk1/2 by using both in vitro gst pulldown and in vivo co-immunoprecipitation assays. Ms analysis identified phosphorylation of oct4a at ser-111. / serine 111 phosphorylation regulates oct4a protein subcellular distribution and degradation.

SIGNOR-192097

Q96F46

P49841

0

phosphorylation

down-regulates quantity by destabilization

0.2

Glycogen synthase kinase 3 (GSK3) constitutively bound to and phosphorylated IL-17RA at T780, leading to ubiquitination and proteasome-mediated degradation of IL-17RA, thus inhibiting IL-17-mediated inflammation.

SIGNOR-277205

O15550

P31273

1

transcriptional regulation

up-regulates quantity by expression

0.307

Evidence for direct involvement of UTX in regulation of HOX gene activity was demonstrated through UTX knockdown experiments in HEK293T cells in which loss of UTX induced transcriptional repression of HOXA and HOXC clusters.

SIGNOR-260029

P10915

P08254

0

cleavage

down-regulates quantity by destabilization

0.384

Matrix metalloproteinases cleave at two distinct sites on human cartilage link protein. Sequencing studies of modified link protein components revealed that stromelysins-1 and -2, gelatinases A and B and collagenase cleaved specifically between His16 and Ile17, and matrilysin, stromelysin-2 and gelatinase A cleaved between Leu25 and Leu26. Based on previously determined in situ cleavage sites it is evident that matrix metalloproteinases are not solely responsible for the accumulation of link protein degradation products in adult human cartilage, indicating that additional proteolytic agents are involved in the normal catabolism of human cartilage matrix.

SIGNOR-256330

Q9NQB0

Q9UBE8

0

phosphorylation

down-regulates quantity

0.772

NLK Augments the Ubiquitylation Activity of NARF against TCF/LEF. ctivation of NLK induced by unknown ligands leads to the phosphorylation of TCF/LEF. NARF then acts on TCF/LEF as an E3 ubiquitin-ligase and, together with E1 and E2 ubiquitylation enzymes, catalyze the ubiquitylation of TCF/LEF. Finally, ubiquitylated TCF/LEF is degraded by the 26 S proteasome.

SIGNOR-271597

P12931

P01112

1

phosphorylation

down-regulates activity

0.775

Src binds to and phosphorylates GTP-, but not GDP-, loaded Ras on a conserved Y32 residue within the switch I region in vitro and that in vivo, Ras-Y32 phosphorylation markedly reduces the binding to effector Raf and concomitantly increases binding to GTPase-activating proteins and the rate of GTP hydrolysis

SIGNOR-252093

P49841

P42338

0

phosphorylation

down-regulates activity

0.48

In our cultures, both p110alpha and p110beta phosphorylated GSK-3beta at Ser9 confirming previous data.|Whereas p110alpha reduced the protein levels of the CDK2-inhibitor p27 Kip1, p110beta phosphorylated and inactivated GSK-3beta.

SIGNOR-279089

Q5S007

O95295

1

phosphorylation

down-regulates

0.514

Lrrk2 phosphorylates snapin and inhibits interaction of snapin with snap-25. these data suggest that lrrk2 may regulate neurotransmitter release via control of snapin function by inhibitory phosphorylation. hreonine 117 of snapin is one of the sites phosphorylated by lrrk2

SIGNOR-202436

P53671

Q05655

0

phosphorylation

down-regulates

0.256

Activation of pkc by phorbol ester treatment of endothelial cells stimulated limk2 phosphorylation at ser-283 and inhibited nuclear import of limk2

SIGNOR-137927

P24941

P62136

1

phosphorylation

down-regulates activity

0.377

Both of these pp1 isoforms contain an arg-pro-ile/val-thr-pro-pro-arg sequence near the c terminus, a known site of phosphorylation by cdc/cdk kinases, and phosphorylation attenuates phosphatase activity

SIGNOR-92265

Q9Y4P1

Q9BXW4

1

cleavage

up-regulates activity

0.757

Human atg4 homologues cleave the carboxyl termini of the three human atg8 homologues, microtubule-associated protein light chain 3 (lc3), gabarap, and gate-16.

SIGNOR-125489

Q01860

P31751

0

phosphorylation

up-regulates quantity by stabilization

0.255

Here we show that in ECCs, Akt phosphorylated the master pluripotency factor Oct4 at threonine 235, and that the levels of phosphorylated Oct4 in ECCs correlated with resistance to apoptosis and tumorigenic potential. Phosphorylation of Oct4 increased its stability and facilitated its nuclear localization and its interaction with Sox2, which promoted the transcription of the core stemness genes POU5F1 and NANOG.

SIGNOR-242097

O60674

P05107

1

phosphorylation

up-regulates activity

0.265

PTKs of the JAK and SRC families have a regulatory role in LFA-1 affinity triggering, with JAKs showing a positive role (3), whereas SRCs possibly have a negative role.

SIGNOR-254738

O60729

Q93008

1

dephosphorylation

down-regulates quantity by destabilization

0.2

Here, we find that CDC14B antagonizes CDK1-mediated activating mitotic phosphorylation of the deubiquitinase USP9X at serine residue 2563, which we show to be essential for USP9X to mediate mitotic survival. Starting from an unbiased proteome-wide screening approach, we specify Wilms' tumor protein 1 (WT1) as the relevant substrate that becomes deubiquitylated and stabilized by serine 2563-phosphorylated USP9X in mitosis.

SIGNOR-275613

P45983

P31749

1

phosphorylation

up-regulates activity

0.427

We report that JNKs are necessary for the reactivation of Akt after ischemic injury. We identified Thr450 of Akt as a residue that is phosphorylated by JNKs, and the phosphorylation status of Thr450 regulates reactivation of Akt after hypoxia, apparently by priming Akt for subsequent phosphorylation by 3-phosphoinositide-dependent protein kinase.

SIGNOR-252426

Q13621

Q9BYP7

0

phosphorylation

up-regulates activity

0.498

We have shown that with-no-lysine kinase 3 (WNK3) possesses several properties that suggest it could be the Cl−/volume-sensitive regulatory kinase that, in association with protein phosphatases, reciprocally modifies the phosphorylation/dephosphorylation states of the SLC12 proteins and thus their activities|WNK3 activates NKCC1/2 and NCC and inhibits the KCCs

SIGNOR-264626

P03372

P31749

0

phosphorylation

up-regulates

0.765

Studies using mutants of er-alpha demonstrated that akt increased estrogen receptor activity through the amino-terminal activation function-1 (af-1). Serines s104 s106, s118, and s167 appear to play a role in the activation of er-alpha by akt.

SIGNOR-84963

P01213

P35372

1

chemical activation

up-regulates activity

0.674

Accordingly, for the OTDP, the binding affinity and activity of a large number of opiate compounds have been tested at μ-, δ-, and κ-opiate receptors. Binding studies were originally conducted in guinea pig brain membranes, and subsequent studies have been carried out in CHO cells transfected with human receptors. Table 7 shows a biochemical method for determining activity and potency of opioid compounds, stimulation of [35S]GTPγS binding in membranes from cells transfected with human μ, δ, or κ receptors.

SIGNOR-258414

P24941

P55273

1

phosphorylation

up-regulates

0.526

Cdk2 and pka were found to participate in p19ink4d phosphorylation process and that they would mediate serine 76 and threonine 141 modifications respectively. Nuclear translocation of p19ink4d induced by dna damage was shown to be dependent on serine 76 phosphorylation.

SIGNOR-197270

P63000

Q8WZ64

0

gtpase-activating protein

down-regulates activity

0.463

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-260454

Q5VT25

P24844

1

phosphorylation

up-regulates

0.516

More than a dozen kinases have been reported to phosphorylate the rlcs of nm ii (fig. 2), including myosin light chain kinase (mlck;also known as mylk), rho-associated, coiled coil-containing kinase (rock), citron kinase, leucine zipper interacting kinase (zipk;also known as dapk3) and myotonic dystrophy kinase-related cdc42-binding kinase (mrck;also known as cdc42bp)6,34,45,46. These kinases phosphorylate rlcs on ser19, thr18 or both, to relieve the inhibition imposed on the myosin molecule by unphosphorylated rlcs and the head_head interaction outlined above.

SIGNOR-188781

P31751

Q92900

1

phosphorylation

up-regulates activity

0.2

AKT-Mediated UPF1 Phosphorylation at T151 Promotes UPF1 Helicase Activity

SIGNOR-277595

Q14493

Q8IUE6

1

translation regulation

up-regulates quantity by expression

0.2

Synthesis of mature histone mRNA requires only a single processing reaction: an endonucleolytic cleavage between a conserved stem-loop and a purine-rich downstream element to form the 3' end. The stem-loop binding protein (SLBP) is required for processing, and following processing, histone mRNA is transported to the cytoplasm, where SLBP participates in translation of the histone mRNA|We used radiolabeled probes generated by PCR targeting the open reading frame (ORF) to detect histones H2A, H2B, H3, H4, and H1 and used 7SK snRNA as a loading control (Fig. 2A). The abundance of histone H2A, H2B, H3, and H4 mRNAs is reduced to 37% to 70% of control levels in the SLBP knockdown cells when compared to the C2 control.

SIGNOR-265406

Q2TAL8

O95363

1

transcriptional regulation

up-regulates quantity by expression

0.2

QRICH1 promotes the expression of translation-related genes. our combined ChIP-seq and RNA-seq analyses identified that QRICH1 and ATF4 were enriched at the promoters of these specific tRNA synthetases, and that ER stress positively regulated their transcription (Fig. 4I). Together, these findings suggest that QRICH1 and ATF4 modulate tRNA metabolic processes to promote secreted protein synthesis during ER stress.

SIGNOR-269403

P18084

O96013

0

phosphorylation

up-regulates

0.451

Pak4 specifically phosphorylated the integrin beta5 subunit at ser-759 and ser-762 within the beta5-sers-motif. Point mutation of these two serine residues abolished the pak4-induced cell migration, indicating a functional role for these phosphorylations in migration.

SIGNOR-165702

P50552

P54646

0

phosphorylation

down-regulates

0.2

Pharmacological ampk inhibitors and activators and ampk mutants revealed that the kinase specifically targets residue thr-278 but not ser-157 or ser-239. Quantitative fluorescence-activated cell sorter analysis and serum response factor transcriptional reporter assays, which quantify the cellular f-/g-actin equilibrium, indicated that ampk-mediated vasp phosphorylation impaired actin stress fiber formation and altered cell morphology.

SIGNOR-150462

P67870

Q13422

1

phosphorylation

down-regulates

0.2

We identified four novelikarosphosphorylation sites that are phosphorylated by ck2 kinase. / ck2-mediated phosphorylation inhibits ikaros' localization to pc-hc / hyperphosphorylation of ikaros promotes its degradation by the ubiquitin/proteasome pathway

SIGNOR-174844

P49841

P10415

1

phosphorylation

down-regulates quantity by destabilization

0.2

A previous study has demonstrated that GSK3B triggers the degradation of BCL2 by inducing phosphorylation of BCL2 at Ser70, which induced autophagy by interrupting the interaction between BECN1 and BCL2 [32].

SIGNOR-279784

P05129

P07900

1

phosphorylation

down-regulates

0.258

Threonine residue set, thr(115)/thr(425)/thr(603), of hsp90_ is specifically phosphorylated by pkc_phosphorylation of hsp90_ by pkc_ decreases the binding affinity of hsp90_ towards atp and co-chaperones such as cdc37 (cell-division cycle 37), thereby decreasing its chaperone activity.

SIGNOR-202812

P08294

Q04656

0

null

up-regulates activity

0.696

Copper transporter ATP7A (copper-transporting/ATPase) is required for full activation of SOD3 (extracellular superoxide dismutase), which is secreted from vascular smooth muscle cells (VSMCs) and anchors to endothelial cell surface to preserve endothelial function by scavenging extracellular superoxide.

SIGNOR-272267

P21333

Q9Y2H1

0

phosphorylation

up-regulates activity

0.2

Activated Ndr2 Promotes FLNa Release From LFA-1.|Taken together the data depicted in Figures xref and xref indicate that Ndr2 phosphorylates FLNa at S2152 both in vitro and in vivo .

SIGNOR-278501

O14920

O75688

0

dephosphorylation

down-regulates activity

0.404

PPM1A and PPM1B act as IKKbeta phosphatases to terminate TNFalpha-induced IKKbeta-NF-kappaB activation|Overexpression of PPM1A or PPM1B results in dephosphorylation of IKKbeta at Ser177 and Ser181 and termination of IKKbeta-induced NF-kappaB activation.

SIGNOR-248343

Q8WVD3

O75771

1

ubiquitination

down-regulates quantity by destabilization

0.39

RNF138 dependent ubiquitination of RAD51D and proteasome mediated degradation.

SIGNOR-278775

Q9H074

O00308

0

ubiquitination

down-regulates quantity by destabilization

0.332

Here, we show that the E6AP carboxyl terminus (HECT)-type ubiquitin ligase WW domain-containing protein 2 (WWP2), a homolog of the HECT-type ubiquitin ligase WWP1, interacts with and targets Paip1 for ubiquitination and proteasomal degradation.

SIGNOR-272842

Q13188

Q9Y243

0

phosphorylation

down-regulates

0.271

Akt phosphorylates mst2 at thr117 in vitro and in vivo, which leads to mst2 cleavage and kinase activity as well as nuclear translocation.

SIGNOR-164306

P10070

Q9UMX1

0

relocalization

down-regulates activity

0.909

We demonstrate here that Su(fu) prevents the nuclear accumulation of Gli1 and Gli2 through multiple mechanisms

SIGNOR-129065

P45984

P15336

1

phosphorylation

up-regulates

0.698

Phosphorylation of thr-69 by mapk14 and mapk11, and at thr-71 by mapk1/erk2, mapk3/erk1, mapk11, mapk12 and mapk14 in response to external stimulus like insulin causes increased transcriptional activity.

SIGNOR-163266

Q9UHP3

Q86Y07

0

phosphorylation

down-regulates activity

0.294

Here, we report that USP25 is a novel TRiC interacting protein that is also phosphorylated by VRK2. USP25 catalyzed deubiquitination of the TRiC protein and stabilized the chaperonin, thereby reducing accumulation of misfolded polyglutamine protein aggregates. Notably, USP25 deubiquitinating activity was suppressed when VRK2 phosphorylated the Thr(680), Thr(727), and Ser(745) residues.

SIGNOR-273579

P42345

O60516

1

phosphorylation

up-regulates

0.358

While promoting initiation of protein translation through mtor, eukaryoticinitiation factor 4e, and the ribosomal p70-s6 kinase.

SIGNOR-122035

P06493

Q53EZ4

1

phosphorylation

down-regulates

0.45

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-140882

P10275

Q9Y618

0

acetylation

down-regulates

0.562

In this study we assessed the effect of smrt and dax-1 on ar and pr activity in the presence of both agonists and partial antagonists. We show that smrt and dax-1 repress agonist-dependent activity of both receptors, and the mechanism of repression includes disruption of the receptor dimer interactions rather than recruitment of histone deacetylases.

SIGNOR-101286

P09601

O14867

0

transcriptional regulation

down-regulates quantity

0.361

These results indicate that ho-1 regulation involves a competition between the activator Nrf2 and the Bach1 repressor for interactions with the small Maf proteins.

SIGNOR-259336

P04839

P23769

0

transcriptional regulation

down-regulates quantity

0.25

These results suggest that GATA-1 is an activator and that GATA-2 is a relative competitive inhibitor of GATA-1 in the expression of the gp91(phox) gene in human eosinophils.

SIGNOR-259948

Q04760

P35916

0

phosphorylation

up-regulates activity

0.2

We show that Glo1 activity is promoted by phosphorylation on Tyrosine 136 via multiple kinases. Glo1 Y136 is phosphorylated by multiple different kinases including all members of the Src family. Depletion of multiple different kinases led to a partial reduction in Glo1(Y136) phosphorylation. These included members of the Src family (Src, Yes1, FGR, and the related Abl1), and of the FAK, EPHA, FGFR, and VEGFR families (Figure 2B), suggesting phosphorylation of Glo1 on Y136 by multiple different kinases. In vitro kinase assays revealed that all the members of the Src family, as well as Epha5 and VEGFR3, can efficiently phosphorylate recombinant Glo1 on Y136 (Figure 2C–D).

SIGNOR-276180

P14735

P01308

1

cleavage

down-regulates quantity by destabilization

0.719

IDE processively degrades insulin by stochastically cutting either chain without breaking disulfide bonds

SIGNOR-260986

P35670

Q15139

0

phosphorylation

up-regulates activity

0.296

ATP7B trafficking was markedly reduced by the Ser-478/481/1121/1453 to Ala mutation. We conclude that PKD plays a key role in copper-dependent serine phosphorylation, permitting high levels of ATP7B protein expression and trafficking.

SIGNOR-272295

Q9UHF7

P43026

0

relocalization

up-regulates activity

0.306

Treatment of cells with Gdf5 enhanced Trps1 protein levels and phosphorylation of p38 mitogen-activated protein kinase (MAPK) in a dose-dependent manner. Nuclear translocation of Trps1 was also induced by Gdf5. These effects were blocked by a dominant negative form of activin-linked kinase 6 (dn-Alk6) and by SB203580, an inhibitor of the p38 MAPK pathway. Conversely, Gdf5 expression was suppressed by the over-expression of Trps1.

SIGNOR-251867

P17252

O15350

1

phosphorylation

up-regulates activity

0.2

Here, we report that p73 is able to induce cell cycle arrest independently of its amino-terminal transactivation domain, whereas this domain is crucial for p73 proapoptotic functions. its activity is regulated throughout the cell cycle and modified by protein kinase C-dependent phosphorylation at serine residue 388.

SIGNOR-276235

P20042

Q9UI10

0

guanine nucleotide exchange factor

up-regulates activity

0.754

EIF2B converts the protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex owing to its guanine nucleotide exchange factor (GEF) activity.

SIGNOR-269132

P24941

Q03112

1

phosphorylation

up-regulates activity

0.296

The motif harbouring S436 is a target of CDK2 and CDK3 kinases, which interacted with EVI1-WT. The methyltransferase DNMT3A bound preferentially to EVI1-WT compared with EVI1-S436A, and a hypomethylated cell population associated by EVI1-WT expression in murine haematopoietic progenitors is not maintained with EVI1-S436A.

SIGNOR-273426

P10912

P43378

0

dephosphorylation

down-regulates activity

0.314

Protein tyrosine phosphatases (PTPs) play key roles in switching off tyrosine phosphorylation cascades, such as initiated by cytokine receptors. We have used substrate-trapping mutants of a large set of PTPs to identify members of the PTP family that have substrate specificity for the phosphorylated human GH receptor (GHR) intracellular domain. Among 31 PTPs tested, T cell (TC)-PTP, PTP-beta, PTP1B, stomach cancer-associated PTP 1 (SAP-1), Pyst-2, Meg-2, and PTP-H1 showed specificity for phosphorylated GHR

SIGNOR-248505

Q9UBS0

Q53EL6

1

phosphorylation

down-regulates

0.438

Both akt and p70(s6k) phosphorylate pdcd4, allowing for binding of the e3-ubiquitin ligase beta-trcp and consequently ubiquitylation.

SIGNOR-160992

Q8IUQ4

Q9Y6H5

1

ubiquitination

down-regulates

0.676

Siah proteins ubiquitylate synphilin-1 and promote its degradation through the ubiquitin proteasome system

SIGNOR-140612

Q15084

Q9NZJ5

1

null

down-regulates activity

0.2

Protein disulfide isomerase A6 (PDIA6) interacts with protein kinase RNA-like endoplasmic reticulum kinase (PERK) and inositol requiring enzyme (IRE)-1 and inhibits their unfolded protein response signaling.

SIGNOR-256537

P11309

P46527

1

phosphorylation

down-regulates activity

0.382

We show, herein, that all the pim family members (pim1, pim2, and pim3) bind to and directly phosphorylate the cyclin-dependent kinase inhibitor p27(kip1) at threonine-157 and threonine-198 residues in cells and in vitro.|Pim kinases promote cell cycle progression and tumorigenesis by down-regulating p27(Kip1) expression at both transcriptional and posttranslational levels.

SIGNOR-179300

Q9BZL6

Q8WYL5

1

phosphorylation

down-regulates

0.291

Phosphorylation of ser 402 impedes phosphatase activity of slingshot 1.

SIGNOR-173441

O15264

P16949

1

phosphorylation

down-regulates

0.414

Serine 25 of oncoprotein 18 is a major cytosolic target for the mitogen-activated protein kinase.

SIGNOR-36362

Q5T6F2

P07355

1

ubiquitination

down-regulates quantity

0.341

UBAP2 formed a complex with Annexin A2 and promoted the degradation of Annexin A2 protein by ubiquitination

SIGNOR-261314

P01106

P11274

1

transcriptional regulation

up-regulates quantity by expression

0.362

In the present study we demonstrate that MYC and its partner MAX bind to the BCR promoter, leading to up-regulation of BCR and BCR/ABL1 at both transcriptional and protein levels.|Here we describe a regulatory pathway modulating BCR and BCR/ABL1 expression, showing that the BCR promoter is under the transcriptional control of the MYC/MAX heterodimer.

SIGNOR-272144

P37840

Q9NYY3

0

phosphorylation

down-regulates activity

0.478

Polo-like kinase 2 (plk2) phosphorylates alpha-synuclein at serine 129 in central nervous system. The membrane association of pd-linked mutant alpha -synuclein, but not wild-type -synuclein, was increased by serine 129 phosphorylation. Pathological serine 129 phosphorylation regulates membrane accumulation of mutant alpha-synuclein.

SIGNOR-182155

P52907

P68400

0

phosphorylation

up-regulates

0.2

We demonstrate that ser9 of cpalpha is phosphorylated by protein kinase ck2 in vitro, that cpalpha is phosphorylated in vivo. Finally, we demonstrate that ckip-1 and ck2 inhibit the activity of actin capping protein at the barbed ends of actin filaments.

SIGNOR-135422

P17612

P33076

1

phosphorylation

down-regulates activity

0.309

Downregulation of ciita function by protein kinase a (pka)-mediated phosphorylation phosphorylation at ciita serines 834 and 1050 accounts for the inhibitory effects of pka on ciita-driven class ii mhc transcription.

SIGNOR-108569

P19484

P28482

0

phosphorylation

down-regulates activity

0.413

Evidence for ERK2-mediated TFEB phosphorylation came from ERK2-TFEB coimmuno-precipitation (fig. S12C) in normal but not in starved medium and from a peptide-based kinase assay showing that mutation of Ser142 to alanine abolished ERK2-mediated phosphorylation (

SIGNOR-248279

Q96PU5

P51795

1

ubiquitination

down-regulates quantity by destabilization

0.292

The presence of albumin triggers the formation of an endocytic complex that includes ClC-5. (iii) Nedd4-2 is recruited to this complex and ubiquitinates ClC-5. This ubiquitination by Nedd4-2 shunts ClC-5 into the albumin uptake/degradative pathway.

SIGNOR-272665

P12644

Q04206

0

transcriptional regulation

down-regulates quantity by repression

0.2

Co-transfection with pCMV4-RelA alone or in combination with pCMV4p50 repressed pSLA4.1 EX-Lux activity by approximately 75 percent in both H441 and A549 cells

SIGNOR-266087

P17252

P09651

1

phosphorylation

down-regulates

0.2

A survey of seven protein kinases showed that a1 was heavily phosphorylated by protein kinase c (pkc) and also was phosphorylated by casein kinase iiamino acid sequencing revealed that these sites were ser95, ser192, and ser199;phosphorylation at ser192 was more abundant than at ser95 and ser199. Phosphorylation by pkc inhibited the strand annealing activity of a1.

SIGNOR-32291

Q9UHD2

Q04864

1

phosphorylation

up-regulates

0.579

The present results demonstrate that ikkepsilon- and tbk1-mediated phosphorylation of crel in the c-terminal td leads to cytoplasmic dissociation of a crel-ikb_ complex and nuclear accumulation of crel.

SIGNOR-148623

Q9Y2H0

Q9UPX8

1

relocalization

up-regulates activity

0.744

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-264596

P29474

P12931

0

phosphorylation

up-regulates activity

0.42

Two kinases, i.e. abelson-tyrosine protein kinase (ABL)1 and Src were identified as eNOS Tyr81 kinases as their inhibition and down-regulation significantly reduced the basal and Yoda1-induced tyrosine phosphorylation and activity of eNOS.

SIGNOR-277520

P51813

P12931

0

phosphorylation

up-regulates

0.535

Coexpression of v-src and etk led to a transphosphorylation on tyrosine 566 of etk and subsequent autophosphorylation. These events correlated with a substantial increase in the kinase activity of etk.

SIGNOR-75330

P36873

P42575

1

dephosphorylation

up-regulates activity

0.2

nutrient-replete oocytes inhibit C2 via S135 phosphorylation catalyzed by calcium/calmodulin-dependent protein kinase II. We now show that C2 phosphorylated at S135 binds 14-3-3zeta, thus preventing C2 dephosphorylation. Moreover, we determined that S135 dephosphorylation is catalyzed by protein phosphatase-1 (PP1), which directly binds C2.

SIGNOR-248503

P31269

Q8NFU7

0

transcriptional regulation

up-regulates quantity by expression

0.306

Furthermore, TET1 catalytic domain possessed demethylase activity in cancer cells, being able to inhibit the CpG methylation of tumor suppressor gene (TSG) promoters and reactivate their expression, such as SLIT2, ZNF382 and HOXA9.

SIGNOR-259094

P41968

Q5JWF2

1

null

up-regulates activity

0.547

We hypothesize that XLŒ±s may be involved in this regulatory loop by coupling to melanocortin receptors 3 and 4 in the hypothalamus.

SIGNOR-253068

O43148

P06493

0

phosphorylation

up-regulates activity

0.255

We report that CDK1-cyclin B1 phosphorylates the RNMT regulatory domain on T77 during G2/M phase of the cell cycle. RNMT T77 phosphorylation activates the enzyme both directly and indirectly by inhibiting interaction with KPNA2, an RNMT inhibitor.

SIGNOR-265501

A6NI28

Q05397

0

phosphorylation

up-regulates activity

0.309

FAK and Src Mediated Phosphorylation of GRAF3 at Y376 Promotes Allosteric Activation.

SIGNOR-280097

P11309

P30307

1

phosphorylation

up-regulates activity

0.348

First, Pim-1 activates the Cdc25C phosphatase directly through phosphorylation, very probably at the N-terminal part of the protein.|We find that phosphorylation by Pim-1 enhances the phosphatase activity of Cdc25C and in transfected cells that are arrested in G2/M by bleomycin, Pim-1 can enhance progression into G1.

SIGNOR-278298

Q7L5N1

P31749

0

phosphorylation

up-regulates

0.282

Mechanistic studies show that akt causes csn6 phosphorylation at ser 60, which, in turn, reduces ubiquitin-mediated protein degradation of csn6.

SIGNOR-252532

O60674

Q92888

1

phosphorylation

up-regulates

0.325

We found that angiotensin ii activates arhgef1 through a previously undescribed mechanism in which jak2 phosphorylates tyr738 of arhgef1

SIGNOR-163557

P62993

P22681

1

relocalization

up-regulates

0.904

The underlying mechanism seems to involve recruitment of a grb2 c-cbl complex to grb2-specific docking sites of egfr, and concurrent acceleration of receptor ubiquitylation and desensitization.

SIGNOR-114704

P46821

Q13618

0

ubiquitination

down-regulates quantity

0.254

Gigaxonin is the substrate-specific adaptor for a new Cul3-E3-ubiquitin ligase family that promotes the proteasome dependent degradation of its partners MAP1B, MAP8 and tubulin cofactor B.

SIGNOR-268946

P45983

P30307

1

phosphorylation

down-regulates

0.411

Here we show that jnk directly phosphorylates cdc25c at serine 168 during g(2) phase of the cell cycle. Cdc25c phosphorylation by jnk negatively regulates its phosphatase activity and thereby cdk1 activation, enabling a timely control of mitosis onset.

SIGNOR-164089

P49137

P04792

1

phosphorylation

down-regulates

0.809

Notably mk2 is well known to play an important role in actin filament remodellng by phosphorylating hsp27.

SIGNOR-94021

Q15418

Q8TB45

1

phosphorylation

down-regulates

0.492

We found that deptor was rapidly phosphorylated on three serines in a conserved degron, facilitating binding and ubiquitylation by the f box protein _trcp, with consequent proteasomal degradation of deptor. Phosphorylation of the _trcp degron in deptor is executed by ck1

SIGNOR-176883

P49841

O95997

1

phosphorylation

down-regulates activity

0.2

Glycogen synthase kinase-3beta (GSK3beta) negatively regulates PTTG1 and human securin protein stability, and GSK3beta inactivation correlates with securin accumulation in breast tumors.|Here, we demonstrate that glycogen synthase kinase-3\u03b2 (GSK3\u03b2) phosphorylates securin to promote its proteolysis via SCF(\u03b2TrCP) E3 ubiquitin ligase.

SIGNOR-279188

Q15389

Q03112

0

transcriptional regulation

up-regulates quantity by expression

0.2

We finally observed that the forced expression of Evi1 induced GATA-2 expression in a hematopoietic cell line, EML C1, along with GATA-1, Ang-1, Ang-2 and Tie2

SIGNOR-266059

Q13535

P00519

0

phosphorylation

up-regulates

0.599

C-abl can phosphorylate atr on y291 and y310 and this phosphorylation appears to have a positive role in atr activation under genotoxic stress.

SIGNOR-167632

Q5JVL4

Q92949

0

transcriptional regulation

up-regulates quantity by expression

0.356

FOXJ1 expression in basal cells induced the expression of a panel of cilia-associated genes, including centrin 2 (CETN2); dynein, axonemal, heavy chain 11 (DNAH11); dynein, axonemal, intermediate chain 1 (DNAI1); dynein, axonemal, light intermediate chain 1 (DNALI1); EF-hand domain, C-terminal, containing 1 (EFHC1); sperm associated antigen 6 (SPAG6); tektin 1 (TEKT1), TEKT2 and tubulin, alpha 1a (TUBA1A; Figure 3C and Additional file 2: Table S1).

SIGNOR-266934

O43524

Q13043

0

phosphorylation

up-regulates

0.681

Bonni and coworkers demonstrated that mst1 can phosphorylate foxo3 (and subsequently, foxo1) principally ser207 (ser212 in foxo1), a conserved site in the forkhead domain. This phosphorylation interdicts 14-3-3 binding, promotes foxo nuclear residence and transcriptional activity.

SIGNOR-178190

P38936

Q99683

0

phosphorylation

up-regulates

0.589

P21cip1 is phosphorylated in vitro by both ask1 and jnk1 at s98. /phosphorylation of p21cip1 at s98, which in vivo appears to be regulated by ask1, may therefore mediate negative feedback in the ask1 signaling pathway.

SIGNOR-153440

Q13233

Q8IVH8

0

phosphorylation

up-regulates

0.453

With regard to at least mekk1, serine/threonine kinases such as nik,glkand hpk1 appear also to be important for regulation

SIGNOR-61814

O43542

Q13535

0

phosphorylation

up-regulates activity

0.464

HXRCC3 S225 phosphorylation is mediated by ATR via an ATM-dependent signaling pathway. These data clearly indicate that ATR mediates the late activation of XRCC3 following DSB accumulation.

SIGNOR-262666

P49841

O00159

1

phosphorylation

up-regulates activity

0.2

Here, we report that at early G1 the glycogen synthase kinase 3\u03b2 phosphorylates and stabilizes Nuclear myosin 1c, allowing for Nuclear myosin 1c association with the chromatin.

SIGNOR-279184

P31751

Q13835

1

phosphorylation

up-regulates quantity by stabilization

0.267

Akt2 phosphorylates PKP1 in vitro. Phosphorylated PKP1 is more resistant to degradation. PKP1 phosphorylation sites identified by peptide microarray analyses and mass spectrometry.

SIGNOR-273494

Q13489

Q7Z570

0

transcriptional regulation

down-regulates quantity by repression

0.2

ZNF804A has been implicated in susceptibility to schizophrenia by several genome-wide association studies (GWAS), follow-up association studies and meta-analyses. ZNF804A was identified as a schizophrenia-associated gene by GWAS and was predicted to play a role in DNA binding and transcription To identify the genes that are affected by ZNF804A, we manipulated the expression of the ZNF804A protein in HEK293 human embryonic kidney cell lines and performed a cDNA microarray analysis followed by qPCR. We found that ZNF804A-overexpression up-regulated four genes (ANKRD1, INHBE, PIK3AP1, and DDIT3) and down-regulated three genes (CLIC2, MGAM, and BIRC3).

SIGNOR-269467

Q9UQM7

P35367

1

phosphorylation

down-regulates

0.282

As we have shown previously, human h1r can be phosphorylated in vitro by several kinases includingpka, pkc, pkg, and camk ii in summary, these data suggest that thr140, thr142, ser396, ser398, and thr478 can be phosphorylated by the kinases described above (table 2).

SIGNOR-124348

Q15831

Q9Y2K2

1

phosphorylation

up-regulates

0.488

Lkb1 is a master kinase that activates 13 kinases of the ampk subfamily, including mark/par-1we recently demonstrated that the lkb1 tumour suppressor kinase, in complex with the pseudokinase strad and the scaffolding protein mo25, phosphorylates and activates amp-activated protein kinase (ampk). A total of 12 human kinases (nuak1, nuak2, brsk1, brsk2, qik, qsk, sik, mark1, mark2, mark3, mark4 and melk) are related to ampk. Here we demonstrate that lkb1 can phosphorylate the t-loop of all the members of this subfamily, apart from melk, increasing their activity >50-fold

SIGNOR-122835

P53350

Q8NFH5

1

phosphorylation

down-regulates activity

0.415

Collectively, these data show that mitotic hyperphosphorylation of Nup53 by CDK1 and PLK1 contributes to its removal from NPCs.|The combined mutation of the CDK1 and PLK1 sites to phosphomimetic residues almost completely abolished NPC integration of Nup53, indicating that hyperphosphorylation of Nup53 might be incompatible with its NPC association.

SIGNOR-279252

P01189-PRO_0000024969

P16519

0

cleavage

up-regulates quantity

0.2

POMC is post-translationally cleaved by prohormone convertase enzymes 1 and 2 (PC1, PC2) into ACTH, an N-terminal glycopeptide

SIGNOR-268725

Q13049

Q86U86

1

ubiquitination

down-regulates quantity by destabilization

0.2

TRIM32 ubiquitination of PB1 leads to its protein degradation.

SIGNOR-278735