GleghornLab/Signor_2class · Datasets at Hugging Face

IdA string	IdB string	labels int64	mechanism string	effect string	score float64	sentence string	signor_id string
Q12857	A6NFN3	1	transcriptional regulation	up-regulates quantity	0.261	For example, within the NFI targetome, we identified 6 collagen genes, 13 genes encoding potassium channel or glutamate receptor subunits and a range of factors related to axon guidance (e.g. Slit1, Robo1, Epha4, Epha5, Epha8)	SIGNOR-268911
O43395	Q13107	0	deubiquitination	down-regulates activity	0.487	Prp3 is deubiquitinated by Usp4 and its substrate targeting factor, the U4/U6 recycling protein Sart3, which likely facilitates ejection of U4 proteins from the spliceosome during maturation of its active site.	SIGNOR-271975
P55268	Q9NYD6	0	transcriptional regulation	up-regulates quantity by expression	0.2	The specificity of binding of these two proteins to the Lamin B2 origin is confirmed by both band-shift and in vitro footprinting assays. In addition, the ability of HOXC10 and HOXC13 to increase the activity of a promoter containing the 74 bp sequence, as assayed by CAT-assay experiments, demonstrates a direct interaction of these homeoproteins with the origin sequence in mammalian cells.	SIGNOR-261645
P16885	P06239	0	phosphorylation	up-regulates	0.558	In vitro phosphorylation experiments with recombinant plcgamma2 and recombinant lck, fyn, and lyn tyrosine kinases showed that phosphorylation of plcgamma2 led to activation of the recombinant enzyme.	SIGNOR-91477
Q96GX5	P31749	0	phosphorylation	up-regulates activity	0.2	Here, we report that AKT phosphorylates MASTL at residue T299, which plays a critical role in its activation.	SIGNOR-277515
Q9Y458	P56178	1	transcriptional regulation	down-regulates quantity by repression	0.307	the main function of TBX22 as shown in misexpression experiments is to decrease proliferation. We subsequently uncovered three targets of TBX22, DLX5, MSX2, and TBX22 itself. All are downregulated in the presence of viral-derived hTBX22.	SIGNOR-265566
P07951	P48736	0	phosphorylation	up-regulates activity	0.335	Here, we demonstrate a requirement for the protein kinase activity of PI(3)K in agonist-dependent beta-adrenergic receptor (betaAR) internalization. Using PI(3)K mutants with either protein or lipid phosphorylation activity, we identify the cytoskeletal protein non-muscle tropomyosin as a substrate of PI(3)K, which is phosphorylated in a wortmannin-sensitive manner on residue Ser 61. A constitutively dephosphorylated (S61A) tropomyosin mutant blocks agonist-dependent betaAR internalization, whereas a tropomyosin mutant that mimics constitutive phosphorylation (S61D) complements the PI(3)K mutant, with only lipid phosphorylation activity reversing the defective betaAR internalization.	SIGNOR-263028
O43395	P68400	0	phosphorylation	up-regulates	0.2	Our findings provide new insights into the biology of hprp3p and suggest that the loss of hprp3p phosphorylation at thr494 is a key step for initiating thr494met aberrant interactions within u4/u6 snrnp complex and that these are likely linked to the rp18 phenotype.	SIGNOR-158319
Q8N122	Q9UBE8	0	phosphorylation	down-regulates activity	0.327	NLK inhibits mTORC1 lysosomal localization and thereby suppresses mTORC1 activation. Mechanistically, NLK phosphorylates Raptor on S863 to disrupt its interaction with the Rag GTPase, which is important for mTORC1 lysosomal recruitment.	SIGNOR-273908
Q99250	Q96PU5	0	ubiquitination	down-regulates quantity by destabilization	0.317	The control of Nav density at the cell membrane is crucial to ensuring normal neuronal excitability. Navs are subject to posttranslational modifications that may influence their cell membrane availability. Ubiquitylation is a key process that orchestrates the internalization and subsequent degradation or recycling of Navs. This is accomplished by ubiquitin protein ligases, such as NEDD4-2 (neuronal precursor cell expressed developmentally downregulated-4 type 2).	SIGNOR-253459
P49841	P10071	1	phosphorylation	down-regulates quantity by destabilization	0.537	We show that these phosphoserines prime further phosphorylation at adjacent Glycogen Synthase Kinase 3 (GSK3) and Casein Kinase I (CK1) sites. Alteration of the GSK3 or CK1 sites prevents Ci-155 proteolysis and activates Ci in the absence of Hedgehog.	SIGNOR-219231
P27361	Q99814	1	phosphorylation	up-regulates quantity by stabilization	0.26	The activation of ERK1/2 upon hypoxia promoted HIF-2alpha phosphorylation, enhancing its interaction with USP33.Here, we identified USP33 as essential deubiquitinase that stabilizes HIF-2alpha protein in an ERK1/2-dependent manner to promote hypoxia response in cancer cells.	SIGNOR-277584
Q5VT25	P53671	1	phosphorylation	up-regulates activity	0.395	These results indicate that mrckalpha phosphorylates and activates lim kinases downstream of cdc42, which in turn regulates the actin cytoskeletal reorganization through the phosphorylation and inactivation of adf/cofilin.	SIGNOR-107584
Q13434	Q8IVH8	1	ubiquitination	down-regulates quantity	0.2	MKRN4 ubiquitinated GLK at Lys650 residue.\|Remarkably, MKRN4 overexpression induced GLK protein degradation in HEK293T cells and Jurkat T cells (figure 5A and B).	SIGNOR-278658
P42574	P31749	1	cleavage	down-regulates activity	0.602	P53 can inhibit the survival function of integrins by inducing the caspase-dependent cleavage and inactivation of the serine/threonine kinase akt/pkb;the involvement of caspase 3 in akt/pkb regulation was indicated by the ability of z-devd-fmk, a caspase 3 inhibitor, to block the alpha6beta4-associated reduction in akt/pkb levels in vivo, and by the ability of recombinant caspase 3 to promote the cleavage of akt/pkb in vitro	SIGNOR-252624
P17612	P55211	1	phosphorylation	down-regulates	0.2	We show that protein kinase a inhibits activation of caspase-9 and caspase-3 downstream of cytochrome c in xenopus egg extracts and in a human cell-free system. Protein kinase a directly phosphorylates human caspase-9 at serines 99, 183, and 195.	SIGNOR-133884
Q13094	P43403	0	phosphorylation	up-regulates	0.804	Zap-70 phosphorylates slp-76 at specific sites that allow vav sh2 domain bindingwe also show by in vitro and in vivo analysis that two slp-76 pyesp motifs (y113 and y128) mediate binding, the first being more efficient.	SIGNOR-46859
Q13315	P51812	0	phosphorylation	up-regulates activity	0.388	Furthermore, using RSK2 knockout mouse fibroblasts and RSK2 deficient cells from CLS patients, we demonstrate that ablation of RSK2 impairs the phosphorylation of Atm at Ser1981 and the phosphorylation of p53 at Ser18 (mouse) or Ser15 (human) in response to genotoxic stress.\|We postulate that the phosphorylation of RSK2 is required to fully activate Atm at Ser1981 and p53 at Ser18 (mouse) or Ser15 (human) in response to genotoxic stress.	SIGNOR-280118
P37173	Q9HCE7	0	ubiquitination	down-regulates activity	0.615	Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degradation of smads and receptors for tgf-beta and bmps.	SIGNOR-195672
P28482	Q13625	1	phosphorylation	up-regulates activity	0.263	Hence ASPP2 can be phosphorylated at serine 827 by MAPK1 in vitro.\|Phosphorylation of ASPP2 by MAPK is required for RAS-induced increased binding to p53 and increased transactivation of pro-apoptotic genes.	SIGNOR-264414
P16519	P10997	1	cleavage	up-regulates activity	0.465	The processing of proinsulin to insulin occurs in the secretory granules at the C-terminal end of pairs of basic amino acids, Arg31-Arg32 and Lys64-Arg65 [9,10]. Following cleavage, by the prohormone convertases, PC3 (also known as PC1) and PC2, the pair of basic amino acids are removed rapidly by carboxypeptidase E (CPE) to produce the mature insulin molecule	SIGNOR-261791
Q96GD4	P53350	1	phosphorylation	up-regulates activity	0.599	Aurora B phosphorylates PLK1 on Thr210 to activate its kinase activity at the kinetochores during mitosis.\|Thus, we conclude that Aurora B indirectly promotes the phosphorylation of MCAK on Ser715 at the kinetochores through phosphorylation of PLK1 at Thr210 and its ensuing activation.	SIGNOR-279358
Q6UWE0	Q99816	1	monoubiquitination	down-regulates quantity	0.527	Tal increases ubiquitylation of Tsg101 and affects its solubility in a RING- and PTAP-dependent manner. Tal-mediated ubiquitylation of Tsg101 inactivates this sorting function and concomitantly translocates Tsg101 from relatively insoluble membrane subdomains. Presumably, the coordinated action of Tal and a deubiquitylation enzyme (DUB) enables recycling of Tsg101 and reloading of cargo.	SIGNOR-271509
Q9BZK7	P20749	1	ubiquitination	down-regulates	0.401	We also defined the e3 ligase tblr1 as a protein involved in bcl-3 degradation	SIGNOR-166111
P36956	Q13131	0	phosphorylation	down-regulates activity	0.36	Ampk was recently found to phosphorylate a conserved serine near the cleavage site within srebp1, suppressing its activation	SIGNOR-176497
P12931	O60500	1	phosphorylation	up-regulates activity	0.48	Inhibition of Src kinase dependent Nephrin phosphorylation achieved by incubation of WT-Nephrin-overexpressing cells with 1 mum PP2 abolished the positive effect of Nephrin on GSIR (XREF_FIG D).\|We were able to demonstrate a complete prevention of Nephrin phosphorylation, confirming that Nephrin phosphorylation is mediated by Src.	SIGNOR-280129
P10721	Q9NX45	0	transcriptional regulation	up-regulates quantity by expression	0.325	Our results suggest that SOHLH1 and SOHLH2 directly stimulate Kit transcription in postnatal spermatogonia, thus activating the signaling involved in spermatogonia differentiation and spermatogenetic progression.	SIGNOR-266206
Q14790	P51812	0	phosphorylation	down-regulates quantity by destabilization	0.369	The ribosomal S6 kinase 2 (RSK2) is a member of the p90 ribosomal S6 kinase (p90RSK) family of proteins and plays a critical role in proliferation, cell cycle, and cell transformation. Here, we report that RSK2 phosphorylates caspase-8, and Thr-263 was identified as a novel caspase-8 phosphorylation site. In addition, we showed that EGF induces caspase-8 ubiquitination and degradation through the proteasome pathway, and phosphorylation of Thr-263 is associated with caspase-8 stability.	SIGNOR-272997
P31269	O14744	0	methylation	up-regulates activity	0.462	Hoxa9 methylation by prmt5 is essential for endothelial cell expression of leukocyte adhesion molecules. / prmt5 is a critical coactivator component in a newly defined, hoxa9-containing transcription complex./ Hoxa9 is methylated on arg140 by prmt5.	SIGNOR-195526
Q86XI6	Q6VVB1	0	ubiquitination	down-regulates quantity by destabilization	0.398	Here, we show that the laforin-malin complex downregulates PTG-induced glycogen synthesis in FTO2B hepatoma cells through a mechanism involving ubiquitination and degradation of PTG. We show here that laforin and malin play a crucial role in the regulation of glycogen biosynthesis in FTO2B hepatoma cells. In these cells, the laforin–malin complex counteracts the glycogenic effect of PTG because it promotes its ubiquitination and degradation.	SIGNOR-271728
P03372	P00519	0	phosphorylation	up-regulates	0.446	Eralpha can be phosphorylated on two sites, tyrosine 52 (y-52) and tyrosine 219 (y-219). Eralpha phosphorylation by c-abl stabilizes eralpha, resulting in enhanced eralpha transcriptional activity and increased expression of endogenous eralpha target genes.	SIGNOR-163562
Q8NFA2	Q86UR1	1	relocalization	up-regulates activity	0.777	Tks4 and Tks5 bind NoxA1 through their SH3 domains in a Rac-independent manner\|NoxO1 is required for full Nox1 and Nox3 oxidase activity at least partially because of its role in the plasma membrane recruitment of the NoxA1 activator protein\|Tks4 and Tks5 support Nox1- and Nox3-dependent ROS generation	SIGNOR-264709
Q9UEW8	Q9Y6R1	1	phosphorylation	down-regulates activity	0.348	SPAK phosphorylates the transporters to reduce their surface expression and thus their activity and consequently inhibits ductal secretion to stabilize the resting state. PP1 reverses the effect of SPAK. Molecular analysis revealed that the WNK kinases acted as scaffolds to recruit SPAK, which phosphorylated CFTR and NBCe1-B, reducing their cell surface expression.	SIGNOR-263133
P19474	P49327	1	ubiquitination	down-regulates quantity by destabilization	0.2	FASN acetylation enhanced its association with the E3 ubiquitin ligase TRIM21. Acetylation destabilized FASN and resulted in decreased de novo lipogenesis and tumor cell growth. FASN acetylation was frequently reduced in human hepatocellular carcinoma samples, which correlated with increased HDAC3 expression and FASN protein levels.	SIGNOR-267368
P43487	P53350	0	phosphorylation	up-regulates activity	0.359	Here, we demonstrated in vitro and in vivo phosphorylation of RanBP1 by Plk1 as well as the importance of phosphorylation of RanBP1 in the interaction between Plk1 and Ran during early mitosis.	SIGNOR-279751
P48163	P24752	0	acetylation	up-regulates activity	0.249	PGAM5-mediated dephosphorylation of malic enzyme 1 (ME1) at S336 allows increased ACAT1-mediated K337 acetylation, leading to ME1 dimerization and activation, both of which are reversed by NEK1 kinase-mediated S336 phosphorylation. SIRT6 deacetylase antagonizes ACAT1 function in a manner that involves mutually exclusive ME1 S336 phosphorylation and K337 acetylation.	SIGNOR-275571
Q16828	Q13164	1	dephosphorylation	down-regulates activity	0.646	However, whilst the interaction itself might be difficult to monitor, DUSP6 should still be able to promote the de-phosphorylation of ERK5 in cells if it is an ERK5 phosphatase.To test this HEK293 cells were transiently transfected with HA-ERK2 or HA-ERK5 together with EGFP-MEK1E (a constitutively active version of MEK1) or EGFP-MEK5D (a constitutively active version of MEK5).\|Whilst one can envisage scenarios in which the interaction between DUSPs and their substrates might be transient, DUSP6 should still be able to promote the de-phosphorylation and inactivation of ERK5.	SIGNOR-277007
P43403	P51452	1	phosphorylation	up-regulates activity	0.531	ZAP-70 and Syk also tyrosine-phosphorylated VHR in COS-1 cells (Fig. 2d), whereas other kinases (Csk, Lck, Fyn, Jak2, Bcr-Abl and Itk) had little effect. Finally, recombinant ZAP-70 readily phosphorylated VHR in vitro (Fig. 2f).	SIGNOR-276000
A8MYZ6	Q14938	0	transcriptional regulation	down-regulates quantity	0.2	By integrating transcriptomic profiling (RNA-seq) of Nfia- and Nfix-deficient GNPs with epigenomic profiling (ChIP-seq against NFIA, NFIB and NFIX, and DNase I hypersensitivity assays), we reveal that these transcription factors share a large set of potential transcriptional targets, suggestive of complementary roles for these NFI family members in promoting neural development	SIGNOR-268887
Q13541	Q16539	0	phosphorylation	down-regulates activity	0.433	4E-BP1 Is Phosphorylated in Vitro by Active p38 Kinase. In the present study we demonstrated that UVB induced 4E-BP1 phosphorylation at multiple sites, Thr-36, Thr-45, Ser-64, and Thr-69, leading to dissociation of 4E-BP1 from eIF-4E.	SIGNOR-250097
Q5JU85	P42263	1	relocalization	up-regulates quantity	0.2	BRAG1 increases the synaptic recycling pool of AMPARs.these data suggest that the BRAG1 enhancement of AMPAR transmission is mediated by the increased expression of the recycling pool of synaptic GluA2/3 receptors.	SIGNOR-264914
Q9UQ80	P35637	0	sumoylation	up-regulates activity	0.336	Here, we show that Ebp1 p42 isoform can be sumoylated on both K93 and K298 residues, which mediate its nuclear translocation and are required for its anti-proliferative activity .. Hence, TLS-mediated sumoylation is required for Ebp1 transcriptional repressive activity.	SIGNOR-236904
P42345	Q9C0C7	1	phosphorylation	down-regulates activity	0.471	We show that under non-autophagic conditions, mTOR inhibits AMBRA1 by phosphorylation, whereas on autophagy induction, AMBRA1 is dephosphorylated. In this condition, AMBRA1, interacting with the E3-ligase TRAF6, supports ULK1 ubiquitylation by LYS-63-linked chains, and its subsequent stabilization, self-association and function. As ULK1 has been shown to activate AMBRA1 by phosphorylation, the proposed pathway may act as a positive regulation loop, which may be targeted in human disorders linked to impaired autophagy.\|mTOR phosphorylates AMBRA1 at Ser 52, inhibiting its role in ULK1 modification	SIGNOR-272986
P10619	P19484	0	transcriptional regulation	up-regulates quantity by expression	0.298	Nucleus-Translocated ACSS2 Promotes Gene Transcription for Lysosomal Biogenesis and Autophagy\|A chromatin immunoprecipitation (ChIP) assay with antibodies against TFEB or ACSS2 demonstrated that glucose deprivation results in the binding of TFEB (Figure 3D) and ACSS2 (Figure 3E) to the promoter regions of CTSA, GBA, GUSB, and LAMP1\|These results indicated that TFEB and ACSS2 are mutually required for their binding to the promoter regions of lysosomal genes. In line with these findings, glucose deprivation induced mRNA (Figure 3F) and protein (Figure 3G) expression for these lysosomal genes, which was largely abrogated by knockin of ACSS2 mutants	SIGNOR-276549
Q9NS28	P17612	0	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
Q9C029	Q86WV6	1	ubiquitination	down-regulates quantity by destabilization	0.2	RNF90 promoted K48-linked ubiquitination of MITA and its proteasome-dependent degradation.\|Finally, in vitro ubiquitination assays suggested that RNF90 promoted the ubiquitination of MITA directly (Fig 5E and 5F).	SIGNOR-278678
Q9HAW9	Q99626	0	transcriptional regulation	up-regulates quantity by expression	0.26	Using gel shift and functional assays, HNF1alpha was demonstrated to bind to and activate the UGT1A8, -1A9, and -1A10 promoters. In contrast, Cdx2 bound to and activated the UGT1A8 and -1A10 promoters but could not activate the UGT1A9 promoter.	SIGNOR-253969
Q9UHD2	P09769	0	phosphorylation	down-regulates activity	0.2	The Src family kinases (SFKs) Lck, Hck, and Fgr directly phosphorylate TBK1 at Tyr354/394, to prevent TBK1 dimerization and activation.	SIGNOR-276725
O60716	P28827	0	dephosphorylation	down-regulates quantity	0.541	Specifically, RPTP\u03bc dephosphorylated p120 catenin, subsequently leading to a lower level of cytoplasmic protein compared with that observed with the vector control and RPTP\u03bc-CS.	SIGNOR-277042
P19784	P60484	1	phosphorylation	down-regulates activity	0.704	We used mass spectrometric methods to identify Ser(370) and Ser(385) as in vivo phosphorylation sites of PTEN. These sites also are phosphorylated by CK2 in vitro, and phosphorylation inhibits PTEN activity towards its substrate, PIP3. We also identify a novel in vivo phosphorylation site, Thr(366).	SIGNOR-251025
P61586	O15068	0	guanine nucleotide exchange factor	up-regulates activity	0.619	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-260559
O94916	Q00535	0	phosphorylation	up-regulates	0.2	High nacl-induced activation of cdk5 increases phosphorylation of the osmoprotective transcription factor tonebp/orebp at threonine 135, which contributes to its rapid nuclear localization. n hek293 cells, mass spectrometry shows phosphorylation of tonebp/orebp-s120, -s134, -t135, and -s155.	SIGNOR-170886
P12830	O15379	0	transcriptional regulation	down-regulates quantity by repression	0.257	GATA1 is a new substrate of p21-activated kinase 5 (PAK5), which is phosphorylated on serine 161 and 187 (S161 and S187). GATA1 recruits HDAC3/4 to E-cadherin promoter, which is reduced by GATA1 S161A S187A mutant. These data indicate that phosphorylated GATA1 recruits more HDAC3/4 to promote transcriptional repression of E-cadherin, leading to the EMT of breast cancer cells.	SIGNOR-275662
O15111	Q00653	1	phosphorylation	up-regulates activity	0.791	Ikkalfa phosphorylates p100, leading to its proteasomal processing to p52.	SIGNOR-124230
P35638	P17676	1	transcriptional regulation	down-regulates quantity	0.668	We find that expression of CHOP, a nuclear protein that dimerizes avidly with C/EBP isoforms alpha and beta and directs the resulting heterodimer away from classic C/EBP-binding sites, markedly inhibits this differentiation process.	SIGNOR-255914
P07910	P48729	0	phosphorylation	down-regulates	0.354	A kinase activity was identified in mouse liver that phosphorylates the acd of hnrnp-c at ser(240) and at two sites at ser(225)-ser(228). The kinase was purified and identified by tandem mass spectrometry as protein kinase ck1alpha (formerly casein kinase 1alpha).hnrnp-c1 that was also modified at the ck1alpha phosphorylation sites exhibited a 14-500-fold decrease in binding affinity, demonstrating that ck1alpha-mediated phosphorylation modulates the mrna binding ability of hnrnp-c.	SIGNOR-133528
P68400	P27348	1	phosphorylation	down-regulates activity	0.347	The neuroprotective effect of 14-3-3theta against rotenone toxicity is dependent on the inhibition of the pro-apoptotic factor Bax\|Phosphorylation at S232 induced by rotenone is reduced by casein kinase inhibitors, and is not dependent on alphasyn.\| The S232D mutant partially reduced the ability of 14-3-3theta to inhibit Bax activation in response to rotenone. Based on these findings, we propose that phosphorylation of 14-3-3s at serine 232 contributes to the neurodegenerative process in PD.	SIGNOR-264405
Q14653	P78527	0	phosphorylation	up-regulates	0.43	Phosphorylation of irf-3 by dna-pk after virus infection results in its nuclear retention and delayed proteolysis	SIGNOR-115331
P42345	O00429	1	phosphorylation	up-regulates activity	0.345	Furthermore, we confirmed also in Jurkat cells that the specific silencing of both ERK1/2 and mTOR by siRNA downregulates Drp1 phosphorylation on Ser616	SIGNOR-275430
P06213	P60484	1	phosphorylation	down-regulates activity	0.442	Our results show that the kinase region of IRβ subunit physically binds to PTEN and phosphorylates on Y27 and Y174. In the current study, we discovered that IR also downregulates PTEN through tyrosine phosphorylation and suggest that Y27 and 174 are the two key tyrosines.	SIGNOR-276470
Q13547	Q96KB5	0	phosphorylation	up-regulates activity	0.245	TOPK overexpression promotes HDAC1 and HDAC2 phosphorylation and Histone 3 and Histone 4 acetylation in BV2 cells.\|The results of in vitro studies further confirmed the effect of TOPK on HDAC activity by showing that TOPK overexpression significantly up-regulated p-HDAC1 and p-HDAC2, resulting in an increase in the acetylation of histones H3 and H4 in BV2 cells.	SIGNOR-279086
Q9BYF1	P01019-PRO_0000420660	1	cleavage	up-regulates quantity	0.2	At first, ACE2 has been demonstrated to induce conversion of Ang I into Ang (1–7) by means of intermediate production of Ang (1–9), a fragment with unknown function.	SIGNOR-260227
Q05655	P18031	0	dephosphorylation	down-regulates	0.2	Dephosphorylation of tyrosine residues by ptp1b, a protein tyrosine phosphatase, reduced the enhanced pkcdelta activity.	SIGNOR-107754
O15530	Q9Y243	1	phosphorylation	up-regulates	0.651	The activation of pkbbeta and pkbgamma by pdk1 was accompanied by the phosphorylation of the residues equivalent to thr308 in pkbalpha, namely thr309 (pkbbeta) and thr305 (pkbgamma)	SIGNOR-55937
P12931	Q13322	1	phosphorylation	down-regulates	0.447	Grb10 tyrosine phosphorylation was stimulated by expression of constitutively active src or fyn in cells and by incubation with purified src or fyn in vitro. The insulin stimulated or src/fyn-mediated tyrosine phosphorylation in vivo was significantly reduced when grb10 tyrosine 67 was changed to glycine. This mutant form of grb10 bound with higher affinity to the ir in cells than that of the wild-type protein, suggesting that tyrosine phosphorylation of grb10 may normally negatively regulate its binding to the ir.	SIGNOR-78706
Q7Z5H3	P63000	1	gtpase-activating protein	down-regulates activity	0.529	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-260477
P10636	P20807	0	cleavage	down-regulates activity	0.324	Besides tau phosphorylation, calpain activation might play a role in tau-mediated neurodegeneration by inducing tau cleavage. In vitro studies have shown that both fetal and adult tau isoforms are rapidly proteolyzed by calpains	SIGNOR-251605
P17252	Q6ZVD8	0	dephosphorylation	down-regulates quantity	0.253	In addition, knockdown of PHLPP expression reduces the rate of phorbol ester-triggered dephosphorylation of the hydrophobic motif, but not turn motif, of PKC alpha	SIGNOR-237051
Q9Y574	Q02363	1	polyubiquitination	down-regulates quantity by destabilization	0.341	Using JAR placental cells, we determined that ASB4 ubiquitinates and represses ID2 expression in a proteasome-dependent fashion.	SIGNOR-272053
P17252	P19086	1	phosphorylation	up-regulates	0.442	Functional role of amino-terminal serine16 and serine27 of g alphaz in receptor and effector coupling.	SIGNOR-48681
Q00535	P30086	1	phosphorylation	down-regulates quantity by destabilization	0.337	Here, we demonstrate that RKIP is a substrate of cyclin-dependent kinase 5 (CDK5) in neurons and that the phosphorylation of RKIP at T42 causes the release of Raf-1. Moreover, T42 phosphorylation promotes the exposure and recognition of the target motif "KLYEQ" in the C-terminus of RKIP by chaperone Hsc70 and the subsequent degradation of RKIP via chaperone-mediated autophagy (CMA).	SIGNOR-276672
Q8TD19	P53350	0	phosphorylation	up-regulates activity	0.611	We now identify Plk1 as Nek9 direct activator and propose a two-step activation mechanism that involves Nek9 sequential phosphorylation by CDK1 and Plk1. while CDK1 activity is necessary for Nek9 phosphorylation in mitosis and the resulting change in electrophoretical mobility, Nek9 Thr210 phosphorylation and mitotic activation requires both CDK1 and Plk1.	SIGNOR-273888
P19429	Q05655	0	phosphorylation	up-regulates activity	0.272	Src phosphorylates pkcdelta at tyr311 and tyr332 leading to enhanced pkcdelta autophosphorylation at thr505 (its activation loop) and pkcdelta-dependent ctni phosphorylation at both ser23/ser24 and thr144.	SIGNOR-178880
P12931	Q14289	1	phosphorylation	up-regulates	0.624	These data indicate that pyk2 activation via phosphorylation at tyr-402 requires ?V?3 Ligation and src activity.	SIGNOR-133870
Q08999	O43524	0	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
P28482	P49715	1	phosphorylation	down-regulates	0.352	Ccaat/enhancer-binding protein alpha (c/ebpalpha) is one of the key transcription factors that mediate lineage specification and differentiation of multipotent myeloid progenitors into mature granulocytes.Here we report that inducers of monocyte differentiation inhibit the alternate cell fate choice, that of granulopoiesis, through inhibition of c/ebpalpha. This inhibition is mediated by extracellular signal-regulated kinases 1 and/or 2 (erk1/2), which interact with c/ebpalpha through an fxfp docking site and phosphorylate serine 21.	SIGNOR-120566
Q04759	P22681	1	phosphorylation	up-regulates activity	0.355	PKC-θ-mediated phosphorylation of serine and tyrosine residues of c-Cbl prevents its inhibitory effect. Phosphorylation of c-Cbl by PKC-θ inhibits the recruitment of Sh2-containing proteins and subsequent association of cbl E3 ubiquitin ligase with its target proteins	SIGNOR-274144
Q8WVD3	Q9UJU2	1	polyubiquitination	down-regulates quantity by destabilization	0.307	Here, we show that NARF induces the ubiquitylation of TCF/LEF in vitro and in vivo, and functions as an E3 ubiquitin-ligase that specifically cooperates with the E2 conjugating enzyme E2-25K. We found that NLK augmented NARF binding and ubiquitylation of TCF/LEF, and this required NLK kinase activity. The ubiquitylated TCF/LEF was subsequently degraded by the proteasome.	SIGNOR-271595
Q00535	Q05682	1	phosphorylation	down-regulates quantity by destabilization	0.341	Together, these data demonstrate that phosphorylation of caldesmon on Ser527 by Cdk5 serves to down regulate its stability.	SIGNOR-280215
Q02086	P49585	1	transcriptional regulation	down-regulates quantity by repression	0.2	Sp3 is an activator, and Sp2 a repressor, of the Ctpct promoter in SL2 cells.	SIGNOR-266230
P49841	P17812	1	phosphorylation	down-regulates activity	0.2	We found that low serum conditions increased phosphorylation of endogenous CTPS1 and this phosphorylation was inhibited by the glycogen synthase kinase 3 (GSK3) inhibitor indirubin-3'-monoxime and GSK3beta short interfering RNAs, demonstrating the involvement of GSK3 in phosphorylation of endogenous human CTPS1. Separating tryptic peptides from [(32)P]orthophosphate-labeled cells and analyzing the phosphopeptides by mass spectrometry identified Ser-574 and Ser-575 as phosphorylated residues. Incubation with an alkaline phosphatase increased CTPS1 activity in a time-dependent manner, demonstrating that phosphorylation inhibits CTPS1 activity.	SIGNOR-276069
O00141	P49815	1	phosphorylation	down-regulates activity	0.579	SGK1, which is activated by PDK1, contributes to the maintenance of residual mTORC1 activity through direct phosphorylation and inhibition of TSC2.	SIGNOR-277266
P40763	Q13233	0	phosphorylation	up-regulates activity	0.291	Phosphorylation of s727 induces pin1 binding which increases transcription. Pin1 binding increases stat3 interaction with p300 and dna.	SIGNOR-236346
P06493	Q96QE3	1	phosphorylation	down-regulates activity	0.24	To determine whether mitotic CDK phosphorylates ATAD5, a CDK1 inhibitor (RO3306) was applied to nocodazole-arrested cells (Figure S3F). CDK1 inhibition resulted in a loss of S653 phosphorylation (Figure S3F). These data meant that the S653 residue in the BET BD of ATAD5 is phosphorylated by mitotic CDK. This result suggested that the BRD4-ATAD5 interaction is inhibited during mitosis.	SIGNOR-266410
P43026	Q9UHF7	1	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
Q05655	P53004	1	phosphorylation	up-regulates activity	0.2	LC-MS/MS analysis of PKCdelta-activated intact hBVR identified phosphorylated serine positions 21, 33, 230, and 237, corresponding to the hBVR Src homology-2 domain motif (Ser(230) and Ser(237)), flanking the ATP-binding motif (Ser(21)) and in PHPS sequence (Ser(33)) as targets of PKCdelta. \|PKCdelta potentiated hBVR reductase activity and accelerated the rate of bilirubin formation.	SIGNOR-275525
P51812	O60825	1	phosphorylation	up-regulates activity	0.2	Heart 6-phosphofructo-2-kinase activation by insulin results from ser-466 and ser-483 phosphorylation and requires 3-phosphoinositide-dependent kinase-1, but not protein kinase b.	SIGNOR-23753
P52333	P42229	1	phosphorylation	up-regulates	0.854	For these assays, coexpression of wt jak3 with stat5a was found to result in tyrosine phosphorylation of stat5a (lane 2) mediated by jak3, since stat5a coexpressed with the kinase-inactive k855a mutant form of jak3 was not tyrosine phosphorylated.	SIGNOR-182817
Q9GZV5	O95835	0	phosphorylation	down-regulates	0.791	In response to high cell densities, activated LATS1/2 phosphorylates the WW-domain containing transcriptional co-activators YAP at Ser127 and TAZ at Ser89, promoting 14-3-3 binding and thereby inhibiting their translocation into the nucleus.	SIGNOR-197643
Q12972	P68400	0	phosphorylation	up-regulates activity	0.471	Phosphorylation of NIPP-1 in a heterodimeric complex with the catalytic subunit of protein phosphatase-1 resulted in an activation of the holoenzyme without a release of NIPP-1. Sequencing and phosphoamino acid analysis of tryptic phosphopeptides enabled us to identify Ser178 and Ser199 as the phosphorylation sites of protein kinase A, whereas Thr161 and Ser204 were phosphorylated by protein kinase CK2.	SIGNOR-250931
P16949	P53779	0	phosphorylation	down-regulates	0.301	Involved in the regulation of the microtubule (mt) filament system by destabilizing microtubules. Prevents assembly and promotes disassembly of microtubules. Here we show that in response to hyperosmotic stress, jnk phosphorylates a key cytoplasmic microtubule regulatory protein, stathmin (stmn), on conserved ser-25 and ser-38 residues. In in vitro biochemical studies, we identified stmn ser-38 as the critical residue required for efficient phosphorylation by jnk and identified a novel kinase interaction domain in stmn required for recognition by jnk. We revealed that jnk was required for microtubule stabilization in response to hyperosmotic stress.	SIGNOR-166690
P02647	O60674	0	null	up-regulates activity	0.298	ApoA-I interactions with ABCA1 and lipid efflux to apoA-I were substantially impaired by inhibiting or abolishing JAK2, whereas ABCA1 protein levels were unaffected, and ABCA1 cholesterol translocase activity was only slightly reduced. The most likely explanation for these findings is that JAK2 promotes apolipoprotein interactions with ABCA1 or a closely proximal site, and this facilitates the removal of cellular lipids. the interaction of apolipoproteins with ABCA1-expressing cells activates JAK2, which in turn activates a process that enhances apolipoprotein interactions with ABCA1 and lipid removal from cells	SIGNOR-252107
Q9UNH5	P48200	1	dephosphorylation	up-regulates activity	0.348	IRP2 Ser-157 is phosphorylated by Cdk1/cyclin B1 during G(2)/M and is dephosphorylated during mitotic exit by the phosphatase Cdc14A. Ser-157 phosphorylation during G(2)/M reduces IRP2 RNA-binding activity and increases ferritin synthesis, whereas Ser-157 dephosphorylation during mitotic exit restores IRP2 RNA-binding activity and represses ferritin synthesis.	SIGNOR-248829
P43405	Q06124	0	dephosphorylation	down-regulates activity	0.545	Another SHP isoform, SHP-2, has been linked to negative regulation of Syk.\|Syk and LAT are differentially dephosphorylated by SHP-2 and SHP-1, respectively.	SIGNOR-277085
Q13131	Q13363	1	phosphorylation	down-regulates	0.2	We found that an activated amp-activated protein kinase (ampk) phosphorylates ctbp1 on ser-158 upon metabolic stresses. Moreover, ampk-mediated phosphorylation of ctbp1 (s158) attenuates the repressive function of ctbp1	SIGNOR-200250
P78527	O00743	0	dephosphorylation	up-regulates activity	0.538	In addition, siRNA knockdown of either PP6R1 or PP6 significantly decreased IR activation of DNA-PK, suggesting that PP6 activates DNA-PK by association and dephosphorylation.\|PP6 may dephosphorylate sites in DNA-PKcs to reduce binding with heterodimer Ku proteins, because DNA-PK activation completely depends on Ku-mediated complex formation with DNA.	SIGNOR-277164
Q16531	Q9NRC8	0	deacetylation	down-regulates activity	0.357	Here, we show that DDB1 is acetylated and acetylation promotes DDB1 binding to CUL4. We also identify nucleolar sirtuin 7 (SIRT7) as a major deacetylase that negatively regulates DDB1-CUL4 interaction.	SIGNOR-275900
Q9NZQ7	Q96J02	0	ubiquitination	down-regulates quantity by destabilization	0.2	ITCH Ubiquitinates and Down-Regulates Tumor-Surface PD-L1.\|The current study supports a model (Fig. 7) in which the E3 ligase ITCH mediates poly-ubiquitination of PD-L1 and down-regulates tumor cell-surface PD-L1 levels (via ubiquitin-directed lysosomal degradation) in MAPKi-adapted melanoma cells and in potentially other biologic contexts such quasi-mesenchymal tumor cell-states that contribute to therapy resistance and metastatic potential.	SIGNOR-278815
P06493	P15927	1	phosphorylation	up-regulates activity	0.508	Cdc2 family kinases phosphorylate a human cell dna replication factor, rpa, and activate dna replication. therefore, the serines on rpa p34 that were necessary for phosphorylation by cdc2 kinase were also necessary for phosphorylation in the cell	SIGNOR-16975
P17844	O75925	0	sumoylation	up-regulates	0.546	We demonstrate that the sumo e3 ligase pias1 interacts with p68 and enhances its sumo modification in vivo / sumo modification enhances p68 transcriptional repression activity and inhibits the ability of p68 to function as a coactivator of p53.	SIGNOR-153719

Q12857

A6NFN3

1

transcriptional regulation

up-regulates quantity

0.261

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

SIGNOR-268911

O43395

Q13107

0

deubiquitination

down-regulates activity

0.487

Prp3 is deubiquitinated by Usp4 and its substrate targeting factor, the U4/U6 recycling protein Sart3, which likely facilitates ejection of U4 proteins from the spliceosome during maturation of its active site.

SIGNOR-271975

P55268

Q9NYD6

0

transcriptional regulation

up-regulates quantity by expression

0.2

The specificity of binding of these two proteins to the Lamin B2 origin is confirmed by both band-shift and in vitro footprinting assays. In addition, the ability of HOXC10 and HOXC13 to increase the activity of a promoter containing the 74 bp sequence, as assayed by CAT-assay experiments, demonstrates a direct interaction of these homeoproteins with the origin sequence in mammalian cells.

SIGNOR-261645

P16885

P06239

0

phosphorylation

up-regulates

0.558

In vitro phosphorylation experiments with recombinant plcgamma2 and recombinant lck, fyn, and lyn tyrosine kinases showed that phosphorylation of plcgamma2 led to activation of the recombinant enzyme.

SIGNOR-91477

Q96GX5

P31749

0

phosphorylation

up-regulates activity

0.2

Here, we report that AKT phosphorylates MASTL at residue T299, which plays a critical role in its activation.

SIGNOR-277515

Q9Y458

P56178

1

transcriptional regulation

down-regulates quantity by repression

0.307

the main function of TBX22 as shown in misexpression experiments is to decrease proliferation. We subsequently uncovered three targets of TBX22, DLX5, MSX2, and TBX22 itself. All are downregulated in the presence of viral-derived hTBX22.

SIGNOR-265566

P07951

P48736

0

phosphorylation

up-regulates activity

0.335

Here, we demonstrate a requirement for the protein kinase activity of PI(3)K in agonist-dependent beta-adrenergic receptor (betaAR) internalization. Using PI(3)K mutants with either protein or lipid phosphorylation activity, we identify the cytoskeletal protein non-muscle tropomyosin as a substrate of PI(3)K, which is phosphorylated in a wortmannin-sensitive manner on residue Ser 61. A constitutively dephosphorylated (S61A) tropomyosin mutant blocks agonist-dependent betaAR internalization, whereas a tropomyosin mutant that mimics constitutive phosphorylation (S61D) complements the PI(3)K mutant, with only lipid phosphorylation activity reversing the defective betaAR internalization.

SIGNOR-263028

O43395

P68400

0

phosphorylation

up-regulates

0.2

Our findings provide new insights into the biology of hprp3p and suggest that the loss of hprp3p phosphorylation at thr494 is a key step for initiating thr494met aberrant interactions within u4/u6 snrnp complex and that these are likely linked to the rp18 phenotype.

SIGNOR-158319

Q8N122

Q9UBE8

0

phosphorylation

down-regulates activity

0.327

NLK inhibits mTORC1 lysosomal localization and thereby suppresses mTORC1 activation. Mechanistically, NLK phosphorylates Raptor on S863 to disrupt its interaction with the Rag GTPase, which is important for mTORC1 lysosomal recruitment.

SIGNOR-273908

Q99250

Q96PU5

0

ubiquitination

down-regulates quantity by destabilization

0.317

The control of Nav density at the cell membrane is crucial to ensuring normal neuronal excitability. Navs are subject to posttranslational modifications that may influence their cell membrane availability. Ubiquitylation is a key process that orchestrates the internalization and subsequent degradation or recycling of Navs. This is accomplished by ubiquitin protein ligases, such as NEDD4-2 (neuronal precursor cell expressed developmentally downregulated-4 type 2).

SIGNOR-253459

P49841

P10071

1

phosphorylation

down-regulates quantity by destabilization

0.537

We show that these phosphoserines prime further phosphorylation at adjacent Glycogen Synthase Kinase 3 (GSK3) and Casein Kinase I (CK1) sites. Alteration of the GSK3 or CK1 sites prevents Ci-155 proteolysis and activates Ci in the absence of Hedgehog.

SIGNOR-219231

P27361

Q99814

1

phosphorylation

up-regulates quantity by stabilization

0.26

The activation of ERK1/2 upon hypoxia promoted HIF-2alpha phosphorylation, enhancing its interaction with USP33.Here, we identified USP33 as essential deubiquitinase that stabilizes HIF-2alpha protein in an ERK1/2-dependent manner to promote hypoxia response in cancer cells.

SIGNOR-277584

Q5VT25

P53671

1

phosphorylation

up-regulates activity

0.395

These results indicate that mrckalpha phosphorylates and activates lim kinases downstream of cdc42, which in turn regulates the actin cytoskeletal reorganization through the phosphorylation and inactivation of adf/cofilin.

SIGNOR-107584

Q13434

Q8IVH8

1

ubiquitination

down-regulates quantity

0.2

MKRN4 ubiquitinated GLK at Lys650 residue.|Remarkably, MKRN4 overexpression induced GLK protein degradation in HEK293T cells and Jurkat T cells (figure 5A and B).

SIGNOR-278658

P42574

P31749

1

cleavage

down-regulates activity

0.602

P53 can inhibit the survival function of integrins by inducing the caspase-dependent cleavage and inactivation of the serine/threonine kinase akt/pkb;the involvement of caspase 3 in akt/pkb regulation was indicated by the ability of z-devd-fmk, a caspase 3 inhibitor, to block the alpha6beta4-associated reduction in akt/pkb levels in vivo, and by the ability of recombinant caspase 3 to promote the cleavage of akt/pkb in vitro

SIGNOR-252624

P17612

P55211

1

phosphorylation

down-regulates

0.2

We show that protein kinase a inhibits activation of caspase-9 and caspase-3 downstream of cytochrome c in xenopus egg extracts and in a human cell-free system. Protein kinase a directly phosphorylates human caspase-9 at serines 99, 183, and 195.

SIGNOR-133884

Q13094

P43403

0

phosphorylation

up-regulates

0.804

Zap-70 phosphorylates slp-76 at specific sites that allow vav sh2 domain bindingwe also show by in vitro and in vivo analysis that two slp-76 pyesp motifs (y113 and y128) mediate binding, the first being more efficient.

SIGNOR-46859

Q13315

P51812

0

phosphorylation

up-regulates activity

0.388

Furthermore, using RSK2 knockout mouse fibroblasts and RSK2 deficient cells from CLS patients, we demonstrate that ablation of RSK2 impairs the phosphorylation of Atm at Ser1981 and the phosphorylation of p53 at Ser18 (mouse) or Ser15 (human) in response to genotoxic stress.|We postulate that the phosphorylation of RSK2 is required to fully activate Atm at Ser1981 and p53 at Ser18 (mouse) or Ser15 (human) in response to genotoxic stress.

SIGNOR-280118

P37173

Q9HCE7

0

ubiquitination

down-regulates activity

0.615

Smurf1 and smurf2 are e3 ubiquitin ligases known to suppress tgf-beta signaling through degradation of smads and receptors for tgf-beta and bmps.

SIGNOR-195672

P28482

Q13625

1

phosphorylation

up-regulates activity

0.263

Hence ASPP2 can be phosphorylated at serine 827 by MAPK1 in vitro.|Phosphorylation of ASPP2 by MAPK is required for RAS-induced increased binding to p53 and increased transactivation of pro-apoptotic genes.

SIGNOR-264414

P16519

P10997

1

cleavage

up-regulates activity

0.465

The processing of proinsulin to insulin occurs in the secretory granules at the C-terminal end of pairs of basic amino acids, Arg31-Arg32 and Lys64-Arg65 [9,10]. Following cleavage, by the prohormone convertases, PC3 (also known as PC1) and PC2, the pair of basic amino acids are removed rapidly by carboxypeptidase E (CPE) to produce the mature insulin molecule

SIGNOR-261791

Q96GD4

P53350

1

phosphorylation

up-regulates activity

0.599

Aurora B phosphorylates PLK1 on Thr210 to activate its kinase activity at the kinetochores during mitosis.|Thus, we conclude that Aurora B indirectly promotes the phosphorylation of MCAK on Ser715 at the kinetochores through phosphorylation of PLK1 at Thr210 and its ensuing activation.

SIGNOR-279358

Q6UWE0

Q99816

1

monoubiquitination

down-regulates quantity

0.527

Tal increases ubiquitylation of Tsg101 and affects its solubility in a RING- and PTAP-dependent manner. Tal-mediated ubiquitylation of Tsg101 inactivates this sorting function and concomitantly translocates Tsg101 from relatively insoluble membrane subdomains. Presumably, the coordinated action of Tal and a deubiquitylation enzyme (DUB) enables recycling of Tsg101 and reloading of cargo.

SIGNOR-271509

Q9BZK7

P20749

1

ubiquitination

down-regulates

0.401

We also defined the e3 ligase tblr1 as a protein involved in bcl-3 degradation

SIGNOR-166111

P36956

Q13131

0

phosphorylation

down-regulates activity

0.36

Ampk was recently found to phosphorylate a conserved serine near the cleavage site within srebp1, suppressing its activation

SIGNOR-176497

P12931

O60500

1

phosphorylation

up-regulates activity

0.48

Inhibition of Src kinase dependent Nephrin phosphorylation achieved by incubation of WT-Nephrin-overexpressing cells with 1 mum PP2 abolished the positive effect of Nephrin on GSIR (XREF_FIG D).|We were able to demonstrate a complete prevention of Nephrin phosphorylation, confirming that Nephrin phosphorylation is mediated by Src.

SIGNOR-280129

P10721

Q9NX45

0

transcriptional regulation

up-regulates quantity by expression

0.325

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

SIGNOR-266206

Q14790

P51812

0

phosphorylation

down-regulates quantity by destabilization

0.369

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

SIGNOR-272997

P31269

O14744

0

methylation

up-regulates activity

0.462

Hoxa9 methylation by prmt5 is essential for endothelial cell expression of leukocyte adhesion molecules. / prmt5 is a critical coactivator component in a newly defined, hoxa9-containing transcription complex./ Hoxa9 is methylated on arg140 by prmt5.

SIGNOR-195526

Q86XI6

Q6VVB1

0

ubiquitination

down-regulates quantity by destabilization

0.398

Here, we show that the laforin-malin complex downregulates PTG-induced glycogen synthesis in FTO2B hepatoma cells through a mechanism involving ubiquitination and degradation of PTG. We show here that laforin and malin play a crucial role in the regulation of glycogen biosynthesis in FTO2B hepatoma cells. In these cells, the laforin–malin complex counteracts the glycogenic effect of PTG because it promotes its ubiquitination and degradation.

SIGNOR-271728

P03372

P00519

0

phosphorylation

up-regulates

0.446

Eralpha can be phosphorylated on two sites, tyrosine 52 (y-52) and tyrosine 219 (y-219). Eralpha phosphorylation by c-abl stabilizes eralpha, resulting in enhanced eralpha transcriptional activity and increased expression of endogenous eralpha target genes.

SIGNOR-163562

Q8NFA2

Q86UR1

1

relocalization

up-regulates activity

0.777

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

SIGNOR-264709

Q9UEW8

Q9Y6R1

1

phosphorylation

down-regulates activity

0.348

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

SIGNOR-263133

P19474

P49327

1

ubiquitination

down-regulates quantity by destabilization

0.2

FASN acetylation enhanced its association with the E3 ubiquitin ligase TRIM21. Acetylation destabilized FASN and resulted in decreased de novo lipogenesis and tumor cell growth. FASN acetylation was frequently reduced in human hepatocellular carcinoma samples, which correlated with increased HDAC3 expression and FASN protein levels.

SIGNOR-267368

P43487

P53350

0

phosphorylation

up-regulates activity

0.359

Here, we demonstrated in vitro and in vivo phosphorylation of RanBP1 by Plk1 as well as the importance of phosphorylation of RanBP1 in the interaction between Plk1 and Ran during early mitosis.

SIGNOR-279751

P48163

P24752

0

acetylation

up-regulates activity

0.249

PGAM5-mediated dephosphorylation of malic enzyme 1 (ME1) at S336 allows increased ACAT1-mediated K337 acetylation, leading to ME1 dimerization and activation, both of which are reversed by NEK1 kinase-mediated S336 phosphorylation. SIRT6 deacetylase antagonizes ACAT1 function in a manner that involves mutually exclusive ME1 S336 phosphorylation and K337 acetylation.

SIGNOR-275571

Q16828

Q13164

1

dephosphorylation

down-regulates activity

0.646

However, whilst the interaction itself might be difficult to monitor, DUSP6 should still be able to promote the de-phosphorylation of ERK5 in cells if it is an ERK5 phosphatase.To test this HEK293 cells were transiently transfected with HA-ERK2 or HA-ERK5 together with EGFP-MEK1E (a constitutively active version of MEK1) or EGFP-MEK5D (a constitutively active version of MEK5).|Whilst one can envisage scenarios in which the interaction between DUSPs and their substrates might be transient, DUSP6 should still be able to promote the de-phosphorylation and inactivation of ERK5.

SIGNOR-277007

P43403

P51452

1

phosphorylation

up-regulates activity

0.531

ZAP-70 and Syk also tyrosine-phosphorylated VHR in COS-1 cells (Fig. 2d), whereas other kinases (Csk, Lck, Fyn, Jak2, Bcr-Abl and Itk) had little effect. Finally, recombinant ZAP-70 readily phosphorylated VHR in vitro (Fig. 2f).

SIGNOR-276000

A8MYZ6

Q14938

0

transcriptional regulation

down-regulates quantity

0.2

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

SIGNOR-268887

Q13541

Q16539

0

phosphorylation

down-regulates activity

0.433

4E-BP1 Is Phosphorylated in Vitro by Active p38 Kinase. In the present study we demonstrated that UVB induced 4E-BP1 phosphorylation at multiple sites, Thr-36, Thr-45, Ser-64, and Thr-69, leading to dissociation of 4E-BP1 from eIF-4E.

SIGNOR-250097

Q5JU85

P42263

1

relocalization

up-regulates quantity

0.2

BRAG1 increases the synaptic recycling pool of AMPARs.these data suggest that the BRAG1 enhancement of AMPAR transmission is mediated by the increased expression of the recycling pool of synaptic GluA2/3 receptors.

SIGNOR-264914

Q9UQ80

P35637

0

sumoylation

up-regulates activity

0.336

Here, we show that Ebp1 p42 isoform can be sumoylated on both K93 and K298 residues, which mediate its nuclear translocation and are required for its anti-proliferative activity .. Hence, TLS-mediated sumoylation is required for Ebp1 transcriptional repressive activity.

SIGNOR-236904

P42345

Q9C0C7

1

phosphorylation

down-regulates activity

0.471

We show that under non-autophagic conditions, mTOR inhibits AMBRA1 by phosphorylation, whereas on autophagy induction, AMBRA1 is dephosphorylated. In this condition, AMBRA1, interacting with the E3-ligase TRAF6, supports ULK1 ubiquitylation by LYS-63-linked chains, and its subsequent stabilization, self-association and function. As ULK1 has been shown to activate AMBRA1 by phosphorylation, the proposed pathway may act as a positive regulation loop, which may be targeted in human disorders linked to impaired autophagy.|mTOR phosphorylates AMBRA1 at Ser 52, inhibiting its role in ULK1 modification

SIGNOR-272986

P10619

P19484

0

transcriptional regulation

up-regulates quantity by expression

0.298

Nucleus-Translocated ACSS2 Promotes Gene Transcription for Lysosomal Biogenesis and Autophagy|A chromatin immunoprecipitation (ChIP) assay with antibodies against TFEB or ACSS2 demonstrated that glucose deprivation results in the binding of TFEB (Figure 3D) and ACSS2 (Figure 3E) to the promoter regions of CTSA, GBA, GUSB, and LAMP1|These results indicated that TFEB and ACSS2 are mutually required for their binding to the promoter regions of lysosomal genes. In line with these findings, glucose deprivation induced mRNA (Figure 3F) and protein (Figure 3G) expression for these lysosomal genes, which was largely abrogated by knockin of ACSS2 mutants

SIGNOR-276549

Q9NS28

P17612

0

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

Q9C029

Q86WV6

1

ubiquitination

down-regulates quantity by destabilization

0.2

RNF90 promoted K48-linked ubiquitination of MITA and its proteasome-dependent degradation.|Finally, in vitro ubiquitination assays suggested that RNF90 promoted the ubiquitination of MITA directly (Fig 5E and 5F).

SIGNOR-278678

Q9HAW9

Q99626

0

transcriptional regulation

up-regulates quantity by expression

0.26

Using gel shift and functional assays, HNF1alpha was demonstrated to bind to and activate the UGT1A8, -1A9, and -1A10 promoters. In contrast, Cdx2 bound to and activated the UGT1A8 and -1A10 promoters but could not activate the UGT1A9 promoter.

SIGNOR-253969

Q9UHD2

P09769

0

phosphorylation

down-regulates activity

0.2

The Src family kinases (SFKs) Lck, Hck, and Fgr directly phosphorylate TBK1 at Tyr354/394, to prevent TBK1 dimerization and activation.

SIGNOR-276725

O60716

P28827

0

dephosphorylation

down-regulates quantity

0.541

Specifically, RPTP\u03bc dephosphorylated p120 catenin, subsequently leading to a lower level of cytoplasmic protein compared with that observed with the vector control and RPTP\u03bc-CS.

SIGNOR-277042

P19784

P60484

1

phosphorylation

down-regulates activity

0.704

We used mass spectrometric methods to identify Ser(370) and Ser(385) as in vivo phosphorylation sites of PTEN. These sites also are phosphorylated by CK2 in vitro, and phosphorylation inhibits PTEN activity towards its substrate, PIP3. We also identify a novel in vivo phosphorylation site, Thr(366).

SIGNOR-251025

P61586

O15068

0

guanine nucleotide exchange factor

up-regulates activity

0.619

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-260559

O94916

Q00535

0

phosphorylation

up-regulates

0.2

High nacl-induced activation of cdk5 increases phosphorylation of the osmoprotective transcription factor tonebp/orebp at threonine 135, which contributes to its rapid nuclear localization. n hek293 cells, mass spectrometry shows phosphorylation of tonebp/orebp-s120, -s134, -t135, and -s155.

SIGNOR-170886

P12830

O15379

0

transcriptional regulation

down-regulates quantity by repression

0.257

GATA1 is a new substrate of p21-activated kinase 5 (PAK5), which is phosphorylated on serine 161 and 187 (S161 and S187). GATA1 recruits HDAC3/4 to E-cadherin promoter, which is reduced by GATA1 S161A S187A mutant. These data indicate that phosphorylated GATA1 recruits more HDAC3/4 to promote transcriptional repression of E-cadherin, leading to the EMT of breast cancer cells.

SIGNOR-275662

O15111

Q00653

1

phosphorylation

up-regulates activity

0.791

Ikkalfa phosphorylates p100, leading to its proteasomal processing to p52.

SIGNOR-124230

P35638

P17676

1

transcriptional regulation

down-regulates quantity

0.668

We find that expression of CHOP, a nuclear protein that dimerizes avidly with C/EBP isoforms alpha and beta and directs the resulting heterodimer away from classic C/EBP-binding sites, markedly inhibits this differentiation process.

SIGNOR-255914

P07910

P48729

0

phosphorylation

down-regulates

0.354

A kinase activity was identified in mouse liver that phosphorylates the acd of hnrnp-c at ser(240) and at two sites at ser(225)-ser(228). The kinase was purified and identified by tandem mass spectrometry as protein kinase ck1alpha (formerly casein kinase 1alpha).hnrnp-c1 that was also modified at the ck1alpha phosphorylation sites exhibited a 14-500-fold decrease in binding affinity, demonstrating that ck1alpha-mediated phosphorylation modulates the mrna binding ability of hnrnp-c.

SIGNOR-133528

P68400

P27348

1

phosphorylation

down-regulates activity

0.347

The neuroprotective effect of 14-3-3theta against rotenone toxicity is dependent on the inhibition of the pro-apoptotic factor Bax|Phosphorylation at S232 induced by rotenone is reduced by casein kinase inhibitors, and is not dependent on alphasyn.| The S232D mutant partially reduced the ability of 14-3-3theta to inhibit Bax activation in response to rotenone. Based on these findings, we propose that phosphorylation of 14-3-3s at serine 232 contributes to the neurodegenerative process in PD.

SIGNOR-264405

Q14653

P78527

0

phosphorylation

up-regulates

0.43

Phosphorylation of irf-3 by dna-pk after virus infection results in its nuclear retention and delayed proteolysis

SIGNOR-115331

P42345

O00429

1

phosphorylation

up-regulates activity

0.345

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

SIGNOR-275430

P06213

P60484

1

phosphorylation

down-regulates activity

0.442

Our results show that the kinase region of IRβ subunit physically binds to PTEN and phosphorylates on Y27 and Y174. In the current study, we discovered that IR also downregulates PTEN through tyrosine phosphorylation and suggest that Y27 and 174 are the two key tyrosines.

SIGNOR-276470

Q13547

Q96KB5

0

phosphorylation

up-regulates activity

0.245

TOPK overexpression promotes HDAC1 and HDAC2 phosphorylation and Histone 3 and Histone 4 acetylation in BV2 cells.|The results of in vitro studies further confirmed the effect of TOPK on HDAC activity by showing that TOPK overexpression significantly up-regulated p-HDAC1 and p-HDAC2, resulting in an increase in the acetylation of histones H3 and H4 in BV2 cells.

SIGNOR-279086

Q9BYF1

P01019-PRO_0000420660

1

cleavage

up-regulates quantity

0.2

At first, ACE2 has been demonstrated to induce conversion of Ang I into Ang (1–7) by means of intermediate production of Ang (1–9), a fragment with unknown function.

SIGNOR-260227

Q05655

P18031

0

dephosphorylation

down-regulates

0.2

Dephosphorylation of tyrosine residues by ptp1b, a protein tyrosine phosphatase, reduced the enhanced pkcdelta activity.

SIGNOR-107754

O15530

Q9Y243

1

phosphorylation

up-regulates

0.651

The activation of pkbbeta and pkbgamma by pdk1 was accompanied by the phosphorylation of the residues equivalent to thr308 in pkbalpha, namely thr309 (pkbbeta) and thr305 (pkbgamma)

SIGNOR-55937

P12931

Q13322

1

phosphorylation

down-regulates

0.447

Grb10 tyrosine phosphorylation was stimulated by expression of constitutively active src or fyn in cells and by incubation with purified src or fyn in vitro. The insulin stimulated or src/fyn-mediated tyrosine phosphorylation in vivo was significantly reduced when grb10 tyrosine 67 was changed to glycine. This mutant form of grb10 bound with higher affinity to the ir in cells than that of the wild-type protein, suggesting that tyrosine phosphorylation of grb10 may normally negatively regulate its binding to the ir.

SIGNOR-78706

Q7Z5H3

P63000

1

gtpase-activating protein

down-regulates activity

0.529

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-260477

P10636

P20807

0

cleavage

down-regulates activity

0.324

Besides tau phosphorylation, calpain activation might play a role in tau-mediated neurodegeneration by inducing tau cleavage. In vitro studies have shown that both fetal and adult tau isoforms are rapidly proteolyzed by calpains

SIGNOR-251605

P17252

Q6ZVD8

0

dephosphorylation

down-regulates quantity

0.253

In addition, knockdown of PHLPP expression reduces the rate of phorbol ester-triggered dephosphorylation of the hydrophobic motif, but not turn motif, of PKC alpha

SIGNOR-237051

Q9Y574

Q02363

1

polyubiquitination

down-regulates quantity by destabilization

0.341

Using JAR placental cells, we determined that ASB4 ubiquitinates and represses ID2 expression in a proteasome-dependent fashion.

SIGNOR-272053

P17252

P19086

1

phosphorylation

up-regulates

0.442

Functional role of amino-terminal serine16 and serine27 of g alphaz in receptor and effector coupling.

SIGNOR-48681

Q00535

P30086

1

phosphorylation

down-regulates quantity by destabilization

0.337

Here, we demonstrate that RKIP is a substrate of cyclin-dependent kinase 5 (CDK5) in neurons and that the phosphorylation of RKIP at T42 causes the release of Raf-1. Moreover, T42 phosphorylation promotes the exposure and recognition of the target motif "KLYEQ" in the C-terminus of RKIP by chaperone Hsc70 and the subsequent degradation of RKIP via chaperone-mediated autophagy (CMA).

SIGNOR-276672

Q8TD19

P53350

0

phosphorylation

up-regulates activity

0.611

We now identify Plk1 as Nek9 direct activator and propose a two-step activation mechanism that involves Nek9 sequential phosphorylation by CDK1 and Plk1. while CDK1 activity is necessary for Nek9 phosphorylation in mitosis and the resulting change in electrophoretical mobility, Nek9 Thr210 phosphorylation and mitotic activation requires both CDK1 and Plk1.

SIGNOR-273888

P19429

Q05655

0

phosphorylation

up-regulates activity

0.272

Src phosphorylates pkcdelta at tyr311 and tyr332 leading to enhanced pkcdelta autophosphorylation at thr505 (its activation loop) and pkcdelta-dependent ctni phosphorylation at both ser23/ser24 and thr144.

SIGNOR-178880

P12931

Q14289

1

phosphorylation

up-regulates

0.624

These data indicate that pyk2 activation via phosphorylation at tyr-402 requires ?V?3 Ligation and src activity.

SIGNOR-133870

Q08999

O43524

0

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

P28482

P49715

1

phosphorylation

down-regulates

0.352

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

SIGNOR-120566

Q04759

P22681

1

phosphorylation

up-regulates activity

0.355

PKC-θ-mediated phosphorylation of serine and tyrosine residues of c-Cbl prevents its inhibitory effect. Phosphorylation of c-Cbl by PKC-θ inhibits the recruitment of Sh2-containing proteins and subsequent association of cbl E3 ubiquitin ligase with its target proteins

SIGNOR-274144

Q8WVD3

Q9UJU2

1

polyubiquitination

down-regulates quantity by destabilization

0.307

Here, we show that NARF induces the ubiquitylation of TCF/LEF in vitro and in vivo, and functions as an E3 ubiquitin-ligase that specifically cooperates with the E2 conjugating enzyme E2-25K. We found that NLK augmented NARF binding and ubiquitylation of TCF/LEF, and this required NLK kinase activity. The ubiquitylated TCF/LEF was subsequently degraded by the proteasome.

SIGNOR-271595

Q00535

Q05682

1

phosphorylation

down-regulates quantity by destabilization

0.341

Together, these data demonstrate that phosphorylation of caldesmon on Ser527 by Cdk5 serves to down regulate its stability.

SIGNOR-280215

Q02086

P49585

1

transcriptional regulation

down-regulates quantity by repression

0.2

Sp3 is an activator, and Sp2 a repressor, of the Ctpct promoter in SL2 cells.

SIGNOR-266230

P49841

P17812

1

phosphorylation

down-regulates activity

0.2

We found that low serum conditions increased phosphorylation of endogenous CTPS1 and this phosphorylation was inhibited by the glycogen synthase kinase 3 (GSK3) inhibitor indirubin-3'-monoxime and GSK3beta short interfering RNAs, demonstrating the involvement of GSK3 in phosphorylation of endogenous human CTPS1. Separating tryptic peptides from [(32)P]orthophosphate-labeled cells and analyzing the phosphopeptides by mass spectrometry identified Ser-574 and Ser-575 as phosphorylated residues. Incubation with an alkaline phosphatase increased CTPS1 activity in a time-dependent manner, demonstrating that phosphorylation inhibits CTPS1 activity.

SIGNOR-276069

O00141

P49815

1

phosphorylation

down-regulates activity

0.579

SGK1, which is activated by PDK1, contributes to the maintenance of residual mTORC1 activity through direct phosphorylation and inhibition of TSC2.

SIGNOR-277266

P40763

Q13233

0

phosphorylation

up-regulates activity

0.291

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

SIGNOR-236346

P06493

Q96QE3

1

phosphorylation

down-regulates activity

0.24

To determine whether mitotic CDK phosphorylates ATAD5, a CDK1 inhibitor (RO3306) was applied to nocodazole-arrested cells (Figure S3F). CDK1 inhibition resulted in a loss of S653 phosphorylation (Figure S3F). These data meant that the S653 residue in the BET BD of ATAD5 is phosphorylated by mitotic CDK. This result suggested that the BRD4-ATAD5 interaction is inhibited during mitosis.

SIGNOR-266410

P43026

Q9UHF7

1

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

Q05655

P53004

1

phosphorylation

up-regulates activity

0.2

LC-MS/MS analysis of PKCdelta-activated intact hBVR identified phosphorylated serine positions 21, 33, 230, and 237, corresponding to the hBVR Src homology-2 domain motif (Ser(230) and Ser(237)), flanking the ATP-binding motif (Ser(21)) and in PHPS sequence (Ser(33)) as targets of PKCdelta. |PKCdelta potentiated hBVR reductase activity and accelerated the rate of bilirubin formation.

SIGNOR-275525

P51812

O60825

1

phosphorylation

up-regulates activity

0.2

Heart 6-phosphofructo-2-kinase activation by insulin results from ser-466 and ser-483 phosphorylation and requires 3-phosphoinositide-dependent kinase-1, but not protein kinase b.

SIGNOR-23753

P52333

P42229

1

phosphorylation

up-regulates

0.854

For these assays, coexpression of wt jak3 with stat5a was found to result in tyrosine phosphorylation of stat5a (lane 2) mediated by jak3, since stat5a coexpressed with the kinase-inactive k855a mutant form of jak3 was not tyrosine phosphorylated.

SIGNOR-182817

Q9GZV5

O95835

0

phosphorylation

down-regulates

0.791

In response to high cell densities, activated LATS1/2 phosphorylates the WW-domain containing transcriptional co-activators YAP at Ser127 and TAZ at Ser89, promoting 14-3-3 binding and thereby inhibiting their translocation into the nucleus.

SIGNOR-197643

Q12972

P68400

0

phosphorylation

up-regulates activity

0.471

Phosphorylation of NIPP-1 in a heterodimeric complex with the catalytic subunit of protein phosphatase-1 resulted in an activation of the holoenzyme without a release of NIPP-1. Sequencing and phosphoamino acid analysis of tryptic phosphopeptides enabled us to identify Ser178 and Ser199 as the phosphorylation sites of protein kinase A, whereas Thr161 and Ser204 were phosphorylated by protein kinase CK2.

SIGNOR-250931

P16949

P53779

0

phosphorylation

down-regulates

0.301

Involved in the regulation of the microtubule (mt) filament system by destabilizing microtubules. Prevents assembly and promotes disassembly of microtubules. Here we show that in response to hyperosmotic stress, jnk phosphorylates a key cytoplasmic microtubule regulatory protein, stathmin (stmn), on conserved ser-25 and ser-38 residues. In in vitro biochemical studies, we identified stmn ser-38 as the critical residue required for efficient phosphorylation by jnk and identified a novel kinase interaction domain in stmn required for recognition by jnk. We revealed that jnk was required for microtubule stabilization in response to hyperosmotic stress.

SIGNOR-166690

P02647

O60674

0

null

up-regulates activity

0.298

ApoA-I interactions with ABCA1 and lipid efflux to apoA-I were substantially impaired by inhibiting or abolishing JAK2, whereas ABCA1 protein levels were unaffected, and ABCA1 cholesterol translocase activity was only slightly reduced. The most likely explanation for these findings is that JAK2 promotes apolipoprotein interactions with ABCA1 or a closely proximal site, and this facilitates the removal of cellular lipids. the interaction of apolipoproteins with ABCA1-expressing cells activates JAK2, which in turn activates a process that enhances apolipoprotein interactions with ABCA1 and lipid removal from cells

SIGNOR-252107

Q9UNH5

P48200

1

dephosphorylation

up-regulates activity

0.348

IRP2 Ser-157 is phosphorylated by Cdk1/cyclin B1 during G(2)/M and is dephosphorylated during mitotic exit by the phosphatase Cdc14A. Ser-157 phosphorylation during G(2)/M reduces IRP2 RNA-binding activity and increases ferritin synthesis, whereas Ser-157 dephosphorylation during mitotic exit restores IRP2 RNA-binding activity and represses ferritin synthesis.

SIGNOR-248829

P43405

Q06124

0

dephosphorylation

down-regulates activity

0.545

Another SHP isoform, SHP-2, has been linked to negative regulation of Syk.|Syk and LAT are differentially dephosphorylated by SHP-2 and SHP-1, respectively.

SIGNOR-277085

Q13131

Q13363

1

phosphorylation

down-regulates

0.2

We found that an activated amp-activated protein kinase (ampk) phosphorylates ctbp1 on ser-158 upon metabolic stresses. Moreover, ampk-mediated phosphorylation of ctbp1 (s158) attenuates the repressive function of ctbp1

SIGNOR-200250

P78527

O00743

0

dephosphorylation

up-regulates activity

0.538

In addition, siRNA knockdown of either PP6R1 or PP6 significantly decreased IR activation of DNA-PK, suggesting that PP6 activates DNA-PK by association and dephosphorylation.|PP6 may dephosphorylate sites in DNA-PKcs to reduce binding with heterodimer Ku proteins, because DNA-PK activation completely depends on Ku-mediated complex formation with DNA.

SIGNOR-277164

Q16531

Q9NRC8

0

deacetylation

down-regulates activity

0.357

Here, we show that DDB1 is acetylated and acetylation promotes DDB1 binding to CUL4. We also identify nucleolar sirtuin 7 (SIRT7) as a major deacetylase that negatively regulates DDB1-CUL4 interaction.

SIGNOR-275900

Q9NZQ7

Q96J02

0

ubiquitination

down-regulates quantity by destabilization

0.2

ITCH Ubiquitinates and Down-Regulates Tumor-Surface PD-L1.|The current study supports a model (Fig. 7) in which the E3 ligase ITCH mediates poly-ubiquitination of PD-L1 and down-regulates tumor cell-surface PD-L1 levels (via ubiquitin-directed lysosomal degradation) in MAPKi-adapted melanoma cells and in potentially other biologic contexts such quasi-mesenchymal tumor cell-states that contribute to therapy resistance and metastatic potential.

SIGNOR-278815

P06493

P15927

1

phosphorylation

up-regulates activity

0.508

Cdc2 family kinases phosphorylate a human cell dna replication factor, rpa, and activate dna replication. therefore, the serines on rpa p34 that were necessary for phosphorylation by cdc2 kinase were also necessary for phosphorylation in the cell

SIGNOR-16975

P17844

O75925

0

sumoylation

up-regulates

0.546

We demonstrate that the sumo e3 ligase pias1 interacts with p68 and enhances its sumo modification in vivo / sumo modification enhances p68 transcriptional repression activity and inhibits the ability of p68 to function as a coactivator of p53.

SIGNOR-153719