Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.24 (mitogen-activated protein kinase)
95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We hypothesized that glutathione transferases could be induced and may participate to cellular defenses against the oxidative stress occurring during liver regeneration. Here, we evidenced that murine GSTA1 (mGSTA1), A4, Pi, and Mu are up-regulated during mouse liver regeneration, exhibiting a biphasic pattern of induction correlating early G(1) phase and G(1)/S transition of the cell cycle. Using confocal microscopy immunolocalization and subcellular fractionation, mGSTA4 was demonstrated in both mitochondria and cytosol and found preferentially increased in cytosol during liver regeneration. In addition, mGSTA4 was induced in vivo and in cultured hepatocytes by tumor necrosis factor alpha (TNFalpha), interleukin-6 (IL-6), and epidermal growth factor (EGF), factors that play crucial roles in hepatocyte survival and proliferation during liver regeneration. However, the mitogenic effect of EGF was not responsible for the induction of mGSTA4. In transient transfections, IL-6 and EGF, but not TNFalpha, transactivated the human GSTA4 (hGSTA4) promoter cloned upstream of the luciferase reporter gene suggesting that IL-6 and EGF up-regulated hGSTA4 at a transcriptional level, whereas TNFalpha could rather act at a post-transcriptional level. The inhibition of phosphoinositide 3-kinase, p38 MAPK, and MEK/ERK signaling pathways, using specific inhibitors, prevented EGF-dependent induction of mGSTA4 and transactivation of hGSTA4 promoter. Altogether, these data favor the conclusion that, in regenerating hepatocytes, several GST isoforms are induced and that cytokines TNFalpha and IL-6 and survival factor EGF positively regulate mGSTA4 via survival signaling pathways.
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PMID:Pro-inflammatory cytokines tumor necrosis factor alpha and interleukin-6 and survival factor epidermal growth factor positively regulate the murine GSTA4 enzyme in hepatocytes. 1188 96

The carboxyl-terminal domain (CTD) of the p90 ribosomal S6 kinases (RSKs) is an important regulatory domain in RSK and a model for kinase regulation of FXXFXF(Y) motifs in AGC kinases. Its properties had not been studied. We reconstituted activation of the CTD in Escherichia coli by co-expression with active ERK2 mitogen-activated protein kinase (MAPK). GST-RSK2-(aa373-740) was phosphorylated in the P-loop (Thr(577)) by MAPK, accompanied by increased phosphorylation on the hydrophobic motif site, Ser(386). Activated GST-RSK2-(aa373-740) phosphorylates synthetic peptides based on Ser(386). The peptide RRQLFRGFSFVAK, which was termed CTDtide, was phosphorylated with K(m) and V(max) values of approximately 140 microm and approximately 1 micromol/min/mg, respectively. Residues Leu at p -5 and Arg at p -3 are important for substrate recognition, but a hydrophobic residue at p +4 is not. RSK2 CTD is a much more selective peptide kinase than MAPK-activated protein kinase 2. CTDtide was used to probe regulation of hemagglutinin-tagged RSK proteins immunopurified from epidermal growth factor-stimulated BHK-21 cells. K100A but not K451A RSK2 phosphorylates CTDtide, indicating a requirement for the CTD. RSK2-(aa1-389) phosphorylates the S6 peptide, and this activity is inactivated by S386A mutation, but RSK2-(aa1-389) does not phosphorylate CTDtide. In contrast, RSK2-(aa373-740) containing only the CTD phosphorylates CTDtide robustly. Thus, CTDtide is phosphorylated by the CTD but not the NH(2)-terminal domain (NTD). Epidermal growth factor activates the CTD and NTD in parallel. Activity of the CTD for peptide phosphorylation correlates with Thr(577) phosphorylation. CTDtide activity is constrained in full-length RSK2. Interestingly, mutation of the conserved lysine in the ATP-binding site of the NTD completely eliminates S6 kinase activity, but a similar mutation of the CTD does not completely ablate kinase activity for intramolecular phosphorylation of Ser(386), even though it greatly reduces CTDtide activity. The standard lysine mutation used routinely to study kinase functions in vivo may be unsatisfactory when the substrate is intramolecular or in a tight complex.
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PMID:Characterization of the p90 ribosomal S6 kinase 2 carboxyl-terminal domain as a protein kinase. 1201 17

The p25(rum1) is an inhibitor of Cdc2 kinase expressed in fission yeast and plays an important role in cell-cycle control. As its amino-acid sequence suggests that p25(rum1) has putative phosphorylation sites for mitogen-activated protein kinase (MAPK), we investigated the ability of MAPK to phosphorylate p25(rum1). Direct in vitro kinase assay using GST-fusion proteins of wild-type as well as various mutants of p25(rum1) demonstrated that MAPK phosphorylates the N-terminal portion of p25(rum1) and residues Thr13 and Ser19 are major phosphorylation sites for MAPK. In addition, phosphorylation of p25(rum1) by MAPK revealed markedly reduced Cdc2 kinase inhibitor ability of the protein. Together with the fact that replacement of both Thr13 and Ser19 with Glu, which mimics the phosphorylated state of these residues, also significantly reduces the activity of p25(rum1) as a Cdc2 inhibitor, it was suggested that the phosphorylation of Thr13 and Ser19 negatively regulates the function of p25(rum1). Further evidence indicates that phosphorylation of Thr13 and Ser19 may retain a negative effect on the function of p25(rum1) even in vivo. Therefore, MAPK may regulate the function of p25(rum1) via phosphorylation of its Thr and Ser residues and thus participate in cell cycle control in fission yeast.
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PMID:Rum1, an inhibitor of cyclin-dependent kinase in fission yeast, is negatively regulated by mitogen-activated protein kinase-mediated phosphorylation at Ser and Thr residues. 1213 91

The interactions between biomolecules and human glutathione transferase M2-2 (GST M2-2) were probed by using 9- and 15-mer combinatorial peptide libraries displayed on phage. The peptide libraries were based on random DNA sequences fused to gIII, a gene that expresses a phage coat protein and thus causes the peptides to be displayed on the surface of phage particles. A peptide sequence was enriched through binding to GST M2-2, which indicated a successful selection. Binding studies with the peptide displayed on phage showed binding specificity. The sequence of the peptide had similarities to segments of proteins in the Swiss-Prot Database, to c-Jun N-terminal kinase (JNK), and to the protein Bcl3. JNK is linked to the regulation of the transcription factor AP-1. Use of cell-based assays of the transcriptional activity of AP-1 allowed a novel coactivation function of GST M2-2 to be demonstrated. Specificity in the activation was indicated by the lack of effect of GST A1-1. No coactivator function of GST M2-2 could be demonstrated in assays with Bcl3. These results suggest that GST M2-2 has biological roles in addition to catalysis of detoxication reactions, and demonstrate the potential of phage display in functional genomics research.
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PMID:Probing biomolecular interactions of glutathione transferase M2-2 by using peptide phage display. 1221 Sep 82

Many drugs and xenobiotics induce signal transduction events leading to gene expression of either pharmacologically beneficial effects, or unwanted side effects such as cytotoxicity which can compromise drug therapy. Using dietary chemopreventive compounds (isothiocyanates and green tea polyphenols), which are effective against various chemically-induced carcinogenesis models in animals studies, we studied the signal transduction events and gene expression profiles. These compounds have typically generated cellular "oxidative stress" and modulated gene expression including phase II detoxifying enzymes GST and QR as well as cellular defensive enzymes, heme oxygenase 1 (HO-1) and GST via the antioxidant/electrophile response element (ARE/EpRE). Members of the bZIP transcription factor, Nrf2 which heterodimerizes with Maf G/K, were found to bind to ARE, and transcriptionally activate ARE. Additionally the mitogen-activated protein kinases (MAPK; ERK, JNK and p38) were differentially activated by these compounds, and involved in the transcriptional activation of ARE-mediated reporter gene. Transfection studies with various cDNA encoding for wild-type of MAPK and Nrf2 showed synergistic response during co-transfection and to these agents. However, by increasing the concentrations of these xenobiotics, caspase activities and apoptosis were observed which were preceded by mitochondria damage and cytochrome c mitochondria release. Further, increased concentrations led to rapid cell necrosis. [corrected] Thus, we have proposed a model, that at low concentrations, these compounds activate MAPK pathway leading to activation of Nrf2 and ARE with subsequent induction of phase II and other defensive genes which protect cells against toxic insults thereby enhancing cell survival, a beneficial homeostatic response. At higher concentrations, these agents activate the caspase pathways, leading to apoptosis, a potential cytotoxic effect if it occurred in normal cells. The studies of these signaling pathways may yield important insights into the pharmacodynamic and toxicodynamic effects of drugs and xenobiotics during pharmaceutical drug discovery and development.
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PMID:Antioxidants and oxidants regulated signal transduction pathways. 1221 68

Hepatoprotection mediated by free radical scavenging molecules such as dimethyl sulfoxide (Me(2)SO) arose the question as to whether this effect involved one or several anti-apoptotic signals. Here, using primary cultures of rat hepatocytes and in vivo thioacetamide-induced liver failure, we showed that Me(2)SO failed to prevent any cleavage of initiator caspase-8 and -9 but constantly inhibited procaspase-3 maturation and apoptosis execution, pointing to an efficient inhibition of cleaved initiator caspase activities. Evidence was recently provided that apoptosis might require both caspase and ASK1/JNK-p38 activities. We demonstrated that this kinase pathway was strongly inhibited in the presence of Me(2)SO whereas overexpression of ASK1 was able to restore caspase-3 activity and apoptosis. Interestingly, we also found that GST M1/2 and GST Alpha1/2 dropped under apoptotic conditions; furthermore transfection of GST M1, A1, or P1 to cells overexpressing ASK1, abolished caspase-3 activity and restored viability. This role of GSTs was further assessed by showing that their high expression level was tightly associated with inhibition of ASK1 activity in Me(2)SO-protected hepatocytes. Together, these results demonstrate that Me(2)SO-mediated hepatoprotection involves a dual inhibition of cleaved initiator caspase and ASK1/JNK-p38 activities. Furthermore, in highlighting the control of apoptosis by GSTs, these data provide new insights for analyzing the complex mechanisms of hepatoprotection.
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PMID:Liver protection from apoptosis requires both blockage of initiator caspase activities and inhibition of ASK1/JNK pathway via glutathione S-transferase regulation. 1237 Jan 86

LCPTP (leucocyte-phosphotyrosine phosphatase) is a 42kDa protein tyrosine phosphatase expressed predominantly in haematopoietic cells which has been implicated in the early stages of the T cell receptor signalling pathway. The substrates of LCPTP have been shown to include MAP kinase family members, but it remains unclear whether LCPTP is found in stable constitutive association with these enzymes, or associates transiently during dephosphorylation. Here we report on LCPTP/MAP kinase interactions in CD3-stimulated Jurkat T cells. Pull-downs from Jurkat T cells using a recombinant GST-LCPTP substrate-trap protein, but not wild-type LCPTP show a clear specific association with both ERK1 and ERK2. In Jurkat cells overexpressing LCPTP, a small fraction of cell ERK1 can be immunoprecipitated in stable association with LCPTP. However, in both unstimulated and anti-CD3 antibody stimulated Jurkat T cells, we were unable to demonstrate any constitutive interaction between endogenous LCPTP and any MAP kinase family members. We propose that both ERK1 and ERK2 interact transiently with LCPTP as substrates for the phosphatase rather than as constitutive protein partners.
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PMID:LCPTP-MAP kinase interaction: permanent partners or transient associates? 1241 99

The GLH proteins belong to a family of four germline RNA helicases in Caenorhabditis elegans. These putative ATP-dependent enzymes localize to the P granules, which are nonmembranous complexes of protein and RNA exclusively found in the cytoplasm of all C. elegans germ cells and germ cell precursors. To determine what proteins the GLHs bind, C. elegans cDNA libraries were screened by the yeast two-hybrid method, using GLHs as bait. Three interacting proteins, CSN-5, KGB-1, and ZYX-1, were identified and further characterized. GST pull-down assays independently established that these proteins bind GLHs. CSN-5 is closely related to the subunit 5 protein of COP9 signalosomes, conserved multiprotein complexes of plants and animals. RNA interference (RNAi) with csn-5 results in sterile worms with small gonads and no oocytes, a defect essentially identical to that produced by RNAi with a combination of glh-1 and glh-4. KGB-1 is a putative JNK MAP kinase that GLHs bind. A kgb-1 deletion strain has a temperature-sensitive, sterile phenotype characterized by the absence of mature oocytes and the presence of trapped, immature oocytes that have undergone endoreplication. ZYX-1 is a LIM domain protein most like vertebrate Zyxin, a cytoskeletal adaptor protein. In C. elegans, while zyx-1 appears to be a single copy gene, neither RNAi depletion nor a zyx-1 deletion strain results in an obvious phenotype. These three conserved proteins are the first members in each of their families reported to associate with germline helicases. Similar to the loss of GLH-1 and GLH-4, loss of either CSN-5 or KGB-1 causes oogenesis to cease, but does not affect the initial assembly of P granules.
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PMID:The GLH proteins, Caenorhabditis elegans P granule components, associate with CSN-5 and KGB-1, proteins necessary for fertility, and with ZYX-1, a predicted cytoskeletal protein. 1243 62

In mating mixtures of Saccharomyces cerevisiae, cells polarize their growth toward their conjugation partners along a pheromone gradient. This chemotropic phenomenon is mediated by structural proteins such as Far1 and Bem1 and by signaling proteins such as Cdc24, Cdc42, and Gbetagamma. The Gbetagamma subunit is thought to provide a positional cue that recruits the polarity establishment proteins, and thereby induces polarization of the actin cytoskeleton. We identified RHO1 in a screen for allele-specific high-copy suppressors of Gbetagamma overexpression, suggesting that Rho1 binds Gbetagamma in vivo. Inactivation of Rho1 GTPase activity augmented the rescue phenotype, suggesting that it is the activated form of Rho1 that binds Gbetagamma. We also found, in a pull-down assay, that Rho1 associates with GST-Ste4 and that Rho1 is localized to the neck and tip of mating projections. Moreover, a mutation in STE4 that disrupts Gbetagamma-Rho1 interaction reduces the projection tip localization of Rho1 and compromises the integrity of pheromone-treated cells deficient in Rho1 activity. In addition to its roles as a positive regulator of 1,3-beta-glucan synthase and of the cell integrity MAP kinase cascade, it was recently shown that Rho1 is necessary for the formation of mating projections. Together, these results suggest that Gbetagamma recruits Rho1 to the site of polarized growth during mating.
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PMID:Gbetagamma recruits Rho1 to the site of polarized growth during mating in budding yeast. 1266 Feb 44

Osmotic stress causes actin cytoskeleton disassembly, a cell cycle arrest, and activation of the high osmolarity growth mitogen-activated protein kinase pathway. A previous study showed that Ssk2p, a mitogen-activated protein kinase kinase kinase of the high osmolarity growth pathway, promotes actin cytoskeleton recovery to the neck of late cell cycle, osmotically stressed yeast cells. Data presented herein examined the role of Ssk2p in actin recovery early in the cell cycle. We found that actin recovery at all stages of the cell cycle is not controlled by Ssk1p, the known activator of Ssk2p, but required a polarized distribution of Ssk2p as well as its actin-interacting and kinase activity. Stress-induced localization of Ssk2p to the neck required the septin Shs1p, whereas localization to the bud cortex depended on the polarity scaffold protein Spa2p. spa2delta cells, like ssk2delta cells, were defective for actin recovery from osmotic stress. These spa2delta defects could be suppressed by overexpression of catalytically active Ssk2p. Furthermore, Spa2p could be precipitated by GST-Ssk2p from extracts of osmotically stressed cells. The Ssk2p mediated actin recovery pathway seems to be conserved; MTK1, a human mitogen-activated protein kinase kinase kinase of the p38 stress response pathway and Ssk2p homolog, was also able to localize at polarized growth sites, form a complex with actin and Spa2p, and complement actin recovery defects in osmotically stressed ssk2delta and spa2delta yeast cells. We hypothesize that osmotic stress-induced actin disassembly leads to the formation of an Ssk2p-actin complex and the polarized localization of Ssk2p. Polarized Ssk2p associates with the scaffold protein Spa2p in the bud and Shs1p in the neck, allowing Ssk2p to regulate substrates involved in polarized actin assembly.
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PMID:Actin recovery and bud emergence in osmotically stressed cells requires the conserved actin interacting mitogen-activated protein kinase kinase kinase Ssk2p/MTK1 and the scaffold protein Spa2p. 1285 82


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