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)

Interleukin-9 (IL-9) stimulates the proliferation of mast cells and lymphocytes. In the present study, we showed that IL-9 induced a transient phosphorylation of MEK, ERK2 and p90/RSK in murine lymphoid and mast cell lines. ERK2 in vitro kinase activity was also increased upon IL-9 stimulation. Similar results were obtained with IL-4, which had not been previously reported to activate these kinases in hematopoietic cells. Analysis of IL-9 receptor mutants showed that activation of the pathway was correlated with proliferation and with phosphorylation of the adaptor protein SHC, but not IRS2 or GAB2. The MEK inhibitor PD98059 reduced the mitogenic response to IL-4 and IL-9. In addition, expression of a dominant-negative RAS variant blocked ERK phosphorylation and significantly decreased Ba/F3 cell growth in the presence of IL-9, but did not affect expression of pim-1, a STAT target gene. In summary, these results indicate that IL-9 can transiently activate the mitogen-activated protein kinase pathway, which contributes to growth stimulation of hematopoietic cell lines.
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PMID:MAP kinase activation by interleukin-9 in lymphoid and mast cell lines. 1266 Aug 12

The Raf/MEK/ERK kinase cascade is pivotal in transmitting signals from membrane receptors to transcription factors that control gene expression culminating in the regulation of cell cycle progression. This cascade can prevent cell death through ERK2 and p90(Rsk) activation and phosphorylation of apoptotic and cell cycle regulatory proteins. The PI3K/Akt kinase cascade also controls apoptosis and can phosphorylate many apoptotic and cell cycle regulatory proteins. These pathways are interwoven as Akt can phosphorylate Raf and result in its inactivation, and Raf can be required for the antiapoptotic effects of Akt. In this study, the effects of activated Raf (Raf-1, A-Raf and B-Raf) and PI3K/Akt proteins on abrogation of cytokine dependence in FL5.12 hematopoietic cells were examined. Activated Raf, PI3K or Akt expression, by themselves, did not readily relieve cytokine dependence. The presence of activated Raf and PI3K/Akt increased the isolation of factor-independent cells from 400- to 2500-fold depending upon the particular combination examined. The individual effects of activated Raf and Akt on proliferation, apoptosis and autocrine growth factor synthesis were further examined with hormone-inducible constructs (Delta Raf-1:AR and Delta Akt:ER*(Myr(+)). Activation of either Raf or Akt hindered cell death; however, both proliferation and maximal synthesis of autocrine cytokines were dependent upon activation of both signaling pathways. The effects of small molecular weight inhibitors on DNA synthesis and cytokine gene expression were also examined. The PI3K inhibitor, LY294002, inhibited growth and cytokine gene expression. This effect could be synergistically increased by addition of the MEK inhibitor UO126. These cells will be useful in elucidating the interactions between Raf/MEK/ERK and PI3K/Akt cascades in proliferation, apoptosis, and leukemogenesis, as well as evaluating the efficacy of signal transduction inhibitors that target these cascades.
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PMID:Effects of the RAF/MEK/ERK and PI3K/AKT signal transduction pathways on the abrogation of cytokine-dependence and prevention of apoptosis in hematopoietic cells. 1271 25

Stimulation of the Ras/extracellular signal-regulated kinase (ERK) pathway can modulate cell growth, proliferation, survival, and motility. The p90 ribosomal S6 kinases (RSKs) comprise a family of serine/threonine kinases that lie at the terminus of the ERK pathway. Efficient RSK activation by ERK requires its interaction through a docking site located near the C terminus of RSK, but the regulation of this interaction remains unknown. In this report we show that RSK1 and ERK1/2 form a complex in quiescent HEK293 cells that transiently dissociates upon mitogen stimulation. Complex dissociation requires phosphorylation of RSK1 serine 749, which is a mitogen-regulated phosphorylation site located near the ERK docking site. Using recombinant RSK1 proteins, we find that serine 749 is phosphorylated by the N-terminal kinase domain of RSK1 in vitro, suggesting that ERK1/2 dissociation is mediated through RSK1 autophosphorylation of this residue. Consistent with this hypothesis, we find that inactivating mutations in the RSK1 kinase domains disrupted the mitogen-regulated dissociation of ERK1/2 in vivo. Analysis of different RSK isoforms revealed that RSK1 and RSK2 readily dissociate from ERK1/2 following mitogen stimulation but that RSK3 remains associated with active ERK1/2. RSK activity assays revealed that RSK3 also remains active longer than RSK1 and RSK2, suggesting that prolonged ERK association increased the duration of RSK3 activation. These results provide new evidence for the regulated nature of ERK docking interactions and reveal important differences among the closely related RSK family members.
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PMID:Phosphorylation of p90 ribosomal S6 kinase (RSK) regulates extracellular signal-regulated kinase docking and RSK activity. 1283 67

Mucins are the major components of the mucus layer that covers and protects the respiratory, digestive, and reproductive tracts. Our previous studies showed that MUC8 gene expression was overexpressed in in vivo polyp epithelium in chronic sinusitis and was also increased by treatment with inflammatory mediators in an in vitro culture condition. However, the mechanisms by which the inflammatory mediators-induced MUC8 gene expression in normal nasal epithelial cells evolved remain unclear. We examined the mechanism by which the important proinflammatory mediator, interleukin (IL)-1 beta, increases MUC8 gene expression levels. We found that pharmacologic and genetic inhibition of ERK MAPK pathway abolished IL-1 beta-induced MUC8 gene expression in normal human nasal epithelial cells. Moreover, the overexpression of wide-type or of the dominant-negative mutant of p90 ribosomal S6 protein kinase 1 (RSK1) enhanced or suppressed, respectively, IL-1 beta-induced MUC8 gene expression. RSK1 was found to directly phosphorylate cAMP-response element-binding protein (CREB), and this event led to the stimulation of subsequent CRE-mediated gene transcription. In conclusion, IL-1 beta was found to induce MUC8 gene expression via a sequential ERK/RSK1/CREB pathway in human airway epithelial cells.
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PMID:Induction of MUC8 gene expression by interleukin-1 beta is mediated by a sequential ERK MAPK/RSK1/CREB cascade pathway in human airway epithelial cells. 1284 5

The cyclin-dependent kinase inhibitor p27Kip1 plays an important role in cell cycle regulation. The cyclin-dependent kinase-inhibitory activity of p27Kip1 is regulated by changes in its concentration and its subcellular localization. Several reports suggest that phosphorylation of p27Kip1 at serine 10, threonine 157, and threonine 187 regulate its localization. We have previously identified that carboxyl-terminal threonine 198 (Thr198) in p27Kip1 is a novel phosphorylation site and that Akt is associated with the phosphorylation at the site (Fujita, N., Sato, S., Katayama, K., and Tsuruo, T. (2002) J. Biol. Chem. 277, 28706-28713). We show herein that activation of the Ras/Raf/mitogen-activated protein kinase kinase (MAPK kinase/MEK) pathway also regulates phosphorylation of p27Kip1 at Thr198. MAPKs were not directly associated with p27Kip1 phosphorylation at Thr198, but the p90 ribosomal protein S6 kinases (RSKs) could bind to and directly phosphorylate p27Kip1 at Thr198 in a Ras/Raf/MEK-dependent manner. RSK-dependent phosphorylation promoted the p27Kip1 binding to 14-3-3 and its cytoplasmic localization. To prove the direct relationship between 14-3-3 binding and cytoplasmic localization, we constructed a p27Kip1-R18 fusion protein in which the R18 peptide was fused to the carboxyl-terminal region of p27Kip1. The R18 peptide is known to interact with 14-3-3 independent of phosphorylation. The p27Kip1-R18 distributed mainly in the cytosol, whereas mutant p27Kip1-R18 (p27Kip1-R18-K2) that had no 14-3-3 binding capability existed mainly in the nucleus. These results indicate that RSKs play a crucial role in cell cycle progression through translocation of p27Kip1, in addition to Akt, to the cytoplasm in a phosphorylation and 14-3-3 binding-dependent manner.
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PMID:Phosphorylation of p27Kip1 at threonine 198 by p90 ribosomal protein S6 kinases promotes its binding to 14-3-3 and cytoplasmic localization. 1450 89

Anthracyclines are commonly used chemotherapeutics, and in some models enhance p44/42-mitogen-activated protein kinase (MAPK) pathway signaling by effects on upstream kinases. To evaluate the impact of anthracyclines on p44/42-MAPK in breast cancer, A1N4-myc human mammary and BT-474 and MDA-MB-231 breast carcinoma cells were studied. Treatment with doxorubicin or epirubicin resulted in increased phospho-p44/42-MAPK levels in a time- and concentration-dependent manner. This was associated with p44/42 activation, as reflected by increased p90 ribosomal protein S6 kinase and Bad phosphorylation. Activation of p44/42 appeared to be antiapoptotic, since MAPK stimulation with epidermal growth factor or a dominant-positive p42 construct inhibited apoptosis. Modest activation of the upstream MAPK kinase MEK was noted under some conditions, but inhibition of MEK did not abolish p44/42 activation, suggesting a contribution from another mechanism. Anthracyclines were found to decrease expression of MAPK phosphatase-1 (MKP-1) both in vitro and in vivo. MKP-1 mRNA levels were decreased in anthracycline-treated cells, and transcription from the MKP-1 promoter was repressed. Inhibition of MKP-1 expression through the use of small interfering RNAs decreased the ability of anthracyclines to induce phospho-p44/42. Wild-type mouse embryo fibroblasts (MEFs) treated with doxorubicin showed increased phospho-p44/42-MAPK levels, but MEFs from MKP-1 heterozygous and homozygous knockout mice had blunted p44/42 activation. These studies support the ability of anthracyclines to activate antiapoptotic p44/42-MAPK phosphorylation in breast cancer, and indicate that this occurs in part through the novel mechanism of repression of MKP-1 transcription.
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PMID:Repression of mitogen-activated protein kinase (MAPK) phosphatase-1 by anthracyclines contributes to their antiapoptotic activation of p44/42-MAPK. 1455 75

Numerous external stimuli, including G protein-coupled receptor agonists, cytokines, growth factors, and steroids activate mitogen-activated protein kinases (MAPKs) through phosphorylation of the epidermal growth factor receptor (EGF-R). In immortalized hypothalamic neurons (GT1-7 cells), agonist binding to the gonadotropin-releasing hormone receptor (GnRH-R) causes phosphorylation of MAPKs that is mediated by protein kinase C (PKC)-dependent transactivation of the EGF-R. An analysis of the mechanisms involved in this process showed that GnRH stimulation of GT1-7 cells causes release/shedding of the soluble ligand, heparin binding epidermal growth factor (HB-EGF), as a consequence of metalloprotease activation. GnRH-induced phosphorylation of the EGF-R and, subsequently, of Shc, ERK1/2, and its dependent protein, p90RSK-1 (p90 ribosomal S6 kinase 1 or RSK-1), was abolished by metalloprotease inhibition. Similarly, blockade of the effect of HB-EGF with the selective inhibitor CRM197 or a neutralizing antibody attenuated signals generated by GnRH and phorbol 12-myristate 13-acetate, but not those stimulated by EGF. In contrast, phosphorylation of the EGF-R, Shc, and ERK1/2 by EGF and HB-EGF was independent of PKC and metalloprotease activity. The signaling characteristics of HB-EGF closely resembled those of GnRH and EGF in terms of the phosphorylation of EGF-R, Shc, ERK1/2, and RSK-1 as well as the nuclear translocation of RSK-1. However, neither the selective Src kinase inhibitor PP2 nor the overexpression of negative regulatory Src kinase and dominant negative Pyk2 had any effect on HB-EGF-induced responses. In contrast to GT1-7 cells, human embryonic kidney 293 cells expressing the GnRH-R did not exhibit metalloprotease induction and EGF-R transactivation during GnRH stimulation. These data indicate that the GnRH-induced transactivation of the EGF-R and the subsequent ERK1/2 phosphorylation result from ectodomain shedding of HBEGF through PKC-dependent activation of metalloprotease(s) in neuronal GT1-7 cells.
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PMID:Neuropeptide-induced transactivation of a neuronal epidermal growth factor receptor is mediated by metalloprotease-dependent formation of heparin-binding epidermal growth factor. 1457 93

CD40, a member of the tumor necrosis factor receptor superfamily, is frequently expressed in carcinomas where its stimulation results in induction of apoptosis when de novo protein synthesis is inhibited. The requirement of protein synthesis inhibition for efficient killing suggests that CD40 transduces potent survival signals capable of suppressing its pro-apoptotic effects. We have found that inhibition of CD40 signaling on the phosphatidylinositol 3-kinase (PI3K) and ERK MAPK but not on the p38 MAPK axis disrupts this balance and sensitizes carcinoma cells to CD40-mediated cell death. The CD40-mediated PI3K and ERK activities were found to converge on the regulation of protein synthesis in carcinoma cells via a pathway involving the activation of p90 ribosomal S6 kinase (p90Rsk) and p70S6 kinases, upstream of the translation elongation factor eEF2. In addition, CD40 ligation was found to mediate a PI3K- and mammalian target of rapamycin (mTOR)-dependent phosphorylation of 4E-BP1 and its subsequent dissociation from the mRNA cap-binding protein eIF4E as well as an ERK-dependent phosphorylation of eIF4E, thus promoting translation initiation. Concomitantly, the antiapoptotic protein cFLIP was found to be induced in CD40 ligand-stimulated carcinoma cells in a PI3K-, ERK-, and mammalian target of rapamycin (mTOR)-dependent manner and down-regulation of cFLIPS expression sensitized to CD40-mediated carcinoma cell death. These data underline the significance of the PI3K and ERK pathways in controlling the balance between CD40-mediated survival and death signals through the regulation of the protein synthesis machinery. Pharmacological agents that target this machinery or its upstream kinases could, therefore, be exploited for CD40-based tumor therapy.
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PMID:Inhibition of phosphatidylinositol 3-kinase- and ERK MAPK-regulated protein synthesis reveals the pro-apoptotic properties of CD40 ligation in carcinoma cells. 1458 87

Some human colon cancer cell lines (e.g., H508 cells) express M3 subtype muscarinic receptors that are activated by cholinergic agonists. The objective of the present study was to determine the cellular mechanisms underlying M3 muscarinic receptor-mediated proliferation of H508 human colon cancer cells. In H508 cells, but not in SNU-C4 cells that do not express muscarinic receptors, acetylcholine stimulated calcium-dependent phosphorylation of p44/42 mitogen-activated protein kinase (MAPK) and p90 ribosomal S6 kinase and consequent cell proliferation. Atropine or inhibitors of MAPK phosphorylation blocked these effects. Conversely, the actions of epidermal growth factor (EGF) on H508 cells were neither calcium dependent nor mediated by cholinergic mechanisms. Both acetylcholine- and EGF-induced phosphorylation of p44/42 MAPK was abolished in the presence of EGF receptor (EGFR) inhibitors (AG1478 and PD168393). In Chinese hamster ovary cells transfected with the rat M3 muscarinic receptor, which lack EGFR, acetylcholine-induced MAPK phosphorylation was not altered in the presence of EGFR inhibitors. In H508 cells, protein kinase C inhibitors did not alter acetylcholine- or EGF-induced MAPK phosphorylation. Finally, inhibition of EGFR activation abolished acetylcholine-induced H508 cell proliferation. These data indicate that, in H508 human colon cancer cells, cholinergic ligand interaction with M3 muscarinic receptors results in transactivation of EGFR, thereby stimulating cellular proliferation.
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PMID:Transactivation of the epidermal growth factor receptor mediates cholinergic agonist-induced proliferation of H508 human colon cancer cells. 1458 69

This study presents data suggesting that both human mesothelioma (cell lines and human mesothelioma biopsies) and human normal mesothelial cells express receptors for acetylcholine and that stimulation of these receptors by nicotine prompted cell growth via activation of nicotinic cholinergic receptors. Thus, these data demonstrate that: (a) human mesothelioma cells and human biopsies of mesothelioma as well as of normal pleural mesothelial cells express functionally alpha-7 nicotinic acethlycholine receptors, evaluated by alpha-bungarotoxin-FITC binding, receptor binding assay, Western blot, and reverse transcription-PCR; (b) choline acetyltransferase immunostaining is present in mesothelioma cells; (c) mesothelioma cell growth is modulated by the cholinergic system in which agonists (i.e., nicotine) has a proliferative effect, and antagonists (i.e., curare) has an inhibitory effect, evaluated by cell cloning, DNA synthesis and cell cycle; (d) nicotine induces Ca(+2) influx, evaluated by [(45)Ca(2+)] uptake, and consequently activation of mitogen-activated protein kinase pathway (extracellular signal-regulated kinase and p90(RSK) phosphorylation), evaluated by Western blot; and (e) apoptosis mechanisms in mesothelioma cells are under the control of the cholinergic system (nicotine antiapoptotic via induction of nuclear factor-kappaB complexes and phosphorylation of Bad at Ser(112); curare proapoptotic via G(0)-G(1) arrest p21(waf-1) dependent but p53 independent). The involvement of the nonneuronal cholinergic system in mesothelioma appears reasonable and open up new therapeutic strategies.
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PMID:Alpha7-nicotinic acetylcholine receptors affect growth regulation of human mesothelioma cells: role of mitogen-activated protein kinase pathway. 1472 17


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