Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P51812 (mitogen-activated protein)
 10,636 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This study was designed to evaluate the role of p70 S6 kinase (p70(S6K) ), p90 S6 kinase (p90(RSK)) and mitogen-activated protein (MAP) kinase pathways in the insulin resistance of muscle protein synthesis observed during glucocorticoid treatment. Dexamethasone treatment decreased the effect of insulin on protein synthesis (-35. 2%) in epitrochlearis muscle incubated in vitro. This resistance is associated with a total blockage of the stimulation of p70(S6K) by insulin without any significant decrease in the amount of the kinase. However, the effect of rapamycin (inhibitor of several intracellular pathways including p70(S6K) pathways) on muscle protein synthesis was not modified by dexamethasone in rat muscles. This suggested that 'rapamycin-sensitive pathways' associated with the insulin stimulation of protein synthesis were not altered by glucocorticoids and thus are not responsible for the insulin resistance observed. As incubation of muscles with a MAP kinase inhibitor (PD98059) did not modify the stimulation of protein synthesis by insulin and as glucocorticoids did not alter the effect of insulin on p90(RSK )activity, our results provide evidence that glucocorticoid-induced alterations in muscle protein synthesis regulation by insulin do not involve factors or kinases that are dependent on MAP kinase and/or p90(RSK).
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PMID:Glucocorticoid-induced insulin resistance of protein synthesis is independent of the rapamycin-sensitive pathways in rat skeletal muscle. 1039 23

We examined regulation of the Na(+)/H(+) exchanger isoform 1 by phosphorylation in the rat myocardium. We utilized cell extracts from adult rat hearts, adult rat extracts fractionated by fast performance liquid chromatography, and extracts from cultured neonatal cardiac myocytes. The carboxyl-terminal 178 amino acids of the Na(+)/H(+) exchanger were expressed in Escherichia coli fused with glutathione S-transferase. The purified protein was used as a substrate for in vitro phosphorylation and in-gel kinase assays. Unfractionated extracts from neonatal myocytes or adult hearts phosphorylated the COOH-terminal domain of the antiporter. Western blot analysis revealed that mitogen-activated protein (MAP) kinase (44 and 42 kDa) and p90(rsk) (90 kDa) were present in specific fractions of cardiac extracts that phosphorylated the COOH-terminal protein. In-gel kinase assays confirmed that protein kinases of approximately 44 and 90 kDa could phosphorylate this domain. MAP kinase and p90(rsk)-dependent phosphorylation of the antiporter could be demonstrated by immunoprecipitation of these kinases from extracts of neonatal cardiac myocytes. PD98059, a mitogen-activated protein kinase kinase inhibitor, decreased MAP kinase and p90(rsk) phosphorylation of the antiporter and abolished serum and endothelin 1-stimulated increases in steady-state pH(i). These results confirm the presence of MAP kinase-dependent phosphorylation in the regulation of the Na(+)/H(+) exchanger in the rat myocardium and suggest an important role for p90(rsk) phosphorylation in regulation of the protein by endothelin-mediated stimulation of the antiporter.
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PMID:Protein kinase-mediated regulation of the Na(+)/H(+) exchanger in the rat myocardium by mitogen-activated protein kinase-dependent pathways. 1043 64

Arginine vasopressin (AVP) and lysophosphatidic acid (LPA) have been shown to stimulate protein kinase C (PKC) and mitogen-activated protein (MAP) kinases and the proliferation of vascular smooth muscle cells. However, the actions of these two agents in cardiomyocytes are less well understood. To investigate the signal transduction pathways of AVP and LPA, freshly isolated adult rat cardiomyocytes were examined. Both AVP and LPA induced concentration- and time-dependent stimulation of the phosphotransferase activities of p90 ribosomal S6 kinases (RSK) and their upstream activators, extracellularly regulated kinases (ERK) 1 and 2. The activation of ERK1 and ERK2 by LPA was PKC- and phosphatidylinositol 3-kinase (PI 3-kinase)-dependent. However, AVP-induced activation of RSK2, a downstream substrate of ERK1 and ERK2, was PKC-dependent and PI 3-kinase-independent. AVP and LPA were also observed to increase the phosphotransferase activity of p70 ribosomal protein S6 kinase (p70 S6K) in a time- and concentration-dependent manner. The activation of p70 S6K by LPA and AVP was PI 3-kinase-dependent. PKC was necessary in AVP- but not in LPA-induced activation of p70 S6K. Since RSK and p70 S6K have been implicated in the regulation of translational control of protein synthesis, we concluded that AVP and LPA may stimulate the growth of cardiomyocytes through these two protein kinase cascades.
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PMID:Stimulation of 90- and 70-kDa ribosomal protein S6 kinases by arginine vasopressin and lysophosphatidic acid in rat cardiomyocytes. 1070 47

Insulin and exercise potently stimulate glucose metabolism and gene transcription in vivo in skeletal muscle. A single bout of exercise increases the rate of insulin-stimulated glucose uptake and metabolism in skeletal muscle in the postexercise period. The nature of the intracellular signaling mechanisms that control responses to exercise is not known. In mammalian tissues, numerous reports have established the existence of the mitogen-activated protein (MAP) kinase signaling pathway that is activated by a variety of growth factors and hormones. This study was undertaken to determine how a single bout of exercise and physiological hyperinsulinemia activate the MAP kinase pathway. The euglycemic-hyperinsulinemic clamp and cycle ergometer exercise techniques combined with percutaneous muscle biopsies were used to answer this question. In healthy subjects, within 30 min, insulin significantly increased MAP kinase [isoforms p42(MAPK) and p44(MAPK) (ERK1 and ERK2)] phosphorylation (141 +/- 2%, P < 0.05) and activity (177 +/- 5%, P < 0.05), and the activity of its upstream activator MEK1 (161 +/- 16%, P < 0.05). Insulin also increased the activity of the MAP kinase downstream substrate, the p90 ribosomal S6 kinase 2 (RSK2) almost twofold (198 +/- 45%, P < 0.05). In contrast, a single 30-min bout of moderate-intensity exercise had no effect on the MAP kinase pathway activation from MEK to RSK2 in muscle of healthy subjects. However, 60 min of exercise did increase extracellular signal-related kinase activity. Therefore, despite similar effects on glucose metabolism after 30 min, insulin and exercise regulate the MAP kinase pathway differently. Insulin more rapidly activates the MAP kinase pathway.
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PMID:Regulation of MAP kinase pathway activity in vivo in human skeletal muscle. 1082

Mitogen-activated protein kinase-activated protein kinases (MAPKAPKs) lie immediately downstream of the mitogen-activated protein kinases (MAPKs), extracellular signal-regulated kinase (ERK), and p38 MAPK. Although the family of MAPKAPKs shares sequence similarity, it demonstrates selectivity for the upstream activator. Here we demonstrate that each of the ERK- and p38 MAPK-regulated MAPKAPKs contains a MAPK docking site positioned distally to the residue(s) phosphorylated by MAPKs. The isolated MAPK docking sites show specificity for the upstream activator similar to that reported for the full-length proteins. Moreover, replacement of the ERK docking site of p90 ribosomal S6 kinase with the p38 MAPK docking site of MAPKAPK2 converts p90 ribosomal S6 kinase into a stress-activated kinase in vivo. It is apparent that mechanisms controlling events downstream of the proline-directed MAPKs involve specific MAPK docking sites within the carboxyl termini of the MAPKAPKs that determine the cascade in which the MAPKAPK functions.
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PMID:Creation of a stress-activated p90 ribosomal S6 kinase. The carboxyl-terminal tail of the MAPK-activated protein kinases dictates the signal transduction pathway in which they function. 1092 75

The 90-kDa ribosomal S6 kinases, the p90 Rsks, are a family of intracellular serine/threonine protein kinases distinguished by two distinct kinase domains. Rsks are activated downstream of the ERK1 (p44) and ERK2 (p42) mitogen-activated protein (MAP) kinases in diverse biological contexts, including progression through meiotic and mitotic M phases in Xenopus oocytes and cycling Xenopus egg extracts, and are critical for the M phase functions of Xenopus p42 MAPK. Here we report the cloning and biochemical characterization of Xenopus Rsk2. Xenopus Rsk1 and Rsk2 are specifically recognized by commercially available RSK1 and RSK2 antisera on immunoblots, but both Rsk1 and Rsk2 are immunoprecipitated by RSK1, RSK2, and RSK3 sera. Rsk2 is about 20-fold more abundant than the previously described Xenopus Rsk1 protein; their concentrations are approximately 120 and 5 nm, respectively. Rsk2, like Rsk1, forms a heteromeric complex with p42 MAP kinase. This interaction depends on sequences at the extreme C terminus of Rsk2 and can be disrupted by a synthetic peptide derived from the C-terminal 20 amino acids of Rsk2. Finally, we demonstrate that p42 MAP kinase can activate recombinant Rsk2 in vitro to a specific activity comparable to that found in Rsk2 that has been activated maximally in vivo. These findings underscore the importance of the Rsk2 isozyme in the M phase functions of p42 MAP kinase and provide tools for further examining Rsk2 function.
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PMID:Cloning and characterization of Xenopus Rsk2, the predominant p90 Rsk isozyme in oocytes and eggs. 1093 12

Exercise/contraction is a powerful stimulator of mitogen-activated protein (MAP) kinase cascades in skeletal muscle. Little is known regarding the physiological activation of enzymes downstream of MAP kinase. We investigated whether acute exercise results in activation of mitogen- and stress-activated kinases (MSK) 1 and 2, p90 ribosomal S6 kinase (p90rsk), and MAP kinase-activated protein kinase 2 (MAPKAPK2). Muscle biopsies were obtained from healthy volunteers before, during, and after 60 min one-leg cycle ergometry, from exercising and resting legs. MSK1 and MSK2 activities were increased 400-500% and 200-300%, respectively, in exercised muscle (P < 0.05 vs. rest). A dramatic increase in activity of p90rsk (MAPKAPK1) (>2,500%), and to a lesser extent MAPKAP2 (300%), was noted with exercise (P < 0.05 vs. rest). MSK1, MSK2, p90rsk, and MAPKAP2 activities were sustained throughout exercise. Exercise-induced activation of these enzymes was limited to working muscle, indicating that local rather than systemic factors activate these signaling cascades. Thus physical exercise leads to activation of multiple enzymes downstream of MAP kinase.
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PMID:Effects of exercise on mitogen- and stress-activated kinase signal transduction in human skeletal muscle. 1104 54

Asthmatic airways are characterized by an increase in smooth muscle mass, due mainly to hyperplasia. Many studies suggest that extracellular signal-regulated kinases 1 and 2 (ERK1 and ERK2, respectively), one group of the mitogen-activated protein (MAP) kinase superfamily, play a key role in the signal transduction pathway leading to cell proliferation. PGE(2) and forskolin inhibited mitogen-induced ERK activation. Inhibition of MAP kinase kinases 1 and 2 (MEK1 and MEK2, respectively), which are upstream from ERK, with the specific MEK inhibitor U-0126 blocked both cell proliferation and ERK activation. In addition, U-0126 inhibited mitogen-induced activation of p90 ribosomal S6 kinase and expression of c-Fos and cyclin D1, all of which are downstream from ERK in the signaling cascade that leads to cell proliferation. Antisense oligodeoxynucleotides directed to ERK1 and -2 mRNAs reduced ERK protein and cell proliferation. These results indicate that ERK is required for human airway smooth muscle cell proliferation. Thus targeting the control of ERK activation may provide a new therapeutic approach for hyperplasia seen in asthma.
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PMID:ERK activation and mitogenesis in human airway smooth muscle cells. 1129 May 27

N-terminal tail phosphorylation of histone H3 plays an important role in gene expression, chromatin remodeling, and chromosome condensation. Phosphorylation of histone H3 at serine 10 was shown to be mediated by RSK2, mitogen- and stress-activated protein kinase-1 (MSK1), and mitogen-activated protein kinases depending on the specific stimulation or stress. Our previous study showed that mitogen-activated protein kinases MAP kinases are involved in ultraviolet B-induced phosphorylation of histone H3 at serine 28 (Zhong, S., Zhong, Z., Jansen, J., Goto, H., Inagaki, M., and Dong, Z., J. Biol. Chem. 276, 12932-12937). However, downstream effectors of MAP kinases remain to be identified. Here, we report that H89, a selective inhibitor of the nucleosomal response, totally inhibits ultraviolet B-induced phosphorylation of histone H3 at serine 28. H89 blocks MSK1 activity but does not inhibit ultraviolet B-induced activation of MAP kinases p70/85(S6K), p90(RSK), Akt, and protein kinase A. Furthermore, MSK1 markedly phosphorylated serine 28 of histone H3 and chromatin in vitro. Transfection experiments showed that an N-terminal mutant MSK1 or a C-terminal mutant MSK1 markedly blocked MSK1 activity. Compared with wild-type MSK1, cells transfected with N-terminal or C-terminal mutant MSK1 strongly blocked ultraviolet B-induced phosphorylation of histone H3 at serine 28 in vivo. These data illustrate that MSK1 mediates ultraviolet B-induced phosphorylation of histone H3 at serine 28.
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PMID:Ultraviolet B-induced phosphorylation of histone H3 at serine 28 is mediated by MSK1. 1144 Oct 12

Hepatocyte growth factor/scatter factor (HGF/SF) is considered to be a mesenchymal-derived factor that acts via a dual system receptor, consisting of the MET receptor and proteoglycans present on adjacent epithelial cells. Surprisingly, HGS/SF stimulated the migration of rat mammary (Rama) 27 fibroblasts, although it failed to stimulate their proliferation. HGF/SF stimulated a transient activation of mitogen-activated protein kinases p44 and p42 (p42/44(MAPK)), with a maximum level of dual phosphorylation of p42/44(MAPK) occurring 10-15 min after the addition of the growth factor, which was followed by a rapid decrease to near basal levels after 20 min. Interestingly, a second phase of p42/44(MAPK) dual phosphorylation was observed at later times (3 h to 10 h). PD098059, a specific inhibitor of MEK-1, prevented the dual phosphorylation of p42/44(MAPK) and also the phosphorylation of p90(RSK) (ribosomal subunit S6 kinase), which mirrored the kinetics of p42/44(MAPK) phosphorylation. Moreover, PD098059 prevented the HGF/SF-induced migration of Rama 27 cells. HGF/SF also induced an early increase in the phosphorylation of protein kinase B/Akt. Akt phosphorylation was elevated 15 min after the addition of HGF/SF and then declined to basal levels by 30 min. Wortmannin, an inhibitor of phosphatidylinositol 3-kinase (PtdIns3K), prevented the increase in Akt phosphorylation and abolished HGF/SF-induced migration of fibroblasts. PD098059 also inhibited the stimulation of Akt phosphorylation by HGF/SF and wortmannin similarly inhibited the stimulation of p42/44(MAPK) dual phosphorylation. These results suggest that HGF/SF-induced motility depends on both the transient dual phosphorylation of p42/44(MAPK) and the activation of PtdIns3K in Rama 27 fibroblasts and that these pathways are mutually dependent.
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PMID:Hepatocyte growth factor/scatter factor stimulates migration of rat mammary fibroblasts through both mitogen-activated protein kinase and phosphatidylinositol 3-kinase/Akt pathways. 1150 2


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