Cross-talk between the ERK and p70 S6 kinase (S6K) signaling pathways. MEK-dependent activation of S6K2 in cardiomyocytes.
The alpha(1)-adrenergic agonist phenylephrine (PE) and insulin each stimulate protein synthesis in cardiomyocytes. Activation of protein synthesis by PE is involved in the development of cardiac hypertrophy. One component involved here is p70 S6 kinase 1 (S6K1), which lies downstream of mammalian target of rapamycin, whose regulation is thought to involve phosphatidylinositol 3-kinase and protein kinase B (PKB). S6K2 is a recently identified homolog of S6K1 whose regulation is poorly understood. Here we demonstrate that in adult rat ventricular cardiomyocytes, PE and insulin each activate S6K2, activation being 3.5- and 5-fold above basal, respectively. Rapamycin completely blocked S6K2 activation by either PE or insulin. Three different inhibitors of MEK1/2 abolished PE-induced activation of S6K2 whereas expression of constitutively active MEK1 activated S6K2, without affecting the p38 mitogen-activated protein kinase and JNK pathways, indicating that MEK/ERK signaling plays a key role in regulation of S6K2 by PE. PE did not activate PKB, and expression of dominant negative PKB failed to block activation of S6K2 by PE, indicating PE-induced S6K2 activation is independent of PKB. However, this PKB mutant did partially block S6K2 activation by insulin, indicating PKB is required here. Another hypertrophic agent, endothelin 1, also activated S6K2 in a MEK-dependent manner. Our findings provide strong evidence for novel signaling connections between MEK/ERK and S6K2.
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Division of Molecular Physiology, School of Life Sciences, University of Dundee, Dundee, DD1 5EH, United Kingdom.
Gout
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D000818:Animals; D002070:Butadienes / Q000494:pharmacology; D002478:Cells, Cultured; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006321:Heart / Q000187:drug effects / Q000502:physiology*; D006352:Heart Ventricles; D007328:Insulin / Q000494:pharmacology; D007700:Kinetics; D048369:MAP Kinase Kinase 1; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D009570:Nitriles / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D020239:Receptor Cross-Talk / Q000187:drug effects / Q000502:physiology; D011994:Recombinant Proteins / Q000378:metabolism; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism*; D020123:Sirolimus / Q000494:pharmacology; D014162:Transfection
D002070:Butadienes; D004791:Enzyme Inhibitors; D007328:Insulin; D009570:Nitriles; D011518:Proto-Oncogene Proteins; D011994:Recombinant Proteins; C113580:U 0126; D010656:Phenylephrine; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D019893:Ribosomal Protein S6 Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; D020929:Mitogen-Activated Protein Kinase Kinases; D020123:Sirolimus