Akt Phosphorylation Is Not Sufficient for Insulin-Like Growth Factor-Stimulated Myogenin Expression but Must Be Accompanied by Down-Regulation of Mitogen-Activated Protein Kinase/Extracellular Signal-Regulated Kinase Phosphorylation

Department of Pediatrics, University of California, San Francisco, San Francisco, California, United States
Endocrinology (Impact Factor: 4.5). 12/2004; 145(11):4991-6. DOI: 10.1210/en.2004-0101
Source: PubMed


IGF-I has a unique biphasic effect on skeletal muscle differentiation. Initially, IGF-I inhibits expression of myogenin, a skeletal muscle-specific regulatory factor essential for myogenesis. Subsequently, IGF-I switches to stimulating expression of myogenin. The mechanisms that mediate this switch in IGF action are incompletely understood. Several laboratories have demonstrated that the phosphatidylinositol-3-kinase/Akt signaling pathway is essential for myogenic differentiation and have suggested that this pathway mediates IGF-I stimulation of myogenin mRNA expression, an early critical step in the differentiation process. These studies, however, did not address concurrent Akt and MAPK/ERK1/2 phosphorylation, the latter of which is also known to regulate myogenic differentiation. In the present study in rat L6E9 muscle cells, we have manipulated ERK1/2 phosphorylation with either an upstream inhibitor or activator and examined concurrent levels of Akt and ERK1/2 phosphorylation and of myogenin mRNA expression in response to treatment with IGF-I. We find that even in the presence of phosphorylated Akt, it is only when ERK1/2 phosphorylation is inhibited that IGF-I can stimulate myogenin mRNA expression. Thus, although Akt phosphorylation may be necessary, it is not sufficient for induction of myogenic differentiation by IGF-I and must be accompanied by a decrease in ERK1/2 phosphorylation.

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Available from: Nicki Tiffin, Mar 11, 2014
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    • "/ p38 signal transduction is inhibited , stretch - induced myogenesis is blocked even though AKT , another essential mediator of myogenesis ( Li et al . , 2000 ) , is activated normally , which is consistent with previous observations in different settings where AKT phosphorylation alone is not sufficient to induce myogenesis ( Wu et al . , 2000 ; Tiffin et al . , 2004 ) . The dependence of stretch activation of p38 on TNF - ␣ and its receptors suggests that mechanical activation of p38 is mediated by TNF - ␣ released into the medium from myoblasts , a process controlled by TACE ( Blobel , 1997 ; Black , 2002 ) . We show for the first time that TACE is dramatically activated by mechanical stimulation "
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