Insulin receptor substrate-1 and phosphatidylinositol 3-kinase regulate extracellular signal-regulated kinase-dependent and -independent signaling pathways during myogenic differentiation.
Activation of the insulin-like growth factor (IGF) autocrine loop is required for myogenic differentiation and results in sustained activation of extracellular signal-regulated kinases-1 and -2 (ERK-1 and -2). We show here that insulin receptor substrate-1 (IRS-1) phosphorylation on tyrosine and serine residues and association with phosphatidylinositol 3-kinase (PI 3-kinase) are also associated with IGF-dependent myogenic differentiation. Down-regulation of IRS-1 is linked to its serine phosphorylation dependent on PI 3-kinase activity and appears required for differentiation to occur, as IRS-1 is not modified and continues to accumulate in a nondifferentiating myoblast cell line. Furthermore, inhibition of PI 3-kinase activity with LY294002 blocks differentiation, as demonstrated by inhibition of myogenin and myosin heavy chain expression and ERK activation. Blocking the Raf/MEK/ERK cascade with PD98059 does not block myogenic differentiation; however, myotubes do not survive. Thus, PI 3-kinase, in association with IRS-1, is involved in an ERK-independent signaling pathway in myoblasts required for IGF-dependent myogenic differentiation and in inducing sustained activation of ERKs necessary for later stages of differentiation.
Sarbassov
D D
DD
Donald W. Reynolds Department of Geriatrics, University of Arkansas for Medical Sciences and The Geriatric Research, Education, and Clinical Center, McClellan Veterans Hospital, Little Rock 72205, USA.
Peterson
C A
CA
D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002454:Cell Differentiation; D002460:Cell Line; D002867:Chromones / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D055504:Insulin Receptor Substrate Proteins; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D009025:Morpholines / Q000494:pharmacology; D009132:Muscles / Q000166:cytology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism; D019000:Phosphotyrosine / Q000378:metabolism; D015398:Signal Transduction
D017871:Calcium-Calmodulin-Dependent Protein Kinases; D002867:Chromones; D004791:Enzyme Inhibitors; D055504:Insulin Receptor Substrate Proteins; D007334:Insulin-Like Growth Factor I; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010750:Phosphoproteins; D010768:Phosphoserine; D019000:Phosphotyrosine; C526295:Irs1 protein, mouse; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one