This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Sarbassov, D. D. Articles by Peterson, C. A. Search for Related Content PubMed PubMed Citation Articles by Sarbassov, D. D. Articles by Peterson, C. A.

Insulin Receptor Substrate-1 and Phosphatidylinositol 3-Kinase Regulate Extracellular Signal-Regulated Kinase-Dependent and -Independent Signaling Pathways during Myogenic Differentiation

Donald W. Reynolds Department of Geriatrics and the Department of Biochemistry and Molecular Biology University of Arkansas for Medical Sciences and The Geriatric Research, Education, and Clinical Center McClellan Veterans Hospital Little Rock, Arkansas 72205

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.

This article has been cited by other articles:

				T. Koyama, Y. Nakaoka, Y. Fujio, H. Hirota, K. Nishida, S. Sugiyama, K. Okamoto, K. Yamauchi-Takihara, M. Yoshimura, S. Mochizuki, et al. Interaction of Scaffolding Adaptor Protein Gab1 with Tyrosine Phosphatase SHP2 Negatively Regulates IGF-I-dependent Myogenic Differentiation via the ERK1/2 Signaling Pathway J. Biol. Chem., August 29, 2008; 283(35): 24234 - 24244. [Abstract] [Full Text] [PDF]

				H. Sun and R. Baserga Deletion of the Pleckstrin and Phosphotyrosine Binding Domains of Insulin Receptor Substrate-2 Does Not Impair Its Ability to Regulate Cell Proliferation in Myeloid Cells Endocrinology, November 1, 2004; 145(11): 5332 - 5343. [Abstract] [Full Text] [PDF]

				N. Tiffin, S. Adi, D. Stokoe, N.-Y. Wu, and S. M. Rosenthal 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 Endocrinology, November 1, 2004; 145(11): 4991 - 4996. [Abstract] [Full Text] [PDF]

				S. R. Broussard, R. H. MCCusker, J. E. Novakofski, K. Strle, W. Hong Shen, R. W. Johnson, G. G. Freund, R. Dantzer, and K. W. Kelley Cytokine-Hormone Interactions: Tumor Necrosis Factor {alpha} Impairs Biologic Activity and Downstream Activation Signals of the Insulin-Like Growth Factor I Receptor in Myoblasts Endocrinology, July 1, 2003; 144(7): 2988 - 2996. [Abstract] [Full Text] [PDF]

				L. Sciacca, M. Prisco, A. Wu, A. Belfiore, R. Vigneri, and R. Baserga Signaling Differences from the A and B Isoforms of the Insulin Receptor (IR) in 32D Cells in the Presence or Absence of IR Substrate-1 Endocrinology, June 1, 2003; 144(6): 2650 - 2658. [Abstract] [Full Text] [PDF]

				O. Ostrovsky and E. Bengal The Mitogen-activated Protein Kinase Cascade Promotes Myoblast Cell Survival by Stabilizing the Cyclin-dependent Kinase Inhibitor, p21WAF1 Protein J. Biol. Chem., May 30, 2003; 278(23): 21221 - 21231. [Abstract] [Full Text] [PDF]

				G. R. Adams Exercise Effects on Muscle Insulin Signaling and Action: Invited Review: Autocrine/paracrine IGF-I and skeletal muscle adaptation J Appl Physiol, September 1, 2002; 93(3): 1159 - 1167. [Abstract] [Full Text] [PDF]

				J. Tureckova, E. M. Wilson, J. L. Cappalonga, and P. Rotwein Insulin-like Growth Factor-mediated Muscle Differentiation. COLLABORATION BETWEEN PHOSPHATIDYLINOSITOL 3-KINASE-Akt-SIGNALING PATHWAYS AND MYOGENIN J. Biol. Chem., October 12, 2001; 276(42): 39264 - 39270. [Abstract] [Full Text] [PDF]

				B Valentinis and R Baserga IGF-I receptor signalling in transformation and differentiation Mol. Pathol., June 1, 2001; 54(3): 133 - 137. [Abstract] [Full Text]

				M. A. Lawlor and P. Rotwein Coordinate Control of Muscle Cell Survival by Distinct Insulin-like Growth Factor Activated Signaling Pathways J. Cell Biol., December 4, 2000; 151(6): 1131 - 1140. [Abstract] [Full Text] [PDF]

				M. A. Lawlor and P. Rotwein Insulin-Like Growth Factor-Mediated Muscle Cell Survival: Central Roles for Akt and Cyclin-Dependent Kinase Inhibitor p21 Mol. Cell. Biol., December 1, 2000; 20(23): 8983 - 8995. [Abstract] [Full Text]

				R. D. York, D. C. Molliver, S. S. Grewal, P. E. Stenberg, E. W. McCleskey, and P. J. S. Stork Role of Phosphoinositide 3-Kinase and Endocytosis in Nerve Growth Factor-Induced Extracellular Signal-Regulated Kinase Activation via Ras and Rap1 Mol. Cell. Biol., November 1, 2000; 20(21): 8069 - 8083. [Abstract] [Full Text]

				C. Peyssonnaux, S. Provot, M. P. Felder-Schmittbuhl, G. Calothy, and A. Eychène Induction of Postmitotic Neuroretina Cell Proliferation by Distinct Ras Downstream Signaling Pathways Mol. Cell. Biol., October 1, 2000; 20(19): 7068 - 7079. [Abstract] [Full Text]

				M. A. Lawlor, X. Feng, D. R. Everding, K. Sieger, C. E. H. Stewart, and P. Rotwein Dual Control of Muscle Cell Survival by Distinct Growth Factor-Regulated Signaling Pathways Mol. Cell. Biol., May 1, 2000; 20(9): 3256 - 3265. [Abstract] [Full Text]

				M. Dews, M. Prisco, F. Peruzzi, G. Romano, A. Morrione, and R. Baserga Domains of the Insulin-Like Growth Factor I Receptor Required for the Activation of Extracellular Signal-Regulated Kinases Endocrinology, April 1, 2000; 141(4): 1289 - 1300. [Abstract] [Full Text] [PDF]

				A. V. Lee, J. L. Gooch, S. Oesterreich, R. L. Guler, and D. Yee Insulin-Like Growth Factor I-Induced Degradation of Insulin Receptor Substrate 1 Is Mediated by the 26S Proteasome and Blocked by Phosphatidylinositol 3'-Kinase Inhibition Mol. Cell. Biol., March 1, 2000; 20(5): 1489 - 1496. [Abstract] [Full Text]

				K. L. Haugk, H.-M. P. Wilson, K. Swisshelm, and L. S. Quinn Insulin-Like Growth Factor (IGF)-Binding Protein-Related Protein-1: An Autocrine/Paracrine Factor That Inhibits Skeletal Myoblast Differentiation but Permits Proliferation in Response to IGF Endocrinology, January 1, 2000; 141(1): 100 - 110. [Abstract] [Full Text] [PDF]

				D. Gineitis and R. Treisman Differential Usage of Signal Transduction Pathways Defines Two Types of Serum Response Factor Target Gene J. Biol. Chem., June 29, 2001; 276(27): 24531 - 24539. [Abstract] [Full Text] [PDF]

				P. Rojnuckarin, Y. Miyakawa, N. E. Fox, J. Deou, G. Daum, and K. Kaushansky The Roles of Phosphatidylinositol 3-Kinase and Protein Kinase Czeta for Thrombopoietin-induced Mitogen-activated Protein Kinase Activation in Primary Murine Megakaryocytes J. Biol. Chem., October 26, 2001; 276(44): 41014 - 41022. [Abstract] [Full Text] [PDF]