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J. Biol. Chem., Vol. 279, Issue 42, 43900-43909, October 15, 2004

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Role of the p66^Shc Isoform in Insulin-like Growth Factor I Receptor Signaling through MEK/Erk and Regulation of Actin Cytoskeleton in Rat Myoblasts^*

Annalisa Natalicchio, Luigi Laviola, Claudia De Tullio, Lucia Adelaide Renna, Carmela Montrone, Sebastio Perrini, Giovanna Valenti, Giuseppe Procino, Maria Svelto, and Francesco Giorgino¶

From the Department of Emergency and Organ Transplantation, Section on Internal Medicine, Endocrinology and Metabolic Diseases, and the Department of General and Environmental Physiology, University of Bari, 70124 Bari, Italy

To investigate the role of Shc in IGF action and signaling in skeletal muscle cells, Shc protein levels were reduced in rat L6 myoblasts by stably overexpressing a Shc cDNA fragment in antisense orientation (L6/Shcas). L6/Shcas myoblasts showed marked reduction of the p66^Shc protein isoform and no change in p52^Shc or p46^Shc proteins compared with control myoblasts transfected with the empty vector (L6/Neo). When compared with control, L6/Shcas myoblasts demonstrated 3-fold increase in Erk-1/2 phosphorylation under basal conditions and blunted Erk-1/2 stimulation by insulin-like growth factor I (IGF-I), in the absence of changes in total Erk-1/2 protein levels. Increased basal Erk-1/2 activation was paralleled by a greater proportion of phosphorylated Erk-1/2 in the nucleus of L6/Shcas myoblasts in the absence of IGF-I stimulation. The reduction of p66^Shc in L6/Shcas myoblasts resulted in marked phenotypic abnormalities, such as rounded cell shape and clustering in islets or finger-like structures, and was associated with impaired DNA synthesis in response to IGF-I and lack of terminal differentiation into myotubes. In addition, L6/Shcas myoblasts were characterized by complete disruption of actin filaments and cell cytoskeleton. Treatment of L6/Shcas myoblasts with the MEK inhibitor PD98059 reduced the abnormal increase in Erk-1/2 activation to control levels and restored the actin cytoskeleton, re-establishing the normal cell morphology. Thus, the p66^Shc isoform exerts an inhibitory effect on the mitogen-activated protein kinase signaling pathway in rodent myoblasts, which is necessary for maintenance of IGF responsiveness of the MEK/Erk pathway and normal cell phenotype.

Received for publication, April 8, 2004 , and in revised form, June 28, 2004.

^* This work was supported by grants from the Ministero dell'Istruzione, Università e Ricerca (Italy), the Cofinlab 2000, Centro di Eccellenza Genomica Comparata: Geni Coinvolti in Processi Fisiopatologici in Campo Biomedico e Agrario (Italy), the Associazione Italiana Ricerca sul Cancro (Italy), and an educational grant from Pfizer Italia srl (ARADO Program) (to F. G.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: Dept. of Emergency and Organ Transplantation, Section on Internal Medicine, Endocrinology and Metabolic Diseases, University of Bari, Piazza Giulio Cesare, 11, 70124 Bari, Italy. Tel./Fax: 39-080-547-8689; E-mail: f.giorgino{at}endo.uniba.it.

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