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Role for the Pleckstrin Homology Domain-Containing Protein CKIP-1 in Phosphatidylinositol 3-Kinase-Regulated Muscle Differentiation

Alexias Safi ,^1,, Marie Vandromme,^2, Sabine Caussanel,¹ Laure Valdacci,^1,2 Dominique Baas, Marc Vidal,³ Gilbert Brun,¹ Laurent Schaeffer,² and Evelyne Goillot^1*

Equipe de Biologie des Regulations Cellulaires,¹ Equipe Differenciation Neuromusculaire, LBMC, CNRS UMR5665, ENS Lyon, IFR128 BioSciences Lyon-Gerland, Lyon, France,² Dana Farber Cancer Institute and Department of Genetics, Harvard Medical School, Boston, Massachusetts³

Received 29 July 2003/ Returned for modification 10 September 2003/ Accepted 4 November 2003

In this work, we report the implication of the pleckstrin homology (PH) domain-containing protein CKIP-1 in phosphatidylinositol 3-kinase (PI3-K)-regulated muscle differentiation. CKIP-1 is upregulated during muscle differentiation in C2C12 cells. We show that CKIP-1 binds to phosphatidylinositol 3-phosphate through its PH domain and localizes to the plasma membrane in a PI3-K-dependent manner. Activation of PI3-K by insulin or expression of an active form of PI3-K p110 induces a rapid translocation of CKIP-1 to the plasma membrane. Conversely, expression of the 3-phosphoinositide phosphatase myotubularin or PI3-K inhibition by LY294002, wortmannin, or mutant p85 abolishes CKIP-1 binding to the membrane. Upon induction of differentiation in low-serum medium, CKIP-1 overexpression in C2C12 myoblasts first promotes proliferation and then stimulates the expression of myogenin and cell fusion in a manner reminiscent of the dual positive effect of insulin-like growth factors on muscle cells. Interference with the PI3-K pathway impedes the effect of CKIP-1 on C2C12 cell differentiation. Finally, silencing of CKIP-1 by RNA interference abolishes proliferation and delays myogenin expression. Altogether, these data strongly implicate CKIP-1 as a new component of PI3-K signaling in muscle differentiation.

Present address: Department of Biochemistry, Duke University Medical Center, Durham, N.C.

A.S. and M.V. contributed equally to this work.

Present address: Laboratoire Matrice Extracellulaire et Developpement, CNRS UMR 5086, Institut de Biologie et Chimie des Proteines, Lyon, France.

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