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J. Biol. Chem., Vol. 278, Issue 29, 27096-27104, July 18, 2003

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Interaction of Filamin A with the Insulin Receptor Alters Insulin-dependent Activation of the Mitogen-activated Protein Kinase Pathway^*

Hua-Jun He , Sutapa Kole , Yong-Kook Kwon , Michael T. Crow   ¶ and Michel Bernier  ||

From the Diabetes Section, Laboratory of Clinical Investigation and the Vascular Studies Unit, Laboratory of Cardiovascular Science, NIA, National Institutes of Health, Baltimore, Maryland 21224

The biological actions of insulin are associated with a rapid reorganization of the actin cytoskeleton within cells in culture. Even though this event requires the participation of actin-binding proteins, the effect of filamin A (FLNa) on insulin-mediated signaling events is still unknown. We report here that human melanoma M2 cells lacking FLNa expression exhibited normal insulin receptor (IR) signaling, whereas FLNa-expressing A7 cells were unable to elicit insulin-dependent Shc tyrosine phosphorylation and p42/44 MAPK activation despite no significant defect in IR-stimulated phosphorylation of insulin receptor substrate-1 or activation of the phosphatidylinositol 3-kinase/AKT cascade. Insulin-dependent translocation of Shc, SOS1, and MAPK to lipid raft microdomains was markedly attenuated by FLNa expression. Coimmunoprecipitation experiments and in vitro binding assays demonstrated that FLNa binds constitutively to IR and that neither insulin nor depolymerization of actin by cytochalasin D affected this interaction. The colocalization of endogenous FLNa with IR was detected at the surface of HepG2 cells. Ectopic expression of a C-terminal fragment of FLNa (FLNa^CT) in HepG2 cells blocked the endogenous IR-FLNa interaction and potentiated insulin-stimulated MAPK phosphorylation and transactivation of Elk-1 compared with vector-transfected cells. Expression of FLNa^CT had no major effect on insulin-induced phosphorylation of the IR, insulin receptor substrate-1, or AKT, but it elicited changes in actin cytoskeletal structure and ruffle formation in HepG2 cells. Taken together, these results indicate that FLNa interacts constitutively with the IR to exert an inhibitory tone along the MAPK activation pathway.

Received for publication, January 29, 2003 , and in revised form, April 14, 2003.

^* 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.

^¶ Present address: Division of Pulmonary and Critical Care Medicine, Dept. of Medicine, The Johns Hopkins University, Baltimore, MD 21224.

^|| To whom correspondence should be addressed: Diabetes Section, NIA, National Institutes of Health, 5600 Nathan Shock Dr., Box 23, Baltimore, MD 21224-6825. Tel.: 410-558-8199; Fax: 410-558-8381; E-mail: Bernierm{at}vax.grc.nia.nih.gov.

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