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J. Biol. Chem., Vol. 282, Issue 17, 12450-12457, April 27, 2007

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Ceramide Recruits and Activates Protein Kinase C (PKC) within Structured Membrane Microdomains^*

From the Department of Pharmacology College of Medicine, Pennsylvania State University, Hershey, Pennsylvania 17033

We have previously demonstrated that hexanoyl-D-erythro-sphingosine (C₆-ceramide), an anti-mitogenic cell-permeable lipid metabolite, limited vascular smooth muscle growth by abrogating trauma-induced Akt activity in a stretch injury model of neointimal hyperplasia. Furthermore, ceramide selectively and directly activated protein kinase C (PKC) to suppress Akt-dependent mitogenesis. To further analyze the interaction between ceramide and PKC, the ability of ceramide to localize within highly structured lipid microdomains (rafts) and activate PKC was investigated. Using rat aorta vascular smooth muscle cells (A7r5), we now demonstrate that C₆-ceramide treatment results in an increased localization and phosphorylation of PKC within caveolin-enriched lipid microdomians to inactivate Akt. In addition, ceramide specifically reduced the association of PKC with 14-3-3, a scaffold protein localized to less structured regions within membranes. Pharmacological disruption of highly structured lipid microdomains resulted in abrogation of ceramide-activated, PKC-dependent Akt inactivation, whereas molecular strategies suggest that ceramide-dependent PKC phosphorylation of Akt3 at Ser³⁴ was necessary for ceramide-induced vascular smooth muscle cell growth arrest. Taken together, these data demonstrate that structured membrane microdomains are necessary for ceramide-induced activation of PKC and resultant diminished Akt activity, leading to vascular smooth muscle cell growth arrest.

Received for publication, January 3, 2007 , and in revised form, February 15, 2007.

^* This work was supported by National Institutes of Health Grants R01HL66371 and R01HL76789 (to M. K.). 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.

¹ These authors contributed equally to this manuscript.

² Present address: Quest Diagnostics Nichols Institute, San Juan Capistrano, CA 92673.

³ To whom correspondence should be addressed: Dept. of Pharmacology H078, Penn State College of Medicine, Hershey, PA 17033. Tel.: 717-531-8549; Fax: 717-531-5013; E-mail: mkester{at}psu.edu.

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