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J. Biol. Chem., Vol. 279, Issue 46, 48055-48062, November 12, 2004

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G Activation of Src Induces Caveolae-mediated Endocytosis in Endothelial Cells^*

Ayesha N. Shajahan, Chinnaswamy Tiruppathi, Alan V. Smrcka, Asrar B. Malik, and Richard D. Minshall, A Parker B. Francis Fellow in Pulmonary Research¶||

From the Pharmacology and ^¶Anesthesiology, University of Illinois, College of Medicine, Chicago, Illinois 60612 and Department of Pharmacology and Physiology, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642

Caveolae-mediated endocytosis in endothelial cells is stimulated by the binding of albumin to gp60, a specific albumin-binding protein localized in caveolae. The activation of gp60 induces its cell surface clustering and association with caveolin-1, the caveolar-scaffolding protein. This interaction leads to G_i-induced Src kinase activation, which in turn signals dynamin-2-mediated fission and directed migration of caveolae-derived vesicles from apical to basal membrane. In this study, we investigated the possible role of the G heterodimer in signaling G_i-induced Src activation and subsequent caveolae-mediated endocytosis. We observed using rat lung microvascular endothelial cells that expression of the C terminus of -adrenergic receptor kinase (ct-ARK), an inhibitor G signaling, prevented gp60-dependent Src activation as well as caveolae-mediated endocytosis and transcellular transport of albumin and uptake of cholera toxin subunit B, a specific marker of caveolae internalization. Expression of ct-ARK also prevented Src-mediated tyrosine phosphorylation of caveolin-1 and dynamin-2 and the resultant phosphorylation-dependent association of dynamin-2 and caveolin-1. Also, the direct activation of G using a specific cell-permeant activating peptide (myristoylated-SIRKALNILGYPDYD) simulated the effects of gp60 in inducing Src activation, caveolin-1, and dynamin-2 phosphorylation as well as caveolae-mediated endocytosis of cholera toxin subunit B. The myristoylated-SIRKALNILGYPDYD peptide-induced responses were inhibited by the expression of ct-ARK. Taken together, our results demonstrate that G activation of Src signals caveolae-mediated endocytosis and transendothelial albumin transport via transcytosis.

Received for publication, May 25, 2004 , and in revised form, August 19, 2004.

^* This work was supported in part by National Institutes of Health Grants T32 HL07239, HL60678 (to A. B. M.), GM58531 (to C. T.), and HL71626 (to R. D. M.). 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 Pharmacology, University of Illinois at Chicago, m/c 868, 835 S. Wolcott Ave., Chicago, IL 60612. Tel.: 312-996-1655; Fax: 312-996-1225; E-mail: rminsh{at}uic.edu.

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