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J. Biol. Chem., Vol. 282, Issue 22, 16086-16094, June 1, 2007

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Receptor-mediated Endocytosis Involves Tyrosine Phosphorylation of Cortactin^*

Jianwei Zhu¹, Dan Yu^¶1, Xian-Chun Zeng^¶, Kang Zhou^||, and Xi Zhan^¶2

From the Affiliated Hospital of Nantong University, 226001 Nantong, China, the Department of Pathology, Marlene and Stewart Greenebaum Cancer Center, and ^¶Center for Vascular and Inflammatory Disease, University of Maryland School of Medicine, Baltimore, Maryland 21201, and the ^||Biochemistry, Microbiology, and Molecular Biology Doctoral Program, Pennsylvania State University, University Park, Pennsylvania 16802

Efficient internalization of cell surface receptors requires actin polymerization mediated by Arp2/3 complex and cortactin, a prominent substrate of the protein-tyrosine kinase Src. However, the significance of cortactin tyrosine phosphorylation in endocytosis is unknown. We found that overexpression of a cortactin mutant deficient in tyrosine phosphorylation decreased transferrin uptake. Suppression of cortactin expression by RNA interference also reduced transferrin internalization. Such inhibition was effectively rescued by overexpressing wild-type cortactin but not a cortactin mutant deficient in tyrosine phosphorylation or a mutant with deletion of the Src homology 3 domain. Likewise, purified phosphorylation-null cortactin failed to restore the formation of clathrin-coated vesicles in a cortactin-depleted cell extract. In vitro analysis revealed that Src-mediated phosphorylation enhanced the association of cortactin with dynamin-2 in a tyrosine phosphorylation-dependent manner. Quantitative analysis demonstrated that Src enhances the affinity of cortactin for dynamin-2 by more than 3-fold. On the other hand, Src-treated dynamin-2 had no effect on its interaction with cortactin. These data indicate that Src kinase is implicated in clathrin-mediated endocytosis by phosphorylation of cortactin.

Received for publication, March 7, 2007 , and in revised form, April 3, 2007.

^* This work was supported by National Institutes of Health Grants CA113809 and CA091984 (to X. Z.). 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 Both authors contributed equally to this work.

² To whom correspondence should be addressed: Dept. of Pathology, Center for Vascular and Inflammatory Disease, University of Maryland School of Medicine, 800 West Baltimore St., Baltimore, MD 21201. Tel.: 410-706-8228; Fax: 410-706-8234; E-mail: xzhan{at}som.umaryland.edu.

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