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J. Biol. Chem., Vol. 280, Issue 37, 32468-32479, September 16, 2005

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Decorin Evokes Protracted Internalization and Degradation of the Epidermal Growth Factor Receptor via Caveolar Endocytosis^*

Jing-Xu Zhu1, Silvia Goldoni1, Gregory Bix, Rick T. Owens, David J. McQuillan, Charles C. Reed, and Renato V. Iozzo¶2

From the Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, the LifeCell Corporation, Branchburg, New Jersey 08876, and the ^¶Cellular Biology and Signaling Program, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107

Decorin inhibits the epidermal growth factor receptor (EGFR) by down-regulating its tyrosine kinase activity, thereby blocking the growth of a variety of transformed cells and tumor xenografts. In this study we provide evidence that decorin directly binds to the EGFR causing its dimerization, internalization, and ultimately its degradation. Using various pharmacological agents to disrupt clathrin-dependent and -independent endocytosis, we demonstrate that decorin evokes a protracted internalization of the EGFR primarily via caveolar-mediated endocytosis. In contrast to EGF, decorin targets the EGFR to caveolae, but not to early or recycling endosomes. Ultimately, however, both EGF- and decorin-induced pathways converge into late endosomes/lysosomes for final degradation. Thus, we have discovered a novel biological mechanism for decorin that could explain its anti-proliferative and anti-oncogenic mode of action.

Received for publication, April 8, 2005 , and in revised form, June 27, 2005.

^* This work was supported in part by National Institutes of Health Grants RO1 CA39481 and RO1 CA47282 and Department of the Army Grant DAMD17-00-1-0425 (to R. V. I.). 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, Anatomy and Cell Biology, Rm. 249 Jefferson Alumni Hall, Thomas Jefferson University, 1020 Locust St., Philadelphia, PA 19107. E-mail: iozzo{at}mail.jci.tju.edu.

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