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J. Biol. Chem., Vol. 280, Issue 28, 26216-26224, July 15, 2005

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Kaposi's Sarcoma-associated Herpesvirus Activation of Vascular Endothelial Growth Factor Receptor 3 Alters Endothelial Function and Enhances Infection^*

Xuefeng Zhang, Jian Feng Wang, Bala Chandran¶, Kris Persaud||, Bronislaw Pytowski||, Joyce Fingeroth**, and Jerome E. Groopman

From the Divisions of Experimental Medicine and ^**Infectious Diseases, Department of Medicine and Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115, the ^¶Department of Microbiology, Molecular Genetics, and Immunology, The University of Kansas Medical Center, Kansas City, Kansas 66160, and the ^||Department of Molecular and Cellular Biology, ImClone Systems, New York, New York 10014

Kaposi's sarcoma-associated herpesvirus (KSHV; also known as human herpesvirus 8) is the etiologic agent of Kaposi's sarcoma, an endothelial neoplasm. This -herpesvirus encodes for several unique proteins that alter target cell function, including the virion envelope-associated glycoprotein B (gB). Glycoprotein B has an RGD (Arg-Gly-Asp) motif at the extracellular amino terminus region and binds to the ₃₁ surface integrin, which enhances virus entry. We now report that gB can activate the vascular endothelial growth factor receptor 3 (VEGFR-3) on the surface of microvascular endothelial cells and trigger receptor signaling, which can modulate endothelial migration and proliferation. Furthermore, we observed that VEGFR-3 expression and activation enhance KSHV infection and participate in KSHV-mediated transformation. These functional changes in the endothelium may contribute to the pathogenesis of Kaposi's sarcoma and suggest that interventions that inhibit gB activation of VEGFR-3 could be useful in the treatment of this neoplasm.

Received for publication, October 6, 2004 , and in revised form, March 21, 2005.

^* This work was supported in part by National Institutes of Health Grant 1R01 DA15008-01 and Public Health Service Grant CA 75911 (to B. C.). 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.

Bertlesmann Cancer Research Fellow.

To whom correspondence should be addressed: Division of Experimental Medicine, Beth Israel Deaconess Medical Center, Harvard Inst. of Medicine, 4 Blackfan Circle, Boston, MA 02115. Tel.: 617-667-0070; Fax: 617-975-5244; E-mail: jgroopma{at}bidmc.harvard.edu.

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