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J. Biol. Chem. 281 (17): 12069-12080

© 2006 by The American Society for Biochemistry and Molecular Biology, Inc.

Endocytic Function of von Hippel-Lindau Tumor Suppressor Protein Regulates Surface Localization of Fibroblast Growth Factor Receptor 1 and Cell Motility*

Formula

Tien Hsu1, Yair Adereth, Nurgun Kose, , and Vincent Dammai2

Department of Pathology and Laboratory Medicine and Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina 29425

Abstract: The tumor suppressor VHL (von Hippel-Lindau protein) serves as a negative regulator of hypoxia-inducible factor-{alpha} subunits. However, accumulated evidence indicates that VHL may play additional roles in other cellular functions. We report here a novel hypoxia-inducible factor-independent function of VHL in cell motility control via regulation of fibroblast growth factor receptor 1 (FGFR1) endocytosis. In VHL null tumor cells or VHL knock-down cells, FGFR1 internalization is defective, leading to surface accumulation and abnormal activation of FGFR1. The enhanced FGFR1 activity directly correlates with increased cell migration. VHL disease mutants, in two of the mutation hot spots favoring development of renal cell carcinoma, failed to rescue the above phenotype. Interestingly, surface accumulation of the chemotactic receptor appears to be selective in VHL mutant cells, since other surface proteins such as epidermal growth factor receptor, platelet-derived growth factor receptor, IGFR1, and c-Met are not affected. We demonstrate that 1) FGFR1 endocytosis is defective in the VHL mutant and is rescued by reexpression of wild-type VHL, 2) VHL is recruited to FGFR1-containing, but not EGFR-containing, endosomal vesicles, 3) VHL exhibits a functional relationship with Rab5a and dynamin 2 in FGFR1 internalization, and 4) the endocytic function of VHL is mediated through the metastasis suppressor Nm23, a protein known to regulate dynamin-dependent endocytosis.


Received for publication October 26, 2005. Revision received February 16, 2006.

* This work was initially supported by the VHL Family Alliance (to T. H.) and subsequently by National Institutes of Health Grants PO1CA78582 and RO1CA109860 (to T. H.) and a Medical University of South Carolina/Department of Defense phase VII (Geocenters) grant (to V. D.). 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.


Formula

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1 and S2.

1 To whom correspondence may be addressed: Dept. of Pathology and Laboratory Medicine and Hollings Cancer Center, Medical University of South Carolina, 86 Jonathan Lucas St., HCC330, Charleston, SC 29425. Tel.: 843-792-0638; Fax: 843-792-5002; E-mail: hsut{at}musc.edu.

2 To whom correspondence may be addressed: Dept. of Pathology and Laboratory Medicine and Hollings Cancer Center, Medical University of South Carolina, 86 Jonathan Lucas St., HCC321, Charleston, SC 29425. Tel.: 843-792-1677; Fax: 843-792-5002; E-mail: dammaiv{at}musc.edu.


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