Endocytic function of von Hippel-Lindau tumor suppressor protein regulates surface localization of fibroblast growth factor receptor 1 and cell motility

The Journal of Biological Chemistry
Tien HsuVincent Dammai

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 e...Continue Reading

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Citations

Feb 22, 2011·Naunyn-Schmiedeberg's Archives of Pharmacology·Tien Hsu
May 13, 2011·Naunyn-Schmiedeberg's Archives of Pharmacology·Mathieu Boissan, Marie-Lise Lacombe
Apr 18, 2009·Molecular and Cellular Biochemistry·Gouthami NallamothuTien Hsu
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Jun 3, 2010·Molecular and Cellular Biology·Anita HsounaTien Hsu
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Jun 3, 2021·Cells·Patrycja SzybowskaAntoni Wiedlocha

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