Endocytic Function of von Hippel-Lindau Tumor Suppressor Protein Regulates Surface Localization of Fibroblast Growth Factor Receptor 1 and Cell Motility
| Autor: | Vincent Dammai, Tien Hsu, Nurgun Kose, Yair Adereth |
|---|---|
| Rok vydání: | 2006 |
| Předmět: |
endocrine system diseases
Endocytic cycle Biology C-Mer Tyrosine Kinase Kidney urologic and male genital diseases Endocytosis Biochemistry Article Receptor IGF Type 1 Dynamin II Growth factor receptor Cell Movement Proto-Oncogene Proteins Humans Receptors Platelet-Derived Growth Factor Metastasis suppressor Receptor Fibroblast Growth Factor Type 1 Epidermal growth factor receptor Carcinoma Renal Cell neoplasms Molecular Biology Cells Cultured rab5 GTP-Binding Proteins Dynamin c-Mer Tyrosine Kinase Fibroblast growth factor receptor 1 Receptor Protein-Tyrosine Kinases Cell Biology NM23 Nucleoside Diphosphate Kinases Kidney Neoplasms female genital diseases and pregnancy complications Cell biology ErbB Receptors stomatognathic diseases Von Hippel-Lindau Tumor Suppressor Protein Nucleoside-Diphosphate Kinase Mutation biology.protein Hypoxia-Inducible Factor 1 |
| Zdroj: | Journal of Biological Chemistry. 281:12069-12080 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.m511621200 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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