The tumor suppressor von Hippel-Lindau protein (VHL) serves as a negative regulator of hypoxia inducible factor-alpha subunits (HIF-alpha). However, accumulated evidence indicates that VHL may play additional roles in other cellular functions. We report here a novel HIF-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 EGFR, PDGFR, IGFR1 and c-Met are not affected. We demonstrate that: (1) FGFR1 endocytosis is defective in VHL mutant and is rescued by re-expression of wild-type VHL, (2) VHL is recruited to FGFR1-containing, but not EGFR-containing, endosomal vesicles,(3) VHL exhibits functional relationship with Rab5a and dynamin2 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.