Endocytic function of von Hippel-Lindau tumor suppressor protein regulates surface localization of fibroblast growth factor receptor 1 and cell motility.
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.
Hsu
Tien
T
Department of Pathology and Laboratory Medicine and Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina 29425, USA.
Adereth
Yair
Y
Kose
Nurgun
N
Dammai
Vincent
V
D002292:Carcinoma, Renal Cell / Q000378:metabolism / Q000473:pathology; D002465:Cell Movement; D002478:Cells, Cultured / Q000378:metabolism / Q000473:pathology; D034285:Dynamin II / Q000378:metabolism; D004705:Endocytosis; D066246:ErbB Receptors / Q000378:metabolism; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D007680:Kidney Neoplasms / Q000378:metabolism / Q000473:pathology; D009154:Mutation / Q000235:genetics; D054778:NM23 Nucleoside Diphosphate Kinases; D009701:Nucleoside-Diphosphate Kinase / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000378:metabolism*; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D017479:Receptors, Platelet-Derived Growth Factor / Q000378:metabolism; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics / Q000502:physiology*; D000076202:c-Mer Tyrosine Kinase; D020696:rab5 GTP-Binding Proteins / Q000378:metabolism
D051793:Hypoxia-Inducible Factor 1; D054778:NM23 Nucleoside Diphosphate Kinases; D011518:Proto-Oncogene Proteins; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D066246:ErbB Receptors; C097072:MERTK protein, human; D020794:Receptor Protein-Tyrosine Kinases; D051496:Receptor, Fibroblast Growth Factor, Type 1; D017526:Receptor, IGF Type 1; D017479:Receptors, Platelet-Derived Growth Factor; D000076202:c-Mer Tyrosine Kinase; C517938:NME1 protein, human; D009701:Nucleoside-Diphosphate Kinase; D020696:rab5 GTP-Binding Proteins; D034285:Dynamin II; C497446:VHL protein, human