Myoferlin regulates vascular endothelial growth factor receptor-2 stability and function.
Myoferlin and dysferlin are members of the ferlin family of membrane proteins. Recent studies have shown that mutation or genetic disruption of myoferlin or dysferlin promotes muscular dystrophy-related phenotypes in mice, which are the result of impaired plasma membrane integrity. However, no biological functions have been ascribed to myoferlin in non-muscle tissues. Herein, using a proteomic analysis of endothelial cell (EC) caveolae/lipid raft microdomains we identified myoferlin in these domains and show that myoferlin is highly expressed in ECs and vascular tissues. The loss of myoferlin results in lack of proliferation, migration, and nitric oxide (NO) release in response to vascular endothelial growth factor (VEGF). Western blotting and surface biotinylation experiments show that loss of myoferlin reduces the expression level and autophosphorylation of VEGF receptor-2 (VEGFR-2) in native ECs. In a reconstituted cell system, transfection of myoferlin increases VEGFR-2 membrane expression and autophosphorylation in response to VEGF. In vivo, VEGFR-2 levels and VEGF-induced permeability are impaired in myoferlin-deficient mice. Mechanistically, myoferlin forms a complex with dynamin-2 and VEGFR-2, which prevents CBL-dependent VEGFR-2 polyubiquitination and proteasomal degradation. These data are the first to report novel biological activities for myoferlin and reveal the role of membrane integrity to VEGF signaling.
Pubmed ID: 17702744 RIS Download
Animals | Calcium-Binding Proteins | Capillary Permeability | Caveolae | Cell Line | Cell Movement | Cell Proliferation | Dynamin II | Endothelial Cells | Gene Deletion | Humans | Membrane Proteins | Mice | Mice, Knockout | Muscle Proteins | Muscular Dystrophy, Animal | Nitric Oxide | Organ Specificity | Phenotype | Phosphorylation | Proteasome Endopeptidase Complex | Protein Processing, Post-Translational | Proteomics | Proto-Oncogene Proteins c-cbl | Ubiquitin | Vascular Endothelial Growth Factor A | Vascular Endothelial Growth Factor Receptor-2