Myoferlin regulates vascular endothelial growth factor receptor-2 stability and function Journal Article
| Authors: | Bernatchez, P. N.; Acevedo, L.; Fernández-Hernando, C.; Murata, T.; Chalouni, C.; Kim, J.; Erdjument-Bromage, H.; Shah, V.; Gratton, J. P.; McNally, E. M.; Tempst, P.; Sessa, W. C. |
| Article Title: | Myoferlin regulates vascular endothelial growth factor receptor-2 stability and function |
| Abstract: | 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. © 2007 by The American Society for Biochemistry and Molecular Biology, Inc. |
| Keywords: | signal transduction; controlled study; protein expression; vascular endothelial growth factor a; unclassified drug; human cell; gene deletion; nonhuman; ubiquitin; protein domain; protein function; cell proliferation; proteins; animal cell; phenotype; animals; mice; mice, knockout; mus; proteasome endopeptidase complex; protein degradation; cell line; protein stability; membrane proteins; vasculotropin receptor 2; autophosphorylation; phosphorylation; vascular endothelial growth factor receptor-2; proteomics; endothelium cell; endothelial cells; ubiquitination; protein processing, post-translational; genetic transfection; cell culture; membrane protein; western blotting; organ specificity; cell membranes; cell migration; cell movement; lipids; proliferation; proto-oncogene proteins c-cbl; knockout mouse; biotinylation; muscular dystrophy, animal; functional proteomics; nitric oxide; lipid raft; capillary permeability; muscle proteins; caveola; growth kinetics; microdomains; vascular endothelial growth factor (vegf); myoferlin; caveolae; dynamin ii |
| Journal Title: | Journal of Biological Chemistry |
| Volume: | 282 |
| Issue: | 42 |
| ISSN: | 0021-9258 |
| Publisher: | American Society for Biochemistry and Molecular Biology |
| Date Published: | 2007-10-19 |
| Start Page: | 30745 |
| End Page: | 30753 |
| Language: | English |
| DOI: | 10.1074/jbc.M704798200 |
| PUBMED: | 17702744 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 22" - "Export Date: 17 November 2011" - "CODEN: JBCHA" - "Source: Scopus" |
