Myoferlin regulates vascular endothelial growth factor receptor-2 stability and function

Pascal N. Bernatchez, Lisette Acevedo, Carlos Fernandez-Hernando, Takahisa Murata, Cecile Chalouni, Jiae Kim, Hediye Erdjument-Bromage, Vijay Shah, Jean Philippe Gratton, Elizabeth M. McNally, Paul Tempst, William C. Sessa

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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.

Original languageEnglish (US)
Pages (from-to)30745-30753
Number of pages9
JournalJournal of Biological Chemistry
Volume282
Issue number42
DOIs
StatePublished - Oct 19 2007

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Bernatchez, P. N., Acevedo, L., Fernandez-Hernando, C., Murata, T., Chalouni, C., Kim, J., Erdjument-Bromage, H., Shah, V., Gratton, J. P., McNally, E. M., Tempst, P., & Sessa, W. C. (2007). Myoferlin regulates vascular endothelial growth factor receptor-2 stability and function. Journal of Biological Chemistry, 282(42), 30745-30753. https://doi.org/10.1074/jbc.M704798200