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

Research output: Contribution to journalArticle

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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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Vascular Endothelial Growth Factor Receptor-2
Vascular Endothelial Growth Factor Receptor
Vascular Endothelial Growth Factor A
Dynamin II
Tissue
Biotinylation
Membranes
Caveolae
Muscular Dystrophies
Endothelial cells
Cell membranes
Bioactivity
Proteomics
Transfection
Blood Vessels
Permeability
Nitric Oxide
Membrane Proteins
Endothelial Cells
Western Blotting

ASJC Scopus subject areas

  • Biochemistry

Cite this

Bernatchez, P. N., Acevedo, L., Fernandez-Hernando, C., Murata, T., Chalouni, C., Kim, J., ... 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

Myoferlin regulates vascular endothelial growth factor receptor-2 stability and function. / Bernatchez, Pascal N.; Acevedo, Lisette; Fernandez-Hernando, Carlos; Murata, Takahisa; Chalouni, Cecile; Kim, Jiae; Erdjument-Bromage, Hediye; Shah, Vijay; Gratton, Jean Philippe; McNally, Elizabeth M.; Tempst, Paul; Sessa, William C.

In: Journal of Biological Chemistry, Vol. 282, No. 42, 19.10.2007, p. 30745-30753.

Research output: Contribution to journalArticle

Bernatchez, PN, Acevedo, L, Fernandez-Hernando, C, Murata, T, Chalouni, C, Kim, J, Erdjument-Bromage, H, Shah, V, Gratton, JP, McNally, EM, Tempst, P & Sessa, WC 2007, 'Myoferlin regulates vascular endothelial growth factor receptor-2 stability and function', Journal of Biological Chemistry, vol. 282, no. 42, pp. 30745-30753. https://doi.org/10.1074/jbc.M704798200
Bernatchez PN, Acevedo L, Fernandez-Hernando C, Murata T, Chalouni C, Kim J et al. Myoferlin regulates vascular endothelial growth factor receptor-2 stability and function. Journal of Biological Chemistry. 2007 Oct 19;282(42):30745-30753. https://doi.org/10.1074/jbc.M704798200
Bernatchez, Pascal N. ; Acevedo, Lisette ; Fernandez-Hernando, Carlos ; Murata, Takahisa ; Chalouni, Cecile ; Kim, Jiae ; Erdjument-Bromage, Hediye ; Shah, Vijay ; Gratton, Jean Philippe ; McNally, Elizabeth M. ; Tempst, Paul ; Sessa, William C. / Myoferlin regulates vascular endothelial growth factor receptor-2 stability and function. In: Journal of Biological Chemistry. 2007 ; Vol. 282, No. 42. pp. 30745-30753.
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