TY - JOUR
T1 - Myoferlin regulates vascular endothelial growth factor receptor-2 stability and function
AU - Bernatchez, Pascal N.
AU - Acevedo, Lisette
AU - Fernandez-Hernando, Carlos
AU - Murata, Takahisa
AU - Chalouni, Cecile
AU - Kim, Jiae
AU - Erdjument-Bromage, Hediye
AU - Shah, Vijay
AU - Gratton, Jean Philippe
AU - McNally, Elizabeth M.
AU - Tempst, Paul
AU - Sessa, William C.
PY - 2007/10/19
Y1 - 2007/10/19
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=35648929848&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=35648929848&partnerID=8YFLogxK
U2 - 10.1074/jbc.M704798200
DO - 10.1074/jbc.M704798200
M3 - Article
C2 - 17702744
AN - SCOPUS:35648929848
SN - 0021-9258
VL - 282
SP - 30745
EP - 30753
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 42
ER -