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Vol. 14, Issue 1, 334-347, January 2003
*Centre de Cancérologie Charles-Bruneau,
Hôpital Sainte-Justine, Montréal, Quebec, Canada H3T 1C5;
and Université du Québec à Montréal,
Montréal, Québec, Canada H3C 3P8; and the The stimulation of vascular endothelial growth factor receptor-2
(VEGFR-2) by tumor-derived VEGF represents a key event in the
initiation of angiogenesis. In this work, we report that VEGFR-2 is
localized in endothelial caveolae, associated with caveolin-1, and that
this complex is rapidly dissociated upon stimulation with VEGF. The
kinetics of caveolin-1 dissociation correlated with those of
VEGF-dependent VEGFR-2 tyrosine phosphorylation, suggesting that
caveolin-1 acts as a negative regulator of VEGF R-2 activity.
Interestingly, we observed that in an overexpression system in which
VEGFR-2 is constitutively active, caveolin-1 overexpression inhibits
VEGFR-2 activity but allows VEGFR-2 to undergo VEGF-dependent activation, suggesting that caveolin-1 can confer ligand dependency to
a receptor system. Removal of caveolin and VEGFR-2 from caveolae by
cholesterol depletion resulted in an increase in both basal and
VEGF-induced phosphorylation of VEGFR-2, but led to the inhibition of
VEGF-induced ERK activation and endothelial cell migration, suggesting
that localization of VEGFR-2 to these domains is crucial for
VEGF-mediated signaling. Dissociation of the VEGFR-2/caveolin-1 complex
by VEGF or cyclodextrin led to a PP2-sensitive phosphorylation of
caveolin-1 on tyrosine 14, suggesting the participation of Src family
kinases in this process. Overall, these results suggest that caveolin-1
plays multiple roles in the VEGF-induced signaling cascade.
Program in Molecular Cardiology, University of North Carolina, Chapel
Hill, North Carolina 27599-7075
Research scholar of the Fonds de la Recherche en
Santé du Québec.
§
Corresponding author. E-mail:
molmed{at}justine.umontreal.ca.
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