Integrin α9β1 mediates accelerated cell adhesion and migration through interactions with a number of diverse extracellular
ligands. We have shown previously that it directly binds the
vascular endothelial growth factors (
VEGF) A, C, and D and contributes to
VEGF-induced angiogenesis and lymphangiogenesis. Until now, the α9β1 binding site in
VEGF has not been identified. Here, we report that the three-amino acid sequence, EYP, encoded by exon 3 of
VEGF-A is essential for binding of
VEGF to
integrin α9β1 and induces adhesion and migration of endothelial and
cancer cells. EYP is specific for α9β1 binding and neither requires nor activates
VEGFR-2, the cognate receptor for
VEGF-A. Following binding to EYP,
integrin α9β1 transduces cell migration through direct activation of the
integrin signaling intermediates Src and
focal adhesion kinase. This interaction is biologically important because it mediates in vitro endothelial cell tube formation, wound healing, and
cancer cell invasion. These novel findings identify EYP as a potential site for directed
pharmacotherapy.