Heparin-II Domain of Fibronectin Is a Vascular Endothelial Growth Factor-Binding Domain

Abstract

We describe extracellular interactions between fibronectin (Fn) and vascular endothelial growth factor (VEGF) that influence integrin-growth factor receptor crosstalk and cellular responses. In previous work, we found that VEGF bound specifically to fibronectin (Fn) but not vitronectin or collagens. Herein we report that VEGF binds to the heparin-II domain of Fn and that the cell-binding and VEGF-binding domains of Fn, when physically linked, are necessary and sufficient to promote VEGF-induced endothelial cell proliferation, migration, and Erk activation. Using recombinant Fn domains, the C-terminal heparin-II domain of Fn (type III repeats 13 to 14) was identified as a key VEGF-binding site. Mutation of the heparin-binding residues on FnIII13–14 abolished VEGF binding, and peptides corresponding to the heparin-binding sequences in FnIII13–14 inhibited VEGF binding to Fn. Fn fragments containing both the α5β1 integrin-binding domain (III 9 to 10) and the VEGF-binding domain (III 13 to 14) significantly e...