Neuropilin-1 is expressed by endothelial and tumor cells as an isoform-specific receptor for vascular endothelial growth factor

Vascular endothelial growth factor (VEGF), a major regulator of angiogenesis, binds to two Receptor Tyrosine Kinases, VEGFR2/KDR/Flk-1/VEGFR2/KDR/Flk-1 and Flt-1. We now describe the purification and the expression cloning from tumor cells of a third VEGF receptor, one that binds VEGF165 but not VEGF121. This isoform-specific VEGF receptor (VEGF165R) is identical to human neuropilin-1, a receptor for the collapsin/semaphorin family that mediates neuronal cell guidance. When coexpressed in cells with VEGFR2/KDR/Flk-1, neuropilin-1 enhances the binding of VEGF165 to VEGFR2/KDR/Flk-1 and VEGF165-mediated chemotaxis. Conversely, inhibition of VEGF165 binding to neuropilin-1 inhibits its binding to VEGFR2/KDR/Flk-1 and its mitogenic activity for endothelial cells. We propose that neuropilin-1 is a novel VEGF receptor that modulates VEGF binding to VEGFR2/KDR/Flk-1 and subsequent bioactivity and therefore may regulate VEGF-induced angiogenesis.