VASCULAR ENDOTHELIAL GROWTH-FACTOR-D (VEGF-D) IS A LIGAND FOR THE TYROSINE KINASES VEGF RECEPTOR-2 (FLK1) AND VEGF RECEPTOR-3 (FLT4)

We have identified a member of the VEGF family by computer-based homol ogy searching and have designated it VEGF-D. VEGF-D is most closely re lated to VEGF-C by virtue of the presence of N- and C-terminal extensi ons that are not found in other VEGF family members, In adult human ti ssues, VEGF-D mRNA is most abundant in heart, lung, skeletal muscle, c olon, and small intestine, Analyses of VEGF-D receptor specificity rev ealed that VEGF-D is a ligand for both VEGF receptors (VEGFRs) VEGFR-2 (Flk1) and VEGFR-3 (Flt4) and can activate these receptors, However, VEGF-D does not bind to VEGFR-1. Expression of a truncated derivative of VEGF-D demonstrated that the receptor-binding capacities reside in the portion of the molecule that is most closely related in primary st ructure to other VEGF family members and that corresponds to the matur e form of VEGF-C. In addition, VEGF-D is a mitogen for endothelial cel ls. The structural and functional similarities between VEGF-D and VEGF -C define a subfamily of the VEGFs.