The VEGF family is encoded by seven genes (VEGF-A, B, C, D, E: PLGF (Placenta Growth Factor)-1, 2). Six isoforms of VEGF-A protein, containing 121, 145, 165, 183, 189, and 206 amino acid residues, and two isoforms of VEGF-B (167 and 186 residues) are specified by alternatively spliced mRNAs. The active form of each of these proteins is a homodimer.
The specificities of the three VEGF tyrosine kinase receptors, VEGFR-1, VEGFR-2 and VEGFR-3, for these ligands are shown in the figure (Hicklin and Ellis 2005). All VEGF-A isoforms bind both VEGFR-1 and VEGFR-2; PLGF-1 and -2, and VEGF-B isoforms bind only VEGFR-1; VEGF-E binds VEGFR-2; and VEGF-C and -D bind both VEGFR-2 and -3. VEGF-D undergoes a complex series of post-translational modifications that results in secreted forms with increased activity toward VEGFR-3 and VEGFR-2.
Two co-receptor proteins in the cell membrane, neuropilin (NRP)-1 and NRP-2, interact with VEGFR proteins to increase the affinity of the latter for their ligands (Neufeld et al.,2002). They differ from VEGFR proteins in not having intracellular signaling domains.