Interactions of VEGF family members with their receptors. (A) Growth factors and receptors of the VEGF family. Interactions of the VEGF family members VEGF-A, -B, -C, -D, -E, PlGF-1, PlGF-2 and the human immunodeficiency (HIV) Tat protein with the receptor tyrosine kinases VEGFR-1, VEGFR-2, and VEGFR-3; the accessory isoform specific receptors neuropilin-1 and -2 (NPR-1, -2); and heparansulfate proteoglycane (HSP) are shown. The receptors are displayed with their major structural motifs. VEGF-A splicing forms are in boxes. The extracellular domain of VEGFR-1 also is expressed as a soluble protein. (B) VEGFR-1 and -2. VEGF-A mediates its activity mainly via 2 receptor tyrosine kinases, VEGFR-1 and -2. VEGFR-1 and -2 are single-pass transmembrane receptors with 7 immunoglobulin (Ig)–like loops in the extracellular domain and a cytoplasmic tyrosine-kinase domain, separated by an intervening, noncatalytic, 70-aa residue sequence. Two VEGF monomers linked together by disulfide bonds induce receptor dimerization, thereby triggering kinase activation of both the receptor itself and several cytoplasmic signal transduction molecules.