Abstract
Ligands and their tyrosine kinase (TK) receptors regulate a variety of biological systems in animals. Vascular endothelial growth factor (VEGF) and its receptor (Flt/VEGFR family) system play a crucial role not only in physiological but also in most parts of pathological angiogenesis including cancer. Flt-1/VEGFR-1 and KDR/VEGFR-2 bind VEGF-A but have different functions on angiogenesis at early embryogenesis: Flt-1 has a negative role by trapping ligands, whereas KDR (Flk1 in mice) exerts a strong positive signal, resulting in a balance in blood vessel formation. At adult stages, however, both VEGFRs contribute to pathological angiogenesis either directly or through stimulation of migration/activation of macrophage lineage cells and stimulate tumor growth, metastasis, and inflammation. VEGFRs activate downstream signaling of the phospholipase Cγ-protein kinase C-MAP kinase pathway but not Ras pathway for cell proliferation. The VEGF-C/D and Flt-4/VEGFR-3 system regulates lymphangiogenesis. Thus, VEGFs as well as these receptor TKs are attractive targets for suppressing pathological angiogenesis.