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lüll Vascular endothelial growth factor receptor-2: its unique signaling and specific ligand, VEGF-E Shibuya MCancer Sci 2003[Sep]; 94 (9): 751-6Vascular endothelial growth factor receptor-2 (VEGFR-2/KDR/Flk-1) is a high-affinity receptor for vascular endothelial growth factor-A (VEGF-A), and mediates most of the endothelial growth and survival signals from VEGF-A. VEGFR-2 has a typical tyrosine kinase receptor structure with seven immunoglobulin (Ig)-like domains in the extracellular region, as well as a long kinase insert in the tyrosine kinase domain. It utilizes a unique signaling system for DNA synthesis in vascular endothelial cells, i.e. a phospholipase C gamma-protein kinase C-Raf-MAP kinase pathway. Although VEGF-A binds two receptors, VEGFR-1 and -2, a newly isolated ligand VEGF-E (Orf-virus-derived VEGF) binds and activates only VEGFR-2. Transgenic mice expressing VEGF-E(NZ-7) showed a dramatic increase in angiogenesis with very few side effects (such as edema and hemorrhagic spots), suggesting strong angiogenic signaling and a potential clinical utility of VEGF-E. VEGF family members bear three loops produced via three intramolecular disulfide bonds, and cooperation between loop-1 and loop-3 is necessary for the specific binding and activation of VEGFR-2 for angiogenesis. As it directly upregulates tumor angiogenesis, VEGFR-2 is an appropriate target for suppression of solid tumor growth using exogenous antibodies, small inhibitory molecules and in vivo stimulation of the immune system.|*Signal Transduction[MESH]|Angiogenesis Inducing Agents/metabolism[MESH]|Animals[MESH]|Blood Vessels/pathology[MESH]|Humans[MESH]|Ligands[MESH]|Mice[MESH]|Neovascularization, Pathologic/*metabolism[MESH]|Orf virus[MESH]|Vascular Endothelial Growth Factor Receptor-2/*physiology[MESH]|Viral Proteins/*physiology[MESH] |