Vascular endothelial growth factor receptor-2: its unique signaling and specific ligand, VEGF-E.
Vascular 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.
Shibuya
Masabumi
M
Division of Genetics, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639, Japan. shibuya@ims.u-tokyo.ac.jp
D043925:Angiogenesis Inducing Agents / Q000378:metabolism; D000818:Animals; D001808:Blood Vessels / Q000473:pathology; D006801:Humans; D008024:Ligands; D051379:Mice; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D009923:Orf virus; D015398:Signal Transduction; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000502:physiology*; D014764:Viral Proteins / Q000502:physiology*
D043925:Angiogenesis Inducing Agents; D008024:Ligands; C084758:VEGF-like protein, Orf virus; D014764:Viral Proteins; D040301:Vascular Endothelial Growth Factor Receptor-2