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. 2005 Aug 19;94(9):751–756. doi: 10.1111/j.1349-7006.2003.tb01514.x

Vascular endothelial growth factor receptor‐2: Its unique signaling and specific ligand, VEGF‐E

Masabumi Shibuya 1,✉
PMCID: PMC11160205  PMID: 12967471

Abstract

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 Cγ‐protein kinaseC‐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‐ENZ‐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.

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