VEGFR and type-V RTK activation and signaling

Abstract

Vascular endothelial growth factor receptors (VEGFRs) in vertebrates play essential roles in the regulation of angiogenesis and lymphangiogenesis. VEGFRs belong to the receptor-type tyrosine kinase (RTK) supergene family. They consist of a ligand-binding region with seven immunoglobulin (7 Ig) -like domains, a trans-membrane (TM) domain, and a tyrosine kinase (TK) domain with along kinase insert (KI) (also known as atype-V RTK). Structurally, VEGFRs are distantly related to the members of the M-colony stimulating factor receptor/platelet-derived growth factor receptor (CSFR)/(PDGFR) family, which have five immunoglobulin (5 Ig)-like domains. However, signal transduction in VEGFRs significantly differs from that in M-CSFR/PDGFRs. VEGFR2, the major signal transducer for angiogenesis, preferentially usesthe phospholipaseCγ-protein kinaseC(PLC-γ-PKC)-MAPK pathway, whereas M-CSFR/ PDGFRs use the PI3 kinase-Ras-MAPK pathway for cell proliferation. In phylogenetic development, the VEGFR-like receptor in nonvertebrates appears to be the ancestor of the 7 Ig-and 5 Ig-RTK families because most nonvertebrates have only a single 7 Ig-RTK gene. In mammals, VEGFRs are deeply involved in pathological angiogenesis, including cancer and inflammation. Thus, an efficient inhibitor targeting VEGFRs could be useful in suppressing various diseases. © 2013 Cold Spring Harbor Laboratory Press; all rights reserved.