Structure-function analysis of VEGF receptor activation and the role of coreceptors in angiogenic signaling.
Vascular endothelial growth factors (VEGFs) constitute a family of six polypeptides, VEGF-A, -B, -C, -D, -E and PlGF, that regulate blood and lymphatic vessel development. VEGFs specifically bind to three type V receptor tyrosine kinases (RTKs), VEGFR-1, -2 and -3, and to coreceptors such as neuropilins and heparan sulfate proteoglycans (HSPG). VEGFRs are activated upon ligand-induced dimerization mediated by the extracellular domain (ECD). A study using receptor constructs carrying artificial dimerization-promoting transmembrane domains (TMDs) showed that receptor dimerization is necessary, but not sufficient, for receptor activation and demonstrates that distinct orientation of receptor monomers is required to instigate transmembrane signaling. Angiogenic signaling by VEGF receptors also depends on cooperation with specific coreceptors such as neuropilins and HSPG. A number of VEGF isoforms differ in binding to coreceptors, and ligand-specific signal output is apparently the result of the specific coreceptor complex assembled by a particular VEGF isoform. Here we discuss the structural features of VEGF family ligands and their receptors in relation to their distinct signal output and angiogenic potential.
Grünewald
Felix S
FS
Paul Scherrer Institut, Biomolecular Research, 5232 Villigen PSI, Switzerland.
Prota
Andrea E
AE
Giese
Alexandra
A
Ballmer-Hofer
Kurt
K
D000818:Animals; D019812:Heparan Sulfate Proteoglycans / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D018919:Neovascularization, Physiologic / Q000502:physiology*; D039921:Neuropilins / Q000737:chemistry / Q000378:metabolism; D020033:Protein Isoforms / Q000737:chemistry / Q000378:metabolism; D055503:Protein Multimerization / Q000502:physiology*; D017434:Protein Structure, Tertiary / Q000502:physiology; D040262:Receptors, Vascular Endothelial Growth Factor / Q000737:chemistry* / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D013329:Structure-Activity Relationship; D042442:Vascular Endothelial Growth Factors / Q000737:chemistry* / Q000378:metabolism*
D019812:Heparan Sulfate Proteoglycans; D039921:Neuropilins; D020033:Protein Isoforms; D042442:Vascular Endothelial Growth Factors; D040262:Receptors, Vascular Endothelial Growth Factor