VEGF Receptors

Given the similarities in overall architecture between VEGF and PDGF, it is not surprising that their receptors, too, share common features. Both the VEGF receptors and the PDGF receptor family members—PDGFR-a, PDGFR-P, colony-stimulating factor 1 (CSF-1) receptor, stem cell factor (SCF) receptor (or c-kit), and flt3)—have a number of immunoglobulin (Ig)-like repeats in their ectodomain, a single transmembrane helix, and a split tyrosine kinase domain in the cytoplasmic portion. Sequence alignments and functional studies suggest that the five Ig-like repeats of the PDGF receptors correspond to the N-terminal five of the seven Ig-like domains of VEGF receptors [12]. Domain swapping and deletion studies identified the three N-terminal repeats as the growth-factor-binding regions (for references to individual studies, see Robinson and Stringer [3]). The function of the first domain, which is not involved in the interaction with the ligand, may be to regulate binding indirectly, as its deletion from VEGFR-2 enhances the VEGF association rate. The ligand binding determinants are contained in domains 2 and 3, as tandem constructs of these domains of flt1 and of VEGFR-2 bind to VEGF with near wild-type affinity. The isolated second domain of flt1 (but not VEGFR-2) still binds with an affinity of about 1 nM. Its structure shows that this domain is a member of the I-set of the Ig superfamily, but that it contains a number of rare and characteristic features that are conserved in domain 2 of the other receptors of the PDGF and VEGF families, indicating that the structure and function of this domain are conserved [12,13]. The function of the fourth domain has been addressed through ligand-induced cross-linking studies on flt1 and by using dimerization-inhibitory antibodies to SCFR (see references in Robinson and Stringer [3]). For both receptors, a dimerization site was identified within this domain, suggesting that the two copies of domain 4 in the signaling complex may be in direct contact. The function of domains 5 to 7 of the VEGF receptors is less clear, but it has been suggested for VEGFR-2 that they may have a role in inhibiting signaling in the absence of ligand [14].

Figure 2 Crystal structure of the VEGF-flt1-D2 complex, viewed toward the membrane. VEGF is rendered as accessible surface, and D2 of fltl as ribbon [12].

Figure 3 Models of signaling complexes, with receptors rendered as accessible surfaces and ligands as backbone ribbons. The membrane would be at the bottom of the figure. (A) Receptor complex of cystine-knot ligands VEGF, PlGF, or PDGF. (B) Receptor complex of four-helix-bundle ligands SCF, Flt3L, or M-CSF.

Figure 3 Models of signaling complexes, with receptors rendered as accessible surfaces and ligands as backbone ribbons. The membrane would be at the bottom of the figure. (A) Receptor complex of cystine-knot ligands VEGF, PlGF, or PDGF. (B) Receptor complex of four-helix-bundle ligands SCF, Flt3L, or M-CSF.

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