title: Immunoglobulin-like domain 4-mediated receptor-receptor interactions contribute to platelet-derived growth factor-induced receptor dimerization.
abstract: Platelet-derived growth factor (PDGF) is a dimeric growth factor that activates its tyrosine kinase receptor by inducing receptor dimerization. In this study, we investigated if receptor-receptor interactions, in addition to ligand-receptor interactions, contribute to the ligand-induced dimerization of the PDGF receptors. Analysis of two deletion mutants of the PDGF alpha-receptor indicated a role for Ig-like domain 4 in ligand-receptor or receptor-receptor interactions. When the fourth Ig-like domain of the PDGF alpha-receptor instead was replaced with the corresponding sequence of the stem cell factor receptor, the binding of PDGF-AA and -BB was not affected, nor was the ability to form homodimeric receptor complexes. This indicates that Ig-like domain 4 does not participate in ligand-receptor interactions. However, the chimeras did not form heterodimers with wild-type PDGF alpha- or beta-receptors. Together, these findings suggest that Ig-like domain 4 mediates specific receptor-receptor interactions. This notion was also supported by the finding that a soluble form of Ig-like domain 4 of the PDGF alpha-receptor acted as a PDGF alpha-receptor antagonist. We conclude that specific receptor-receptor interactions contribute to PDGF receptor dimerization in vivo and that complementary epitopes in Ig-like domain 4 mediate these interactions. Our experiments also identify Ig-like domain 4 as a target for PDGF antagonists.
authors.affiliation: Ludwig Institute for Cancer Research, S-751 24 Uppsala, Sweden.
authors.forename: T
authors.initials: T
authors.lastname: Omura
authors.forename: C H
authors.initials: CH
authors.lastname: Heldin
authors.forename: A
authors.initials: A
authors.lastname: Ostman
mesh_terms: D000818:Animals; D000077214:Becaplermin; D001665:Binding Sites; D019556:COS Cells; D004591:Electrophoresis, Polyacrylamide Gel; D006801:Humans; D008958:Models, Molecular; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D011487:Protein Conformation; D020574:Proto-Oncogene Proteins c-sis; D017479:Receptors, Platelet-Derived Growth Factor / Q000737:chemistry / Q000378:metabolism*; D014443:Tyrosine / Q000378:metabolism
chemical_list: D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D000077214:Becaplermin; D014443:Tyrosine; D017479:Receptors, Platelet-Derived Growth Factor