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.
Highlights
Deletion of Ig-like Domain 4 in the Platelet-derived growth factor (PDGF) ␣-Receptor Leads to Loss of High Affinity Binding—The region of the PDGF ␣-receptor primarily involved in direct PDGF binding has been mapped to Ig-like domains 1–3 [13, 14]
When the results from the binding data were subjected to Scatchard analysis [26], a Kd value of 0.5 nM was obtained for both the wild-type PDGF ␣-receptor and ␣⌬5-R
We provide evidence that PDGF receptor dimerization involves, in addition to the interaction between ligand and receptor, a direct interaction between the receptors
Summary
COS cells expressing the wild-type PDGF ␣-receptor, ␣⌬5-R, or ␣⌬4,5-R were tested for binding of 125I-PDGF-AA in the presence of various concentrations of unlabeled ligand. Analysis was performed using COS cells transfected with the full-length wild-type PDGF ␣-receptor, ␣⌬5-R, or ␣⌬4,5-R as indicated at the top of the figure. Analysis of Receptor Homo- and Heterodimerization—Cross-linking and immunoprecipitation after binding of 125I-PDGF-AA in the absence or presence of excess unlabeled PDGF-AA were performed using transfected COS cells in 60-mm dishes.
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