Ligand-induced activation of chimeric receptors between the erythropoietin receptor and receptor tyrosine kinases

Ligand-induced dimerization is a key step in the activation of receptor tyrosine kinases, including the epidermal growth factor receptor, stem cell factor receptor (c-kit), and colony-stimulating factor 1 receptor (c-fms). The erythropoietin receptor (EPOR), a member of the cytokine receptor family, contains no kinase motif and its activation mechanism remains unclear. Here we show that chimeric receptors carrying the extracellular domain of the epidermal growth factor receptor or c-kit linked to the cytoplasmic domain of the EPOR, transmitted epidermal growth factor or stem cell factor-dependent proliferation signals in an interleukin 3-dependent cell line. The chimeric receptors as well as the wild-type EPOR also mediated the ligand-induced tyrosine phosphorylation of a set of similar proteins. Moreover, erythropoietin triggered mitogenic signals of chimeric receptors carrying the extracellular domain of the EPOR linked to the tyrosine kinase of c-fms. These data demonstrate the interchangeability of domains between two distinct receptor families and suggest that ligand-induced dimerization is a key step in activating the EPOR.