AbstractThe granulocyte-macrophage colony-stimulating factor (GM-CSF)/interleukin (IL)–3/IL-5 receptor family regulates the production and function of myeloid cells. These cytokines signal through receptor complexes that consist of unique ligand-binding α-chains and common signaling β-chains. IL-5 is distinct from IL-3 and GM-CSF in its capacity to induce eosinophil development, however, the molecular mechanisms that generate functional diversity within this receptor family are mostly unknown. Here, we characterized the selective IL-5Rα–binding adapter protein syntenin in IL-5R function. Syntenin and IL-5Rα colocalize at the plasma membrane and in early endosomal compartments. Manipulation of syntenin expression by ectopic expression or knockdown selectively modulated IL-5R but not GM-CSF receptor signaling, and severely affected IL-5–induced eosinophil differentiation from primary human CD34+ hematopoietic progenitor cells. We found syntenin up-regulated during eosinophilopoiesis but down-regulated during neutropoiesis. Syntenin forms complexes with multiple IL-5Rα chains, suggesting that syntenin-enhanced IL-5R output may result from stabilization of an IL-5–induced oligomeric receptor complex. These data demonstrate that cytokine-specific functions can be transduced by unique receptor α-chain–associating adapter proteins.