Heterodimerization of the  and β Chains of the Interleukin-3 (IL-3) Receptor Is Necessary and Sufficient for IL-3–Induced Mitogenesis

Abstract

The high-affinity receptor for interleukin-3 (IL-3) is a complex of the IL-3–binding subunit (IL-3) and a larger β chain—βc, or, in the mouse, βc or its close relative βIL-3. There is evidence that the critical event that initiates signaling is not the approximation of the cytoplasmic domains of IL-3 and βIL-3, but is, rather, the formation of a β-β homodimer. Many of these studies involved the analyses of receptor chimeras where the cytoplasmic domains were derived from IL-3, βc or βIL-3, and the extracellular domains were derived from other cytokine receptors, such as the erythropoietin receptor (EpoR). However, evidence that the EpoR may also associate with other receptors clouds the interpretation of these experiments. Therefore, we reevaluated the structure of the functional IL-3R using chimeric receptors with extracellular domains derived not from members of the cytokine-receptor family, but from CD8 or CD16. We show, by expression of these chimeras in Ba/F3 or CTLL-2 cells, that mitogenic signals were only generated by heterodimerization of the cytoplasmic domains of IL-3 and βIL-3. Homodimers of either IL-3 or βIL-3, alone or in combination, were nonfunctional. Furthermore, the ability of heterodimers to stimulate mitogenesis correlated with their ability to induce tyrosine phosphorylation of JAK-2. These data suggest that the physiological activation of the IL-3R involves the generation of simple heterodimers of IL-3 and βIL-3.