Heterodimerization of the alpha and beta chains of the interleukin-3 (IL-3) receptor is necessary and sufficient for IL-3-induced mitogenesis

The high-affinity receptor for interleukin-3 (IL-3) is a complex of the IL- 3-binding subunit (alpha(IL-3)) and a larger beta chain-beta(c), or, in the mouse, beta(c) or its close relative beta(IL-3) There is evidence that the critical event that initiates signaling is not the approximation of the cy toplasmic domains of alpha(IL-3) and beta(IL-3) but is, rather, the formati on of a beta-beta homodimer. Many of these studies involved the analyses of receptor chimeras where the cytoplasmic domains were derived from alpha(IL -3), beta(c) or beta(IL-3) and the extracellular domains were derived from other cytokine receptors, such as the erythropoietin receptor (EpoR). Howev er, evidence that the EpoR may also associate with other receptors clouds t he interpretation of these experiments. Therefore, we reevaluated the struc ture of the functional IL-3R using chimeric receptors with extracellular do mains derived not from members of the cytokine-receptor family, but from CD 8 or CD16. We show, by expression of these chimeras in Ba/FB or CTLL-2 call s, that mitogenic signals were only generated by heterodimerization of the cytoplasmic domains of alpha(IL-3) and beta(IL-3) Homodimers of either alph a(IL-3) or beta(IL-3) alone or in combination, were nonfunctional. Furtherm ore, the ability of heterodimers to stimulate mitogenesis correlated with t heir ability to induce tyrosine phosphorylation of JAK-2. These data sugges t that the physiological activation of the IL-3R involves the generation of simple heterodimers of alpha(IL-3) and beta(IL-3) (C) 1999 by The American Society of Hematology.