Blood, Vol. 94 No. 5 (September 1), 1999:
pp. 1614-1622
Heterodimerization of the 
and 
Chains of the Interleukin-3
(IL-3) Receptor Is Necessary and Sufficient for IL-3-Induced
Mitogenesis
Paul C. Orban,
Megan K. Levings, and
John W. Schrader
From The Biomedical Research Centre, University of British Columbia,
Vancouver, BC, Canada.
The high-affinity receptor for interleukin-3 (IL-3) is a complex of
the IL-3-binding subunit (
IL-3) and a larger 
chain
c, or, in the mouse, c or its
close relative IL-3. There is evidence that the critical
event that initiates signaling is not the approximation of the
cytoplasmic domains of IL-3 and IL-3, but
is, rather, the formation of a - homodimer. Many of these studies
involved the analyses of receptor chimeras where the cytoplasmic
domains were derived from IL-3, c or
IL-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 IL-3. Homodimers of either IL-3 or IL-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 IL-3.
