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J Biol Chem, Vol. 275, Issue 7, 5124-5130, February 18, 2000
From the Hanson Centre for Cancer Research, The Institute of
Medical and Veterinary Science,
Adelaide, South Australia 5000, Australia
Cysteine residues 86 and 91 of the
The Role of Disulfide-linked Dimerization in Interleukin-3
Receptor Signaling and Biological Activity*
,
subunit of
the human interleukin (hIL)-3 receptor (hc) participate in
disulfide-linked receptor subunit heterodimerization. This linkage is
essential for receptor tyrosine phosphorylation, since the Cys-86 
Ala (Mc4) and Cys-91 Ala (Mc5) mutations abolished both events. Here, we used these mutants to examine whether disulfide-linked receptor dimerization affects the biological and biochemical activities of the IL-3 receptor. Murine T cells expressing hIL-3R
and Mc4 or
Mc5 did not proliferate in hIL-3, whereas cells expressing wild-type
hc exhibited rapid proliferation. However, a small subpopulation of
cells expressing each mutant could be selected for growth in IL-3, and
these proliferated similarly to cells expressing wild-type hc,
despite failing to undergo IL-3-stimulated hc tyrosine
phosphorylation. The Mc4 and Mc5 mutations substantially reduced, but
did not abrogate, IL-3-mediated anti-apoptotic activity in the
unselected populations. Moreover, the mutations abolished IL-3-induced
JAK2, STAT, and AKT activation in the unselected cells, whereas
activation of these molecules in IL-3-selected cells was normal. In
contrast, Mc4 and Mc5 showed a limited effect on activation of Erk1 and
-2 in unselected cells. These data suggest that whereas
disulfide-mediated cross-linking and hc tyrosine phosphorylation are
normally important for receptor activation, alternative mechanisms can
bypass these requirements.
*
This work was supported by grants from the National Health
and Medical Research Council of Australia (to T. J. G. and to
A. F. L.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Present address: Dept of Biochemistry and Molecular Biology,
Australian National University, Canberra, Australian Capital Territory
0200, Australia.
§
Research Fellow of the Anti-cancer Foundation of the Universities
of South Australia.
¶
Principal Research Fellow of the National Health and Medical
Research Council of Australia. To whom correspondence should be
addressed: Hanson Centre for Cancer Research, The Institute of Medical
and Veterinary Science, Frome Road, Adelaide, South Australia 5000, Australia; Tel.: 61-8-8222-3305; Fax: 61-8-8232-4092; E-mail:
tom.gonda@imvs.sa.gov.au.
Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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