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A constitutively activated chimeric cytokine receptor confers factor-
independent growth in hematopoietic cell lines
Y Shikama, DL Barber, AD D'Andrea and CA Sieff
Division of Pediatric Hematology, Harvard Medical School, Boston, MA, USA.
The high-affinity receptor for granulocyte-macrophage colony- stimulating
factor (GMR) comprises at least 2 distinct subunits, alpha and beta common
(beta c), whereas the normal erythropoietin receptor (nEpoR) comprises only
one known subunit. An arginine to cysteine (R129C) mutation of the
extracytoplasmic domain of the murine EpoR leads to Epo-independent growth
in transduced cells (cEpoR). To investigate the proliferative functions of
the cytoplasmic regions of each GMR subunit separately and the potential of
the R129C EpoR mutation to induce factor-independent growth through
heterologous receptor regions, we constructed four hybrid receptors: the
extracellular region of either murine nEpoR or cEpoR linked to the
transmembrane and cytoplasmic regions of either the human GMR alpha or beta
c subunit (nE alpha, nE beta, cE alpha, and cE beta). We then expressed
them in an interleukin-3-dependent murine cell line, Ba/F3. Expression of
nE beta led to Epo-dependent growth, whereas expression of cE beta
conferred factor-independent growth. Surprisingly, expression of cE alpha
also resulted in factor-independent cell growth, whereas nE alpha did not
respond to Epo. Furthermore, the functional hybrid receptors showed
Epo-dependent (nE beta) or constitutive (cE alpha and cE beta) tyrosine
phosphorylation of the cytoplasmic kinases JAK1 and JAK2. We reasoned that
the proliferative signal of cE alpha was transduced either through the
alpha tail itself or through an accessory protein such as the endogenous
murine beta common subunit (mu beta c). To distinguish these possibilities,
the chimeric receptor cE alpha was expressed in the interleukin-2-dependent
murine cell line, CTLL-2, that does not express mu beta c. cE alpha did not
induce cell growth in CTLL-2; however, when mu beta c was coexpressed with
cE alpha in CTLL-2, factor-independent growth was reconstituted. In
conclusion, the cytoplasmic domain of the GMR alpha subunit requires a beta
chain for transduction of a proliferative signal. Furthermore, the R129C
EpoR mutation can constitutively activate heterologous receptors to mediate
factor-independent proliferation.
Volume 88,
Issue 2,
pp. 455-464,
07/15/1996
Copyright © 1996 by The American Society of Hematology
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