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Signal transduction by the receptors for thrombopoietin (c-mpL) and
interleukin-3 in hematopoietic and nonhematopoietic cells
KK Morella, E Bruno, S Kumaki, CF Lai, J Fu, HM Wang, L Murray, R Hoffman, M Timour and L Benit
Department of Molecular and Cellular Biology, Roswell Park Cancer
Institute, Buffalo, NY 14263, USA.
Antisense oligonucleotide to the translation initiation sequence of human
c-mpI reduced the proliferation of human CD34+ bone marrow cells in
response to interleukin-3 (IL-3) alone or to the combination of IL-3 and
thrombopoietin (TPO). To investigate the molecular basis for these cytokine
interactions, we analyzed the relationship between the receptor subunits
for IL-3 and TPO and determined whether both receptors activate identical
signal transduction pathways. The function of the receptor subunits was
characterized in transiently transfected hepatoma cells and fibroblasts by
the activation of gene expression via specific regulatory elements and by
the stimulation of DNA-binding activity of STAT proteins. Although c-mpl
and IL-3 receptor (IL-3R) reconstituted a qualitatively comparable gene
regulatory response, there was no detectable functional interaction between
their respective receptor subunits. By comparing the receptor action in
different cell lines, we observed that in human hepatoma cells the
signaling of c-mpI was 100-fold less sensitive to TPO than in rat hepatoma
cells. However, IL-3R signaling was comparable between the two cell types,
suggesting that c-mpI and IL-3R do not use identical signal transducing
mechanisms. The cytoplasmic domains necessary for c-mpI signaling were
determined by testing deletion mutants. The membrane-proximal box 1
sequence motif was critical for gene regulation and for STAT protein
activation that seemed to involve the Janus kinase 2 (JAK2). Because IL- 3R
was less dependent on JAK2 than c-mpI, different levels of JAK2 expression
may account, in part, for the quantitative difference in IL- 3 and TPO
response among various cell lines.
Volume 86,
Issue 2,
pp. 557-571,
07/15/1995
Copyright © 1995 by The American Society of Hematology
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