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Blood, Vol. 94 No. 4 (August 15), 1999:
pp. 1273-1282
Thrombopoietin-Induced Activation of the Mitogen-Activated Protein
Kinase (MAPK) Pathway in Normal Megakaryocytes: Role in Endomitosis
Ponlapat Rojnuckarin,
Jonathan G. Drachman, and
Kenneth Kaushansky
From the Division of Hematology, University of Washington, Seattle,
WA.
Thrombopoietin (TPO) plays a critical role in megakaryocyte
proliferation and differentiation. Using various cultured cell lines,
several recent studies have implicated the mitogen-activated protein
kinase (MAPK) pathway in megakaryocyte differentiation. In the study
reported here, we examined the role played by thrombopoietin-induced MAPK activity in a cytokine-dependent cell line (BAF3/Mpl) and in
primary murine megakaryocytes. In both systems, extracellular signal-regulated protein kinase (ERK) 1 and 2 MAPK phosphorylation was
rapidly induced by TPO stimulation. To identify the Mpl domain responsible for MAPK activation, BAF3 cells expressing truncated forms
of the Mpl receptor were studied. Phosphorylation of ERKs did not
require elements of the cytoplasmic signaling domain distal to Box 2 and was not dependent on phosphorylation of the adapter protein Shc.
ERK activation in murine megakaryocytes was maximal at 10 minutes and
was markedly decreased over the subsequent 3 hours. Next, the
physiologic consequences of MAPK inhibition were studied. Using the
MAPK kinase (MEK) inhibitor, PD 98059, blockade of MAPK activity
substantially reduced TPO-dependent proliferation in BAF3/Mpl cells and
markedly decreased mean megakaryocyte ploidy in cultures. To exclude an
indirect effect of MAPK inhibition on stromal cells in whole bone
marrow, CD41+ cells were selected and then cultured in
TPO. The number of polyploid megakaryocytes derived from the
CD41-selected cells was also significantly reduced by MEK inhibition,
as was their geometric mean ploidy. These studies show an important
role for MAPK in TPO-induced endomitosis and underscore the value of
primary cells when studying the physiologic effects of signaling pathways.
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