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Thrombopoietin signal transduction in purified murine megakaryocytes
JG Drachman, DF Sabath, NE Fox and K Kaushansky
University of Washington Medical Center, Division of Hematology, Seattle
98195, USA.
Thrombopoietin (TPO) is a recently cloned cytokine that binds to its
receptor, Mpl, and promotes hematopoietic expansion and maturation,
primarily of the megakaryocyte lineage. The signaling pathways responsible
for these events are thought to involve the Janus family of nonreceptor
tyrosine kinases (JAKs) and the signal transducers and activators of
transcription (STATs), which are activated by tyrosine phosphorylation.
Previous investigators have studied these molecules in engineered and
naturally occurring cell lines. To investigate the molecular basis for TPO
signal transduction in a more physiologic target, we determined the pattern
of JAK and STAT activation in purified, normal urine megakaryocytes. These
results are compared with those of established cell lines that only
proliferate (Ba/F3- mMPL and DA-1-TPO) or only differentiate (L8057) in
response to TPO. From these findings, a model is proposed to explain the
physiologic roles of JAK2, TYK2, STAT3, and STAT5 in TPO signaling.
Furthermore, previous studies of the physical interaction between Mpl and
the JAKs are extended, showing a difference in the association of JAK2 and
TYK2 with the TPO receptor. Finally, we show that, in the cell line
Ba/F3-mMPL, the closely related proteins STAT5A and STAT5B are both
activated by TPO stimulation and are capable of heterodimerization.
Together, these results further our understanding of the early stages of
megakaryocyte and platelet development.
Volume 89,
Issue 2,
pp. 483-492,
01/15/1997
Copyright © 1997 by The American Society of Hematology
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