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Blood, Vol. 94 No. 8 (October 15), 1999:
pp. 2676-2685
A Thrombopoietin Receptor Mutant Deficient in Jak-STAT Activation
Mediates Proliferation But Not Differentiation in UT-7 Cells
Marion Dorsch,
Nika N. Danial,
Paul B. Rothman, and
Stephen P. Goff
From the Howard Hughes Medical Institute, Department of Biochemistry
and Molecular Biophysics, Department of Medicine, and Department of
Microbiology, Columbia University College of Physicians and Surgeons,
New York, NY.
Thrombopoietin (TPO) stimulates proliferation and differentiation of
cells of the megakaryocytic lineage. It exerts its function by binding
and activating c-mpl, a member of the hematopoietic receptor
superfamily. Upon binding of TPO to its receptor, numerous signaling
events are triggered. These include activation of the Jak-STAT (signal
transducers and activators of transcription) pathway, mitogen-activated
protein kinase (MAPK), Tec, and phospatidylinositol (PI) 3-kinase and
phosphorylation of Shc and Vav. The contribution of different signaling
pathways to the induction of specific cellular processes such as
proliferation and differentiation is incompletely understood. We have
previously described a mutant of c-mpl that fails to activate the
Jak-STAT pathway but nevertheless retains its ability to mediate
proliferation and activation of most signaling events in the murine
hematopoietic precursor cell lines BAF/3 and 32D. We confirm here the
ability of this mutant to mediate proliferation in the absence of
Jak-STAT activation in the human cell line UT-7 and further show that
this mutant fails to mediate TPO-induced megakaryocytic
differentiation. Comparison of the signaling capacity of this mutant in
UT-7 and BAF/3 cells shows considerable cell-type-specific
differences. Whereas in BAF/3 cells the mutant still mediates
activation of Shc, MAPK, Vav, and PI 3-kinase at levels comparable to
the wild-type receptor, these events are strongly diminished in UT-7
cells expressing the mutant. Furthermore, we show that the C-terminal
25 amino acid residues of the receptor mutant are crucial for the
mitogenic response in UT-7 cells.
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