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Megakaryocyte growth and development factor and interleukin-3 induce
patterns of protein-tyrosine phosphorylation that correlate with dominant
differentiation over proliferation of mpl-transfected 32D cells
SX Mu, M Xia, G Elliott, J Bogenberger, S Swift, L Bennett, DL Lappinga, R Hecht, R Lee and CJ Saris
Department of Developmental Biology, Amgen Inc, Thousand Oaks, CA 91320,
USA.
Recently, the ligand for c-mpl, a member of the family of cytokine
receptors, was cloned and found to be a physiologic regulator of platelet
homeostasis. We report that megakaryocyte growth and development factor
(MGDF, thrombopoietin [TPO], c-mpl ligand ) induces differentiation in a
majority of mpl-transfected 32D cells, while interleukin (IL)-3 is
exclusively mitogenic in this system. MGDF differentiation, as measured by
decreased proliferation, changes in cellular morphology, increased
adherence, and downregulation of very late antigen (VLA)-4, is dominant
over IL-3 proliferation. MGDF induces tyrosine-phosphorylation of mpl,
JAK2, SHC, SHPTP-1 (HCP, motheaten) and SHPTP-2 (Syp, PTP-1D) within 30
seconds of stimulation, as well as of vav and MAPK with slightly delayed
kinetics. A fraction of mpl and JAK2 is preassociated, and the
stoichiometry of this complex is unaltered by cytokine stimulation. After
MGDF stimulation, we detect interactions among SHC, grb2, SHPTP-1, SHPTP-2,
and the mpl/JAK2 complex. IL-3 induces phosphorylation of the above
proteins with the exception of mpl and also causes weak JAK1
phosphorylation. Although similar in composition, the MGDF- and
IL-3-induced complexes of signal transducers appear to be assembled in
different configurations, especially with respect to SHPTP-2. Both MGDF and
IL-3 induce tyrosine phosphorylation of STAT3 (APRF) and STAT5 (MGF), with
MGDF favoring STAT3 while IL-3 predominantly causes STAT5 phosphorylation.
In addition, some proteins become tyrosine-phosphorylated in response to
MGDF only, suggesting that we may have detected differentiation- specific
signal transducers. These include a number of high-molecular- weight
proteins (140 to 200 kD) and one 28-kD protein that becomes
tyrosine-phosphorylated only briefly.
Volume 86,
Issue 12,
pp. 4532-4543,
12/15/1995
Copyright © 1995 by The American Society of Hematology
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