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Blood, 1 October 2001, Vol. 98, No. 7, pp. 2077-2083
HEMATOPOIESIS
Membrane localization is not required for Mpl function in normal
hematopoietic cells
Kevin G. Otto,
Virginia C. Broudy,
Nancy L. Lin,
Evan Parganas,
Jennifer N. Luthi,
Jonathan G. Drachman,
James N. Ihle, and
C. Anthony Blau
From the Department of Medicine, Division of
Hematology, University of Washington, Seattle; and the Department of
Biochemistry, Howard Hughes Medical Institute, St Jude Children's
Research Hospital, Memphis, TN.
Cellular trafficking of growth factor receptors, including
cross-talk among receptors at the cell surface, may be important for
signal transduction in normal hematopoietic cells. To test this idea,
the signaling domain of Mpl (the thrombopoietin receptor) was targeted
to the plasma membrane, or to the cytoplasm of murine marrow cells, and
the ability of the cells to proliferate and differentiate in response
to Mpl dimerized at the plasma membrane or free in the cytoplasm was
assessed. Constructs encoding the signaling domain of Mpl linked to an
FK506 binding protein domain (to permit dimerization by the
membrane-permeable ligand AP20187) with or without a myristylation
sequence (to target the receptor to the plasma membrane) and a
hemagglutinin epitope tag were generated and introduced into murine
marrow cells using a murine stem cell virus (MSCV)-based
retroviral vector. Both populations of transduced marrow cells
proliferated in Iscoves modified Dulbecco medium-10% FCS-100 nM
AP20187 without exogenous growth factors for more than 100 days and
achieved greater than a 107-fold expansion of cells by day
50 (n = 4 transductions). Growth was dimerizer dependent, and
myeloid, erythroid, and megakaryocytic progenitors were generated.
Activation of Mpl either at the plasma membrane or in the cytoplasm
allowed for the terminal maturation of transduced progenitor cells.
Introduction of membrane-targeted or cytoplasmic Mpl into fetal liver
cells from homozygous JAK2 knock-out mice or wild-type littermates
demonstrated that both forms of Mpl require JAK2 for signaling. These
data show that the activation of Mpl independent of its normal plasma
membrane location can support production of the full range of normal
hematopoietic progenitor cells in vitro.
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