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Blood, 1 January 2001, Vol. 97, No. 1, pp. 154-161
HEMATOPOIESIS
Actin reorganization and proplatelet formation in murine
megakaryocytes: the role of protein kinase C
Ponlapat Rojnuckarin and
Kenneth Kaushansky
From the Division of Hematology, University of
Washington, Seattle, WA.
With the recent cloning and characterization of thrombopoietin,
appreciation of the molecular events surrounding megakaryocyte (MK)
development is growing. However, the final stages of platelet formation
are less well understood. Platelet production occurs after the
formation of MK proplatelet processes. In a study to explore the
molecular mechanisms underlying this process, mature MKs isolated from
suspension murine bone marrow cell cultures were induced to form
proplatelets by exposure to plasma, and the role of various
cell-signaling pathways was assessed. The results showed that (1)
bis-indolylmaleimide I, which blocks protein kinase C (PKC) activation;
(2) down-modulation of conventional or novel classes of PKC by phorbol
myristate acetate; and (3) ribozymes specific for PKC each inhibited
proplatelet formation. Inhibition of several MAP kinases, PI3 kinase,
or protein kinase A failed to affect MK proplatelet formation. To gain
further insights into the function of PKC in proplatelet formation,
its subcellular localization was investigated. In cultures containing
active proplatelet formation, cytoplasmic polymerized actin was
highly aggregated, its subcellular distribution was reorganized, and
PKC colocalized with the cellular actin aggregates. A number of MK
manipulations, including blockade of integrin signaling with a
disintegrin or inhibition of actin polymerization with cytochalasin D,
interrupted actin reorganization, PKC relocalization, and proplatelet
formation. These findings suggest an important role for PKC in
proplatelet development and suggest that it acts by altering actin
dynamics in proplatelet-forming MKs. Identification of the upstream and downstream pathways involved in proplatelet formation should provide greater insights into thrombopoiesis, potentially allowing
pharmacologic manipulation of the process.
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