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J. Biol. Chem., Vol. 275, Issue 44, 34719-34727, November 3, 2000
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From the Protein kinase C (PKC) is implied in the
activation of multiple targets of erythropoietin (Epo) signaling, but
its exact role in Epo receptor (EpoR) signal transduction and in the
regulation of erythroid proliferation and differentiation remained
elusive. We analyzed the effect of PKC inhibitors with distinct modes
of action on EpoR signaling in primary human erythroblasts and in a
recently established murine erythroid cell line. Active PKC appeared
essential for Epo-induced phosphorylation of the Epo receptor itself,
STAT5, Gab1, Erk1/2, AKT, and other downstream targets. Under the same
conditions, stem cell factor-induced signal transduction was not
impaired. LY294002, a specific inhibitor of phosphoinositol 3-kinase,
also suppressed Epo-induced signal transduction, which could be
partially relieved by activators of PKC. PKC inhibitors or LY294002 did
not affect membrane expression of the EpoR, the association of JAK2
with the EpoR, or the in vitro kinase activity of JAK2. The
data suggest that PKC controls EpoR signaling instead of being a
downstream effector. PKC and phosphoinositol 3-kinase may act in
concert to regulate association of the EpoR complex such that it is
responsive to ligand stimulation. Reduced PKC-activity inhibited
Epo-dependent differentiation, although it did not effect
Epo-dependent "renewal divisions" induced in the
presence of Epo, stem cell factor, and dexamethasone.
Protein Kinase C
Controls Erythropoietin Receptor
Signaling*
§,,,,
,,
Institute of Hematology, Erasmus University,
P. O. Box 1738, 3000 DR Rotterdam, The Netherlands, the
¶ Institute of Molecular Pathology, Dr. Bohrgasse 7, A-1030
Vienna, Austria, and the Department of Biochemistry, University
of Nijmegen, P. O. Box 9101, 6500 HB Nijmegen, The Netherlands
*
This work was supported by Dutch Cancer Society Grants EUR
95-1021 and EUR 99-2064, European Community Grant BMH4-CT 96 1355, and
a fellowship from the Dutch Academy for Arts and Sciences (to M. v.
L.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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