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Blood, 15 August 2002, Vol. 100, No. 4, pp. 1287-1293
HEMATOPOIESIS
Role of p38 and ERK MAP kinase in proliferation of
erythroid progenitors in response to stimulation by soluble and
membrane isoforms of stem cell factor
Reuben Kapur,
Saurabh Chandra,
Ryan Cooper,
Jennifer McCarthy, and
David A. Williams
From the Section of Neonatal-Perinatal Medicine,
Department of Pediatrics, Herman B Wells Center for Pediatric Research,
Indiana University School of Medicine, Indianapolis, IN; and
the Division of Experimental Hematology, Cincinnati Children's
Hospital Medical Center, Cincinnati, OH.
Two alternatively spliced stem cell factor (SCF) transcripts encode
protein products, which differ in the duration of membrane presentation. One form, soluble SCF (S-SCF) gets rapidly processed to
yield predominantly secreted protein. The other form,
membrane-associated SCF (MA-SCF) lacks the primary proteolytic
cleavage site but is cleaved slowly from an alternate site, and thus
represents a more stable membrane form of SCF. Mutants of SCF that lack
the expression of MA-SCF (Steel-dickie) or possess a defect
in its presentation (Steel17H) manifest
deficiencies in erythroid cell development. In this study, we have
compared the consequence(s) of activating Kit, the receptor for SCF by
MA-SCF with S-SCF, and an obligate membrane-restricted (MR)
form of SCF (MR-SCF) on erythroid cell survival, proliferation, cell
cycle progression, and the activation of p38 and ERK MAP kinase
pathways. Activation of Kit by MR-SCF was associated with a
significantly lower incidence of apoptosis and cell death in erythroid cells compared to either other isoform. MR- or
MA-SCF-induced stimulation of erythroid cells resulted in similar and
significantly greater proliferation and cell cycle progression compared
to soluble SCF. The increase in proliferation and cell cycle
progression via MA- or MR-SCF stimulation correlated with sustained and
enhanced activation of p38 and ERK MAP kinase pathways. In addition,
MR- or MA-SCF-induced proliferation was more sensitive to the
inhibitory effects of ERK inhibitor compared to S-SCF-induced
proliferation. In contrast, soluble SCF-induced proliferation was more
sensitive to the inhibitory effects of p38 inhibitor compared with MR-
or MA-SCF. These results suggest that different isoforms of SCF may use different biochemical pathways in stimulation of survival and/or proliferation of erythroid cells.
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