Journal
BLOOD
Volume 100, Issue 4, Pages 1287-1293Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood.V100.4.1287.h81602001287_1287_1293
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- NIDDK NIH HHS [2R01 DK48605-06] Funding Source: Medline
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Two alternatively spliced stem cell factor (SCIF) transcripts encode protein products, which differ in the duration of membrane presentation. One form, soluble SCIF (S-SCF) gets rapidly processed to yield predominantly secreted protein. The other form, membrane-associated SCIF (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 SCIF that lack the expression of MA-SCF (Steel-dickie) or possess a defect in its presentation (Steel(17H)) manifest deficiencies in erythroid cell development. In this study, we have compared the consequence(s) of activating Kit, the receptor for SCIF by MA-SCF with S-SCIF, and an obligate membrane-restricted (MR) form of SCIF (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-SCIF-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. (C) 2002 by The American Society of Hematology.
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