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.
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 (Steel(17H)) 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.
Kapur
Reuben
R
Section of Neonatal-Perinatal Medicine, Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA. rkapur@iupui.edu
Chandra
Saurabh
S
Cooper
Ryan
R
McCarthy
Jennifer
J
Williams
David A
DA
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects*; D002460:Cell Line; D002462:Cell Membrane / Q000737:chemistry; D002470:Cell Survival / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015672:Erythroid Precursor Cells / Q000166:cytology*; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D020033:Protein Isoforms / Q000494:pharmacology*; D012995:Solubility; D019089:Stem Cell Factor / Q000172:deficiency / Q000235:genetics / Q000494:pharmacology*; D017154:Stromal Cells / Q000378:metabolism; D014162:Transfection; D048051:p38 Mitogen-Activated Protein Kinases
D004791:Enzyme Inhibitors; D020033:Protein Isoforms; D019089:Stem Cell Factor; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases