Sustained activation of erythropoietin receptor by membrane presentation of stem cell factor: a unique in vivo role for membrane-associated scf in erythropoiesis

R. Kapur, X. Xiao, M. McAndrews-Hill

Research output: Contribution to journalArticle

Abstract

Stem cell factor (SCF) is expressed as a soluble (S) or membraneassociated (MA) protein in the hematopoietic microenvironment (HM). The physiologic role(s) of these isoforms remain unknown. Steel-dickie (SP) mice, in which only a truncated S SCF protein but no MA protein is produced, demonstrate severe erythroid deficiency, suggesting membrane presentation of SCF is critical in the normal development of erythroid lineage. Recently, Lodish et. al (PNAS, 1997) have shown that c-kit activates the erythropoietin receptor (EPO-R) through phosphorylation of tyrosine residues and that a functional interaction of activated c-kit with the EPO-R at or around the late erythroid progenitor stage is crucial for normal erythroid differentiation. Here, we show that stromal cells expressing only a membrane-restricted (MR) form of SCF induce a more persistent tyrosine phosphorylation of both c-kit and EPO-R and leads to a significant increase in the growth of HCD57 erythrocytic progenitor cells compared to S SCF. To examine the in vivo role of MA SCF in erythropoiesis, transgenic mice expressing either a MR or S isoform of SCF were generated. Genetic crosses of these animals into SI/SP mice yielded animals that expressed only MR or S transgenic isoform. SI/S? mutants that express the MR isoform of SCF, demonstrate a dramatic and significant increase in the production of red cells, correction in runting and BM hypocellularity over SI/SP mice. In contrast, transgenic mice expressing the S form of SCF had no effect on erythropoiesis, however, a significant increase in the production of myeloid progenitors was observed in these mice.______ Mice____Weight (qmsl RBCs/mouse Mveloid Progenitors WT 24.5 6×109 180×103 SI/SI" 18.2 1.6×10' 120×103 SI/SF-MR 23.0 2.7×10(tm) 120×103 S//SP-S 17.5 1.5×10" 180×10M Results are shown as mean of at least ten mice from each group. "p<l.01 vs Sl/Sf Since mice deficient in either MA SCF or EPO demonstrate a significant decrease in late erythroid progenitors, and SCF signaling through c-kit has been shown to induce tyrosine phosphorylation of the EPO-R, our in vitro and in vivo findings suggest that erythroid maturation is a unique function of MA SCF isoform in vivo.

Original languageEnglish (US)
Number of pages1
JournalExperimental Hematology
Volume25
Issue number8
StatePublished - Dec 1 1997

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Erythropoietin Receptors
Stem Cell Factor
Erythropoiesis
Membranes
Protein Isoforms
Tyrosine
Erythroid Precursor Cells
Phosphorylation
Transgenic Mice
Genetic Crosses
Proto-Oncogene Proteins c-kit
Proteins
Steel
Stromal Cells

ASJC Scopus subject areas

  • Molecular Biology
  • Hematology
  • Genetics
  • Cell Biology
  • Cancer Research

Cite this

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title = "Sustained activation of erythropoietin receptor by membrane presentation of stem cell factor: a unique in vivo role for membrane-associated scf in erythropoiesis",
abstract = "Stem cell factor (SCF) is expressed as a soluble (S) or membraneassociated (MA) protein in the hematopoietic microenvironment (HM). The physiologic role(s) of these isoforms remain unknown. Steel-dickie (SP) mice, in which only a truncated S SCF protein but no MA protein is produced, demonstrate severe erythroid deficiency, suggesting membrane presentation of SCF is critical in the normal development of erythroid lineage. Recently, Lodish et. al (PNAS, 1997) have shown that c-kit activates the erythropoietin receptor (EPO-R) through phosphorylation of tyrosine residues and that a functional interaction of activated c-kit with the EPO-R at or around the late erythroid progenitor stage is crucial for normal erythroid differentiation. Here, we show that stromal cells expressing only a membrane-restricted (MR) form of SCF induce a more persistent tyrosine phosphorylation of both c-kit and EPO-R and leads to a significant increase in the growth of HCD57 erythrocytic progenitor cells compared to S SCF. To examine the in vivo role of MA SCF in erythropoiesis, transgenic mice expressing either a MR or S isoform of SCF were generated. Genetic crosses of these animals into SI/SP mice yielded animals that expressed only MR or S transgenic isoform. SI/S? mutants that express the MR isoform of SCF, demonstrate a dramatic and significant increase in the production of red cells, correction in runting and BM hypocellularity over SI/SP mice. In contrast, transgenic mice expressing the S form of SCF had no effect on erythropoiesis, however, a significant increase in the production of myeloid progenitors was observed in these mice.______ Mice____Weight (qmsl RBCs/mouse Mveloid Progenitors WT 24.5 6×109 180×103 SI/SI{"} 18.2 1.6×10' 120×103 SI/SF-MR 23.0 2.7×10(tm) 120×103 S//SP-S 17.5 1.5×10{"} 180×10M Results are shown as mean of at least ten mice from each group. {"}p",
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T2 - a unique in vivo role for membrane-associated scf in erythropoiesis

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AU - McAndrews-Hill, M.

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