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Signaling Through the Interaction of Membrane-Restricted Stem
Cell Factor and c-kit Receptor Tyrosine Kinase: Genetic
Evidence for a Differential Role in Erythropoiesis
Reuben Kapur,
Manus Majumdar,
Xiangli Xiao,
Monica McAndrews-Hill,
Karen Schindler, and
David A. Williams
From the Howard Hughes Medical Institute, Indiana University School
of Medicine; and the Section of Pediatric Hematology/Oncology, Herman B
Wells Center for Pediatric Research, James Whitcomb Riley Hospital for
Children, Indiana University School of Medicine, Indianapolis, IN.
Mutations of the receptor tyrosine kinase c-kit or its
ligand stem cell factor (SCF), which is encoded as a soluble and
membrane-associated protein by the Steel gene in mice, lead to
deficiencies of germ cells, melanocytes, and hematopoiesis, including
the erythroid lineage. In the present study, we have used genetic
methods to study the role of membrane or soluble presentation of SCF in
hematopoiesis. Bone marrow-derived stromal cells expressing only a
membrane-restricted (MR) isoform of SCF induced an elevated and
sustained tyrosine phosphorylation of both c-kit and
erythropoietin receptor (EPO-R) and significantly greater proliferation
of an erythrocytic progenitor cell line compared with stromal cells
expressing soluble SCF. Transgene expression of MR-SCF in
Steel-dickie (Sld) mutants
resulted in a significant improvement in the production of red blood
cells, bone marrow hypoplasia, and runting. In contrast, overexpression
of the full-length soluble form of SCF transgene had no effect on
either red blood cell production or runting but corrected the myeloid
progenitor cell deficiency seen in these mutants. These data provide
the first evidence of differential functions of SCF isoforms in vivo
and suggest an abnormal signaling mechanism as the cause of the severe
anemia seen in mutants of the Sl gene.
Blood, Vol. 91 No. 3 (February 1), 1998:
pp. 879-889
© 1998 by The American Society of Hematology.
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