Interaction of the erythropoietin and stem-cell-factor receptors.
Mutations in the KIT transmembrane protein-tyrosine kinase receptor affect erythropoiesis, resulting in fewer committed late progenitors (colony-forming unit erythroid, CFU-E) in the fetal liver. As the survival and proliferation of CFU-Es depend absolutely on erythropoietin (EPO), these results suggest that CFU-Es cannot proliferate or mature further unless both the KIT and EPO receptor signalling pathways are functional. How KIT affects proliferation or differentiation of CFU-Es is not clear. Here we show that the KIT ligand SCF (for stem-cell factor) can replace EPO in supporting the growth and survival of HCD57 cells, an EPO-dependent erythroid-progenitor cell line expressing high levels of KIT. SCF supports the proliferation of 32D cells that express KIT only if they also express the EPO receptor. In HCD57 cells, SCF rapidly induces tyrosine phosphorylation of the EPO receptor, and KIT physically associates with the extended box 2 region in the cytoplasmic domain of the EPO receptor. Our results indicate that KIT may activate the EPO receptor by tyrosine phosphorylation to induce further proliferation and maturation of CFU-Es.
Wu
H
H
Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA.
Klingmüller
U
U
Besmer
P
P
Lodish
H F
HF
D000818:Animals; D002455:Cell Division; D002460:Cell Line; D015672:Erythroid Precursor Cells / Q000166:cytology; D004920:Erythropoiesis / Q000502:physiology; D004921:Erythropoietin / Q000502:physiology*; D016298:Hematopoietic Cell Growth Factors / Q000502:physiology; D006801:Humans; D051379:Mice; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D019009:Proto-Oncogene Proteins c-kit; D020794:Receptor Protein-Tyrosine Kinases / Q000502:physiology*; D016184:Receptors, Colony-Stimulating Factor / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction; D019089:Stem Cell Factor; D014443:Tyrosine / Q000378:metabolism
D016298:Hematopoietic Cell Growth Factors; D011518:Proto-Oncogene Proteins; D016184:Receptors, Colony-Stimulating Factor; D011993:Recombinant Fusion Proteins; D019089:Stem Cell Factor; D004921:Erythropoietin; D014443:Tyrosine; D019009:Proto-Oncogene Proteins c-kit; D020794:Receptor Protein-Tyrosine Kinases