title: Distinct roles of the receptor tyrosine kinases c-ErbB and c-Kit in regulating the balance between erythroid cell proliferation and differentiation.
abstract: In the bone marrow, multipotent and committed hematopoietic progenitors have to closely regulate their balance between sustained proliferation without differentiation (self renewal) and entering a terminal differentiation pathway. A useful model to analyze this regulation at the molecular level is committed avian erythroid progenitors. These are induced to undergo long-term self renewal by the ligand-activated receptor tyrosine kinase (RTK) c-ErbB, in cooperation with steroid hormone receptors. This self-renewal induction by c-ErbB even occurs in the presence of differentiation factors (erythropoietin and insulin). Under the same conditions, the RTK c-Kit is unable to sustain erythroid progenitor self renewal, stimulating cell proliferation without arresting terminal differentiation. Two mechanisms are involved in these differential activities of c-Kit and c-ErbB. The first one, differential regulation of receptor expression, proved to be of minor importance, because c-Kit was unable to induce self renewal, even if exogenously expressed from a retrovirus at high levels. Rather our results support the second mechanism, i.e., that receptor-specific signal transduction is responsible for the differential biological activity of c-Kit and c-ErbB: (a) specific tyrosine kinase inhibitors (tryphostins) were found which selectively inhibited the biological function of either c-Kit or c-ErbB in erythroblasts but did not affect ligand-induced autophosphorylation of either RTK; and (b) c-ErbB selectively induced SHC phosphorylation and STAT5 activation. The Ras pathway was similarly activated by c-Kit and c-ErbB. The c-ErbB-specific tyrphostin AG30 specifically blocked STAT5 activation, implicating this signal transducer in c-ErbB-induced self renewal.
authors.affiliation: Institute of Molecular Pathology, Vienna, Austria.
authors.forename: O
authors.initials: O
authors.lastname: Wessely
authors.forename: G
authors.initials: G
authors.lastname: Mellitzer
authors.forename: M
authors.initials: M
authors.lastname: von Lindern
authors.forename: A
authors.initials: A
authors.lastname: Levitzki
authors.forename: A
authors.initials: A
authors.lastname: Gazit
authors.forename: I
authors.initials: I
authors.lastname: Ischenko
authors.forename: M J
authors.initials: MJ
authors.lastname: Hayman
authors.forename: H
authors.initials: H
authors.lastname: Beug
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002455:Cell Division; D002460:Cell Line; D002642:Chick Embryo; D004900:Erythroblasts / Q000166:cytology* / Q000502:physiology; D019009:Proto-Oncogene Proteins c-kit / Q000502:physiology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000502:physiology*; D015398:Signal Transduction
chemical_list: D019009:Proto-Oncogene Proteins c-kit; D018719:Erb-b2 Receptor Tyrosine Kinases