Distinct roles of the receptor tyrosine kinases c-ErbB and c-Kit in regulating the balance between erythroid cell proliferation and differentiation.

摘要: In the bone marrow, multipotent and committed hematopoietic progenitors have to closely regulate their balance between sustained proliferation without differentiation (self renewal) entering a terminal pathway. A useful model analyze this regulation at molecular level is avian erythroid progenitors. These are induced undergo long-term self renewal by ligand-activated receptor tyrosine kinase (RTK) c-ErbB, in cooperation with steroid hormone receptors. This self-renewal induction c-ErbB even occurs presence of factors (erythropoietin insulin). Under same conditions, RTK c-Kit unable sustain progenitor renewal, stimulating cell arresting differentiation. Two mechanisms involved these differential activities c-ErbB. The first one, expression, proved be minor importance, because was induce if exogenously expressed from retrovirus high levels. Rather our results support second mechanism, i.e., that receptor-specific signal transduction responsible for biological activity c-ErbB: (a) specific inhibitors (tryphostins) were found which selectively inhibited function either or erythroblasts but did not affect ligand-induced autophosphorylation RTK; (b) SHC phosphorylation STAT5 activation. Ras pathway similarly activated c-ErbB-specific tyrphostin AG30 specifically blocked activation, implicating transducer c-ErbB-induced renewal.