DISTINCT ROLES OF THE RECEPTOR TYROSINE KINASES C-ERBB AND C-KIT IN REGULATING THE BALANCE BETWEEN ERYTHROID CELL-PROLIFERATION AND DIFFERENTIATION

In the bone marrow, multipotent and committed hematopoietic progenitor s have to closely regulate their balance between sustained proliferati on without differentiation (self renewal) and entering a terminal diff erentiation pathway. A useful model to analyze this regulation at the molecular level is committed avian erythroid progenitors, These are in duced to undergo long-term self renewal by the ligand-activated recept or tyrosine kinase (RTK) c-ErbB, in cooperation with steroid hormone r eceptors, This self-renewal induction by c-ErbB even occurs in the pre sence of differentiation factors (erythropoietin and insulin), Under t he same conditions, the RTK c-Kit is unable to sustain erythroid proge nitor self renewal, stimulating cell proliferation without arresting t erminal differentiation, Two mechanisms are involved in these differen tial activities of c-Kit and c-ErbB, The first one, differential regul ation of receptor expression, proved to be of minor importance, becaus e c-Kit was unable to induce self renewal, even if exogenously express ed from a retrovirus at high levels, Rather our results support the se cond mechanism, i,e., that receptor specific signal transduction is re sponsible for the differential biological activity of c-Kit and c-ErbB : (a) specific tyrosine kinase inhibitors (tyrphostins) were found whi ch selectively inhibited the biological function of either c-Kit or c- ErbB in erythroblasts but did not affect ligand-induced autophosphoryl ation of either RTK; and (b) c-ErbB selectively induced SHC phosphoryl ation and STAT5 activation. The Ras pathway was similarly activated by c-Kit and c-ErbB. The c-Erbs-specific tyrphostin AG30 specifically bl ocked STAT5 activation, implicating this signal transducer in c-Erbs-i nduced self renewal.