Signal transduction in the erythropoietin receptor system

Events relayed via the single transmembrane receptor for erythropoietin (Ep o) are essential for the development of committed erythroid progenitor cell s beyond the colony-forming unit-erythroid stage, and this clearly involves Epo's inhibition of programmed cell death (PCD), Less well resolved, howev er, are issues regarding the precise nature of Epo-dependent antiapoptotic mechanisms, the extent to which Epo might also promote mitogenesis and/or t erminal erythroid differentiation, and the essential vs modulatory nature o f certain Epo receptor cytoplasmic subdomains, signal transducing factors, and downstream pathways, Accordingly, this review focuses on the following aspects of Epo signal transduction: (1) Epo receptor/Jak2 activation mechan isms; (2) the critical vs dispensable nature of (P)Y sites and SH2 domain-e ncoding effecters in survival, growth, and differentiation responses; (3) p rimary mechanisms by which Epo inhibits PCD; (4) the integration of signals relayed by coexpressed and possibly directly interacting cytokine receptor s; and (5) predictions regarding effector function which are provided by th e association of certain primary and familial polycythemias with mutated hu man Epo receptor forms. (C) 1999 Academic Press.