Signal transduction in the erythropoietin receptor system

Abstract. Developing erythroid cells require the glycoprotein hormone, erythropoietin (EPO) as an activator of the rapid proliferation of early proery‐throblasts (colony forming units‐erythroid [CFU‐e]), and subsequently as an activator of late erythroid gene expression. Activation of these growth and differentiation events proceeds from the binding of EPO at its transmembrane receptor (Class I cytokine receptor), to the engagement of a complex set of signaling pathways. Studies of reconstituted activities of the cloned EPO receptor in transfected hematopoietic cell lines have served well in identifying receptor domains and downstream mediators involved in proliferative signaling. Extracellular domains have been defined which contribute to lig‐and binding, receptor processing and transport, and possible dimerization. Cytosolic regions have been delineated which mediate induced mitogenesis, early gene transcription, activated protein tyrosine phos‐phorylation, down modulation of EPO‐ and gran‐ulocyte‐macrophage colony‐stimulating factor (GM‐CSF)‐induced proliferation, and direct association with PI3‐ and JAK‐2 kinases. These newly defined properties begin to align the EPO receptor mechanistically with growth factor receptors (GFR) which encode, or likewise associate with, regulated protein tyrosine kinases including the Class II cytokine receptors for interferons α/β and γ.

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