The erythropoietin receptor: molecular structure and hematopoietic signaling pathways

Abstract

The process of erythropoiesis in the fetal liver and adult bone marrow is regulated by the hormone erythropoietin (Epo), which is produced in the kidney at low levels under homeostatic conditions. Defects in Epo production result in severe anemia; use of recombinant hormone has improved the lives of patients with renal failure or anemia because of bone marrow suppression. Deletion of the Epo gene in mice leads to embryonic lethality at days 13 to 15, coincident with the establishment of definitive (adult-type) erythropoiesis and underscoring the absolute necessity of Epo function in vivo. Epo has proven to be a successful pharmaceutical agent, one of the early triumphs of recombinant protein technology. Because of its clinical importance, a great deal of attention has focused on the molecular mechanisms of Epo-regulated erythropoiesis. This review highlights the basic concepts of Epo signal transduction within the hematopoietic system, the major site of Epo action in vivo.

Figure 1. Model for EpoR activation mechanism

The EpoR is thought to be expressed at the cell surface as a dimer in the absence of ligand. Epo binding proceeds by an asymmetrical association, first via the high affinity Epo site 1 followed by the lower affinity site 2 interaction (not shown), which stimulates a reorientation of EpoR monomers within the dimeric complex and subsequent activation of the receptor-associated Jak2 kinase, presumably by a transphosphorylation mechanism. Jak2 phosphorylates tyrosine residues in the EpoR cytoplasmic domain and itself, providing docking sites for molecules with phosphotyrosine binding motifs. STAT5 proteins are principal signaling molecules for EpoR, undergoing homodimerization after recruitment and phosphorylation by the receptor-Jak2 complex. STAT5 mediates erythroid survival, proliferation and differentiation signals. Additional signaling cascades are activated by the EpoR (not shown), however their role in erythropoiesis in vivo remains less understood relative to STAT5.