Erythropoietin receptors: their role beyond erythropoiesis.

It has been known for 40 years that erythropoietin, which is mainly produced by the kidney in response to hypoxia, is the primary regulator of red blood cell production and is indispensable for terminal differentiation of erythroid progenitors. It controls proliferation, maturation and also survival of erythroid progenitor cells. The binding of erythropoietin to its receptor, which exists as a preformed dimer, induces a conformational change that brings constitutively associated Janus family tyrosine protein kinase 2 (JAK2) molecules in close proximity and stimulates their activation by transphosphorylation. In turn, JAK2 molecules phosphorylate tyrosine residues in the cytoplasmic domain of the erythropoietin receptor, which then serve as docking sites for various intracellular signalling proteins that contain Src homology 2 (SH2) domains (Figure 1). These proteins can then be activated through JAK2-mediated tyrosine phosphorylation. For example, the transcription factor STAT5 (for ‘signal transducer and activator of transcription 5’) can bind to phosphorylated erythropoietin receptors, become phosphorylated, homodimerize, translocate into the nucleus and activate target genes. Other pathways activated by the erythropoietin receptor through protein phosphorylation include the Ras/MAP kinase and phosphatidylinositol 3-kinase (PI3-kinase) pathways (reviewed in [1]). Initial northern blot analyses showed that the erythropoietin receptor was selectively expressed in cells of the erythroid lineage, which was consistent with an effect of erythropoietin restricted to red blood cell production. However, subsequent studies using more sensitive methods disclosed a more widespread expression of this receptor, raising the possibility of extrahaematopoietic effects of erythropoietin. For example, the presence of mRNA encoding the erythropoietin receptor has been detected in brain, retina, heart, skeletal muscle, kidney and endothelial cells [2,3]. In addition, low-level expression of erythropoietin mRNA also has been demonstrated in tissues other than kidneys and liver, in particular the brain, suggesting paracrine extraerythropoietic actions of erythropoietin [3]. Recently, the importance of erythropoietin signalling outside the bone marrow has been demonstrated during embryonic development. Moreover, studies in various experimental models have shown that injection of high doses of erythropoietin can protect against acute organ injuries.