Erythropoietin receptors: their role beyond erythropoiesis

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Abstract
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]).