EPO and Erythropoiesis

The orchestration of a complex, hierarchical process like erythropoiesis requires the precise coordination of a host of cellular factors that work either in concert or at distinct stages of the process, to regulate effective and sufficient formation of RBCs. The principal regulator of erythropoiesis is Erythropoietin (EPO), a heavily glycosylated protein belonging to the class I cytokine family (Jelkmann, 2004). EPO exerts its effects on erythropoiesis by binding to and activating the EPOreceptor (EpoR), a high affinity receptor that is predominantly expressed on the surface of immature erythroid cells. EpoR belongs to the type I cytokine receptor family and exists as a homodimer. Upon ligand binding, EpoR, which lacks intrinsic catalytic activity, undergoes a conformational change and associates with Janus Kinase 2 (JAK2). JAK2 phosphorylates the ligand-activated EpoR, generating multiple docking sites for signaling molecules, and leading to activation of several signal transduction pathways (Watowich, 2011). While one of the earliest studied signaling pathways activated through the EPO-EpoR cascade is the Janus Kinase and Signal Transducer and Activator of Transcription (JAK/STAT) pathway, phosphorylated EpoR induces activation of other cellular signaling cascades including the mitogen-activated protein kinase/extracellular signal-related kinase (MAPK/ERK) and the phosphatidylinositol 3-kinase /protein kinase B (PI-3K/AKT) pathways (Ingley et al., 2004). These pathways impact erythropoiesis by temporally regulating transcription of genes involved in survival, differentiation, and cell proliferation depending on the stage of erythroid maturation. For example, survival signals are provided to CFU-E cells, the most EPO-sensitive cells amongst the erythroid progenitors, as well as to erythroblasts. The importance of EPO-EpoR signaling in erythropoiesis has been demonstrated by EPO-null and EpoR-null mouse models, which are both embryonically lethal, owing to a lack of erythropoiesis in the fetus (Wu et al., 1995). While the EPO-EpoR signaling axis serves as the central hub for erythropoiesis regulation, several other molecular signals, both extrinsic and intrinsic, are involved and serve to further fine-tune the progression of the multi-faceted process of erythropoiesis (Ingley, 2012; Ingley et al., 2004; Kuhrt and Wojchowski, 2015). more... 

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