Abstract
Erythropoietin (EPO) is a glycoprotein cytokine known for its pleiotropic effects on various types of cells and tissues. EPO and its receptor EPOR trigger signaling cascades JAK2/STAT5, MAPK, and PI3K/AKT that are interconnected and irreplaceable for cell survival. In this article, we describe the role of the MAPK and PI3K/AKT signaling pathways during red blood cell formation as well as in non-hematopoietic tissues and tumor cells. Although the central framework of these pathways is similar for most of cell types, there are some stage-specific, tissue, and cell-lineage differences. We summarize the current state of research in this field, highlight the novel members of EPO-induced PI3K and MAPK signaling, and in this respect also the differences between erythroid and non-erythroid cells.
Highlights
As we have described the role of the STAT5 protein as a key molecule of EPO signaling in our recent paper [12], we will focus on the role of the PI3K and MAPK pathways in both erythroid and non-erythroid cells in more detail
Downstream targets of PI3K/AKT include transcription factors FOXO3 and GATA-1 that are essential for normal erythroid cell development [18,19], hypoxia-induced factor-1α (HIF1α) [20,21], and the mammalian target of rapamycin [11]
While activation of p38 MAPK is associated with stress-induced erythropoiesis [35], ERK1 serves as a negative regulator of the steady-state splenic erythropoiesis [36] operating not through the EPO/EPOR signaling pathway but involving the Sonic Hedgehog/BMP4 pathway [37,38]
Summary
Erythropoiesis is the process of creating mature red blood cells from pluripotent hematopoetic progenitor cells, resulting in the production of approximately two million erythrocytes per second [1]. Downstream targets of PI3K/AKT include transcription factors FOXO3 and GATA-1 that are essential for normal erythroid cell development [18,19], hypoxia-induced factor-1α (HIF1α) [20,21], and the mammalian target of rapamycin (mTOR) [11] Negative regulators such as phosphatase, tensin homologue (PTEN), and carboxyl-terminal modulator protein. While activation of p38 MAPK is associated with stress-induced erythropoiesis [35], ERK1 serves as a negative regulator of the steady-state splenic erythropoiesis [36] operating not through the EPO/EPOR signaling pathway but involving the Sonic Hedgehog/BMP4 pathway [37,38]. Cytoplasmic ERK1/2 can shape a negative feedback regulatory mechanism upstream of the ERK pathway by phosphorylation of protein kinases SOS, Raf-1, and MEK [42]
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