Signaling by Erythropoietin

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Homo sapiens
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Erythropoietin (EPO) is a cytokine that serves as the primary regulator of erythropoiesis, the differentiation of erythrocytes from stem cells in the liver of the fetus and the bone marrow of adult mammals (reviewed in Ingley 2012, Zhang et al. 2014, Kuhrt and Wojchowski 2015). EPO is produced in the kidneys in response to low oxygen tension and binds a receptor, EPOR, located on progenitor cells: burst forming unit-erythroid (BFU-e) cells and colony forming unit-erythroid (CFU-e) cells.
The erythropoietin receptor (EPOR) exists in lipid rafts (reviewed in McGraw and List 2017) as a dimer pre-associated with proteins involved in downstream signaling: the tyrosine kinase JAK2, the tyrosine kinase LYN, and the scaffold protein IRS2. Binding of EPO to the EPOR dimer causes a change in conformation (reviewed in Watowich et al. 2011, Corbett et al. 2016) that activates JAK2, which then transphosphorylates JAK2 and phosphorylates the cytoplasmic domain of EPOR. The phosphorylated EPOR serves directly or indirectly as a docking site for signaling molecules such as STAT5, phosphatidylinositol 4,5-bisphosphate 3-kinase (PI3K), phospholipase C gamma (PLCG1, PLCG2), and activators of RAS (SHC1, GRB2:SOS1, GRB2:VAV1).
EPO activates 4 major signaling pathways: STAT5-activated transcription, PI3K-AKT, RAS-RAF-ERK, and PLC-PKC. JAK2-STAT5 activates expression of BCL2L1 (Bcl-xL) and therefore appears to be important for anti-apoptosis. PI3K-AKT appears to be important for both anti-apoptosis and proliferation. The roles of other signaling pathways are controversial but both RAS-RAF-MEK-ERK and PLCgamma-PKC have mitogenic effects. Phosphatases such as SHP1 are also recruited and downregulate the EPO signal.
EPO also has effects outside of erythropoiesis. The EPOR is expressed in various tissues such as endothelium where it can act to stimulate growth and promote cell survival (Debeljak et al. 2014, Kimáková et al. 2017). EPO and EPOR in the neurovascular system act via Akt, Wnt1, mTOR, SIRT1, and FOXO proteins to prevent apoptotic cell injury (reviewed in Ostrowski and Heinrich 2018, Maiese 2016) and EPO may have therapeutic value in the nervous system (Ma et al. 2016).

Literature References
PubMed ID Title Journal Year
27164096 Erythropoietin Pathway: A Potential Target for the Treatment of Depression

Yue, W, Ma, C, Lian, Y, Cheng, F, Wang, Q, Wang, X, Zhai, C

Int J Mol Sci 2016
28629526 Erythropoietin Receptor Signaling and Lipid Rafts

List, A, McGraw, K

Vitam. Horm. 2017
24918289 Erythropoietin action in stress response, tissue maintenance and metabolism

Zhang, Y, Alnaeeli, M, Dey, S, Wang, L, Suresh, S, Noguchi, CT, Rogers, H, Teng, R

Int J Mol Sci 2014
29393890 Alternative Erythropoietin Receptors in the Nervous System

Heinrich, R, Ostrowski, D

J Clin Med 2018
25887776 Emerging EPO and EPO receptor regulators and signal transducers

Wojchowski, DM, Kuhrt, D

Blood 2015
26549969 Regeneration in the nervous system with erythropoietin

Maiese, K

Front Biosci (Landmark Ed) 2016
25426117 Erythropoietin and cancer: the unintended consequences of anemia correction

Sytkowski, AJ, Debeljak, N, Solár, P

Front Immunol 2014
27490140 Revisiting the scissor-like mechanism of activation for the erythropoietin receptor

Mark, AE, Poger, D, Corbett, MS

FEBS Lett. 2016
22431075 Integrating novel signaling pathways involved in erythropoiesis

Ingley, E

IUBMB Life 2012
28703764 Erythropoietin and Its Angiogenic Activity

Komel, R, Debeljak, N, Solár, P, Kimáková, P, Solárová, Z

Int J Mol Sci 2017
21307776 The erythropoietin receptor: molecular structure and hematopoietic signaling pathways

Watowich, SS

J. Investig. Med. 2011
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