Reactome | Signaling by Erythropoietin

Signaling by Erythropoietin

Stable Identifier

R-HSA-9006335

DOI

10.3180/R-HSA-9006335.1

Type

Pathway

Species

Homo sapiens

ReviewStatus

5/5

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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