Molecular Mechanisms of Erythropoietin Signaling

Abstract

Erythropoietin is an obligatory growth factor for red blood cell production. The receptor for erythropoietin contains a single membrane-spanning domain with no intrinsic tyrosine kinase motifs. On binding to erythropoietin, the receptor dimerizes and activates multiple intracellular signaling molecules, including but not limited to JAK2, STAT5, PI 3-kinase, IRS-2, RAS, and Ca²⁺ channels. This review focuses on cytoplasmic signaling cascades involved in erythropoietin action.

Erythropoietin Modulates Calcium Influx through TRPC2

“…Erythropoietin (Epo) 1 is a hematopoietic growth factor that regulates proliferation, differentiation, and viability of erythroid progenitors and precursors (1)(2)(3). Regulation of intracellular calcium ([Ca] i ) by erythropoietin is one of the signaling mechanisms controlling proliferation and differentiation of erythroid cells (4 -10).…”

New Insights Into Erythropoietin and Epoetin Alfa: Mechanisms of Action, Target Tissues, and Clinical Applications

“…EPO is secreted into the plasma and, upon arrival in the bone marrow, binds to EPO-Rs on the surface of erythroid progenitor cells [11]. This association triggers a conformational change that brings EPO-Rassociated Janus family tyrosine protein kinase 2 (JAK2) molecules into close proximity, stimulating their activation by transphosphorylation [1,12,13]. Subsequently, JAK2 molecules phosphorylate eight tyrosine residues in the cytoplasmic domain of the EPO-R, which then serve as docking sites for various Src homology 2-domain-containing intracellular signaling proteins [1].…”

“…These proteins, in turn, are tyrosine phosphorylated and activated. One of these proteins is a signal transducer and activator of transcription (STAT5) that, on phosphorylation by JAK2, dissociates from the EPO-R, dimerizes, and then translocates to the nucleus to activate numerous target genes [1], including the apoptosis inhibitor Bcl-x [14].…”

“…Erythropoietin (EPO) is an endogenous cytokine that is essential for erythrocyte development [1]. In adults, the kidneys produce and release EPO in response to hypoxia [2].…”

“…In adults, the kidneys produce and release EPO in response to hypoxia [2]. EPO acts by binding to its receptor (EPO-R) and subsequently activating intracellular signal transduction pathways [1]. EPO is essential for life: mice with deletions of the EPO gene or the EPO-R die of anemia in utero [3,4].…”