Emerging EPO and EPO receptor regulators and signal transducers

Abstract

As essential mediators of red cell production, erythropoietin (EPO) and its cell surface receptor (EPO receptor [EPOR]) have been intensely studied. Early investigations defined basic mechanisms for hypoxia-inducible factor induction of EPO expression, and within erythroid progenitors EPOR engagement of canonical Janus kinase 2/signal transducer and activator of transcription 5 (JAK2/STAT5), rat sarcoma/mitogen-activated protein kinase/extracellular signal-regulated kinase (RAS/MEK/ERK), and phosphatidylinositol 3-kinase (PI3K) pathways. Contemporary genetic, bioinformatic, and proteomic approaches continue to uncover new clinically relevant modulators of EPO and EPOR expression, and EPO's biological effects. This Spotlight review highlights such factors and their emerging roles during erythropoiesis and anemia.

Figure 1

Emerging EPO and EPOR regulators, and action circuits. (A) Regulators of EPO expression in renal peritubular interstitial fibroblasts: during embryogenesis, neural tissue derived EPO^pos protein-zero^pos fibroblasts occupy interstitial peritubular sites within the neonatal kidney. Renal damage and fibrosis can convert these cells to EPO^low myofibroblasts. Within EPO^pos interstitial fibroblasts, the EPO production is modulated in part by HIF2α, which itself is regulated at multiple levels. Iron reverses apo-IRP inhibition of HIF2α translation. HIF2α turnover is promoted by VHL and PHDs, and pharmacologic inhibitors of PHDs stabilize HIF2α. During stress erythropoiesis, acetate supplementation can further enhance HIF2α complex acetylation, activity, and EPO production via an Acss2-CBP circuit. (B) Modulation of EPOR signaling by interacting plasma membrane proteins: TFR2 associates with the EPOR and can modulate its trafficking. Upon p-IgA1 ligation, Tfr1 can also enhance EPOR signaling. RHEX also associates with the hEPOR, and promotes EPO-dependent human erythroblast formation. (C) Recently defined EPO/EPOR signal transduction circuits: newly discovered EPO/EPOR response genes include ERFE, Spi2A, and MASL1. As a secreted TNF-related cytokine, ERFE completes a circuit between EPO action, and regulation of systemic iron levels. By inhibiting leached lysosomal cathepsins, Spi2A cytoprotects erythroblasts against consequences of oxidative damage. MASL1 acts within a central RAS/MEK/ERK circuit, together with RHEX, to reinforce ERK1/2 activation. Further dynamic balancing of essential RAS/MEK/ERK signals (and of EPC formation) occurs via RAS down-modulation by Rasa3 and Nf1. Pro-erythropoietic effects also are being established for Akt, Plc-γ1, Lyn, and Src kinases. Akt can affect erythroid development via serine phosphorylation of Gata1, whereas Lyn and Src can act to enhance EPO/EPOR activated growth/development signals,^, and to modulate Cbl’s E3 ligase effects on EPOR turnover.^, For each of these EPO/EPOR signal transducers, their engagement and actions appear to become especially important during anemia and/or stress erythropoiesis.