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.²⁴  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.³¹  HIF2α turnover is promoted by VHL and PHDs,³⁰  and pharmacologic inhibitors of PHDs stabilize HIF2α.³⁴  During stress erythropoiesis, acetate supplementation can further enhance HIF2α complex acetylation, activity, and EPO production via an Acss2-CBP circuit.³³  (B) Modulation of EPOR signaling by interacting plasma membrane proteins: TFR2 associates with the EPOR and can modulate its trafficking.⁴⁴  Upon p-IgA1 ligation, Tfr1 can also enhance EPOR signaling.⁴⁸  RHEX also associates with the hEPOR, and promotes EPO-dependent human erythroblast formation.⁴⁷  (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.⁸⁹  By inhibiting leached lysosomal cathepsins, Spi2A cytoprotects erythroblasts against consequences of oxidative damage.⁷¹  MASL1 acts within a central RAS/MEK/ERK circuit,⁶³  together with RHEX, to reinforce ERK1/2 activation.⁴⁷  Further dynamic balancing of essential RAS/MEK/ERK signals (and of EPC formation) occurs via RAS down-modulation by Rasa3⁵⁶  and Nf1.⁵⁷  Pro-erythropoietic effects also are being established for Akt, Plc-γ1, Lyn, and Src kinases. Akt can affect erythroid development via serine phosphorylation of Gata1,⁹²  whereas Lyn and Src can act to enhance EPO/EPOR activated growth/development signals,^83,84  and to modulate Cbl’s E3 ligase effects on EPOR turnover.^74,75  For each of these EPO/EPOR signal transducers, their engagement and actions appear to become especially important during anemia and/or stress erythropoiesis.