Fyn is Involved in Erythropoietin Signaling Pathway and Interfaces Oxidation to Regulate Erythropoiesis

Abstract

Erythropoiesis is a complex multistep process responsible of the production of circulating mature erythrocytes and involved the production of reactive oxygen species (ROS) during erythroid differentiation. Here, we document that Fyn, a Srcfamily-kinase, participates in erythropoietin (EPO) signaling pathway, by the reducing extent of Tyr-phosphorylation of EPO-R and by decreasing STAT5 activity. The importance of Fyn in EPO cascade is also supported by the increased sensitivity of Fyn -/mice to stress erythropoiesis. Fyn -/mouse erythroblasts adapt to the induced stress by the activation of the redox-related-transcription-factor Nrf2. However, the absence of the Nrf2 physiologic repressor Fyn resulted in the persistent activation of Nrf2 and accumulation of non-functional proteins. This is paralleled by ROS induced over-activation of Jak2-Akt-mTOR pathway and repression of autophagy and perturbation of lysosomal-clearance during Fyn -/reticulocyte maturation. Treatment with Rapamycin, a mTOR inhibitor and autophagy activator, ameliorates Fyn -/-

Effect of arsenate on erythropoietin production and autophagy induction in HepG2 cells

“…Arsenite has been reported to both promote and suppress EPO production [9,20,21] and autophagy induction [22,23]. Moreover, EPO has also been reported to affect autophagy induction [24,25], but the relationship between EPO production and autophagy induction is unclear. Both EPO production and autophagy induction are involved in cellular protection against cytotoxic stress, which are thought to be the cellular responses to arsenic stress.…”