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The signaling cascade induced by the interaction of erythropoietin (EPO) with its receptor (EPO‐R) is a key event of erythropoiesis. We present here data indicating that Fyn, a Src‐family‐kinase, participates in the EPO signaling‐pathway, since Fyn−/− mice exhibit reduced Tyr‐phosphorylation of EPO‐R and decreased STAT5‐activity. The importance of Fyn in erythropoiesis is also supported by the blunted responsiveness of Fyn−/− mice to stress erythropoiesis. Fyn−/− mouse erythroblasts adapt to reactive oxygen species (ROS) by activating the redox‐related‐transcription‐factor Nrf2. However, since Fyn is a physiologic repressor of Nrf2, absence of Fyn resulted in persistent‐activation of Nrf2 and accumulation of nonfunctional proteins. ROS‐induced over‐activation of Jak2‐Akt‐mTOR‐pathway and repression of autophagy with perturbation of lysosomal‐clearance were also noted. Treatment with Rapamycin, a mTOR‐inhibitor and autophagy activator, ameliorates Fyn−/− mouse baseline erythropoiesis and erythropoietic response to oxidative‐stress. These findings identify a novel multimodal action of Fyn in the regulation of normal and stress erythropoiesis.

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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 -/-