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Am J Hematol. 2019 Jan;94(1):10-20. doi: 10.1002/ajh.25295. Epub 2018 Oct 25.

Fyn kinase is a novel modulator of erythropoietin signaling and stress erythropoiesis.

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Department of Medicine, University of Verona, AOUI Verona, Verona, Italy.
Department of Biochemistry, Federico II University, Naples, Italy.
Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy.
New York Blood Center, New York, New York.
Department of Cell, Development and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, New York.


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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