Fyn Is Involved In Erythropoietin Signaling Pathway And Interfaces Oxidation To Regulate Erythropoiesis

Beneduce, E.; Matte, A.; de Falco, L.; Mbiandjeu, S.; Chiabrando, D.; Tolosano, E.; Federti, E.; Petrillo, S.; Narla, M.; Siciliano, A.; Babu, W.; Menon, W.; Ghaffari, S.; Iolascon, A.; de Franceschi, L.

doi:10.1101/323873

bioRxiv · 10.1101/323873

Fyn Is Involved In Erythropoietin Signaling Pathway And Interfaces Oxidation To Regulate Erythropoiesis

Beneduce, E.·Matte, A.·de Falco, L.·Mbiandjeu, S.·Chiabrando, D.·Tolosano, E.·Federti, E.·Petrillo, S.·Narla, M.·Siciliano, A.·Babu, W.·Menon, W.·Ghaffari, S.·Iolascon, A.·de Franceschi, L.

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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 Src-family-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-/- mouse baseline erythropoiesis and restored the erythropoietic response to phenylhydrazine. Taken together these findings have enabled to identify the novel multimodal action of Fyn in the developmental program of erythropoiesis.

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Beneduce, E., Matte, A., de Falco, L., Mbiandjeu, S., Chiabrando, D., Tolosano, E., Federti, E., Petrillo, S., Narla, M., Siciliano, A., Babu, W., Menon, W., Ghaffari, S., Iolascon, A., de Franceschi, L.. 2018-05-18. Fyn Is Involved In Erythropoietin Signaling Pathway And Interfaces Oxidation To Regulate Erythropoiesis. https://doi.org/10.1101/323873

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