Fyn kinase is a novel modulator of erythropoietin signaling and stress erythropoiesis.
Elisabetta BeneduceAlessandro MatteLuigia De FalcoSerge MbiandjeuDeborah ChiabrandoEmanuela TolosanoEnrica FedertiSara PetrilloNarla MohandasAngela SicilianoWilson BabuVijay MenonSaghi GhaffariAchille IolasconLucia De FranceschiPublished in: American journal of hematology (2018)
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.
Keyphrases
- oxidative stress
- signaling pathway
- reactive oxygen species
- cell death
- cell proliferation
- dna damage
- diabetic rats
- induced apoptosis
- tyrosine kinase
- epithelial mesenchymal transition
- pi k akt
- immune response
- high fat diet induced
- adipose tissue
- chronic pain
- inflammatory response
- electronic health record
- ischemia reperfusion injury
- big data
- heat stress
- nuclear factor