c-Src regulates Nrf2 activity through PKCδ after oxidant stimulus

Nrf2 is the main transcription factor involved in expression of cell defense enzymes, which is altered in several oxidant-related disorders. Cytosolic Nrf2 activation is modulated through phosphorylation by PKC delta, an enzyme controlled by Src tyrosine kinases. Of relevance, Src family members are involved in numerous cellular processes and regulated by hydrogen peroxide (H2O2). In this study we analysed the activation of cell survival-related signaling proteins, c-Src and Nrf2, and the influence of c-Src kinase on Nrf2 regulation after exposure to H2O2. Acute exposure of HT22 mouse hippocampal neural cells to H2O2 increased c-Src and Nrf2 phosphorylation/activation at Tyr416 and Ser40, respectively. Nrf2 phosphorylation at Ser40, its nuclear accumulation and transcriptional activity involving heme oxygenase-1 (HO-1) expression were dependent on c-Src kinase activation. Moreover, modulation of Nrf2 activity by c-Src occurred through PKC delta phosphorylation at Tyr311. We demonstrate, for the first time, c-Src-mediated regulation of Nrf2 transcriptional activity, via PKCS activation, following an acute H(2)O2 stimulus. This work supports that the c-Src/PKC delta/Nrf2 pathway may constitute a novel signaling pathway stimulated by H2O2 and a potential target for the treatment of diseases involving redox deregulation.