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The c-Abl-MST1 Signaling Pathway Mediates Oxidative Stress-Induced Neuronal Cell Death

State Key Laboratory of Brain and Cognitive Sciences, Beijing 100101, China.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.75). 06/2011; 31(26):9611-9. DOI: 10.1523/JNEUROSCI.0035-11.2011
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ABSTRACT Oxidative stress influences cell survival and homeostasis, but the mechanisms underlying the biological effects of oxidative stress remain to be elucidated. The protein kinase MST1 (mammalian Ste20-like kinase 1) plays a major role in oxidative stress-induced cell death in primary mammalian neurons. However, the mechanisms that regulate MST1 in oxidative stress responses remain largely unknown. In the present study, we demonstrate that the protein kinase c-Abl phosphorylates MST1 at Y433, which triggers the stabilization and activation of MST1. Inhibition of c-Abl promotes the degradation of MST1 through C terminus of Hsc70-interacting protein (CHIP)-mediated ubiquitination, and thereby attenuates cell death. Oxidative stress induces the c-Abl-dependent tyrosine phosphorylation of MST1 and increases the interaction between MST1 and FOXO3 (Forkhead box O3), thereby activating the MST1-FOXO signaling pathway, leading to cell death in both primary culture neurons and rat hippocampal neurons. The identification of the c-Abl tyrosine kinase as a novel upstream activator of MST1 suggests that the c-Abl-MST1 signaling cascade plays an important role in cellular responses to oxidative stress.

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    • "This induces the nuclear accumulation and activation of FOXO3 even in presence of inhibitory PKB signals. Increased interaction of MST1 and FOXO3 activates the MST1-FOXO3 signaling pathway finally leading to cell death in both primary cultured neurons and rat hippocampal neurons (Xiao et al, 2011). Interestingly, in Drosophila the activation of the JNK/FOXO signaling pathway leads to neuronal resistance to oxidative stress via the expression of Jafrac1 the fly homologue of peroxiredoxin II. "
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