title: The c-Abl-MST1 signaling pathway mediates oxidative stress-induced neuronal cell death.
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.
authors.affiliation: State Key Laboratory of Brain and Cognitive Sciences, Beijing 100101, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Xiao
authors.forename: Dongmei
authors.initials: D
authors.lastname: Chen
authors.forename: Peng
authors.initials: P
authors.lastname: Hu
authors.forename: Junbing
authors.initials: J
authors.lastname: Wu
authors.forename: Weizhe
authors.initials: W
authors.lastname: Liu
authors.forename: Yanhong
authors.initials: Y
authors.lastname: Zhao
authors.forename: Mou
authors.initials: M
authors.lastname: Cao
authors.forename: Yuan
authors.initials: Y
authors.lastname: Fang
authors.forename: Wenzhi
authors.initials: W
authors.lastname: Bi
authors.forename: Zheng
authors.initials: Z
authors.lastname: Zheng
authors.forename: Jian
authors.initials: J
authors.lastname: Ren
authors.forename: Guangju
authors.initials: G
authors.lastname: Ji
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.forename: Zengqiang
authors.initials: Z
authors.lastname: Yuan
mesh_terms: D000818:Animals; D015153:Blotting, Western; D016923:Cell Death / Q000502:physiology*; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D008297:Male; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D016315:Proto-Oncogene Proteins c-abl / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology*; D014162:Transfection; D054875:Ubiquitination / Q000502:physiology
chemical_list: D051858:Forkhead Transcription Factors; D016315:Proto-Oncogene Proteins c-abl; D017346:Protein Serine-Threonine Kinases