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

被引:111
作者
Xiao, Lei [2 ,3 ,4 ]
Chen, Dongmei [2 ,3 ]
Hu, Peng [2 ,3 ]
Wu, Junbing [2 ,3 ,4 ]
Liu, Weizhe [5 ]
Zhao, Yanhong [2 ,3 ]
Cao, Mou [2 ,3 ]
Fang, Yuan [1 ]
Bi, Wenzhi
Zheng, Zheng [3 ,6 ]
Ren, Jian [2 ,3 ]
Ji, Guangju [3 ]
Wang, Yan [1 ]
Yuan, Zengqiang [2 ,3 ]
机构
[1] Chinese Peoples Liberat Army Gen Hosp, Dept Orthopaed, Beijing 100853, Peoples R China
[2] State Key Lab Brain & Cognit Sci, Beijing 100101, Peoples R China
[3] Chinese Acad Sci, Inst Biophys, Beijing 100101, Peoples R China
[4] Chinese Acad Sci, Coll Life Sci, Grad Sch, Beijing 100049, Peoples R China
[5] Shandong Univ, Coll Life Sci, Jinan 250100, Shangdong, Peoples R China
[6] Capital Med Univ, Xuanwu Hosp, Beijing Inst Geriatr, Beijing 100053, Peoples R China
基金
美国国家科学基金会;
关键词
UBIQUITIN LIGASE CHIP; ABL TYROSINE KINASE; C-ABL; MST1; KINASE; PHOSPHORYLATION; PROTEIN; ACTIVATION; AGGREGATION; DEGRADATION; APOPTOSIS;
D O I
10.1523/JNEUROSCI.0035-11.2011
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
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.
引用
收藏
页码:9611 / 9619
页数:9
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