期刊
NEUROBIOLOGY OF AGING
卷 35, 期 12, 页码 2870-2880出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.neurobiolaging.2014.05.034
关键词
Chaperone-mediated autophagy; Cyclin-dependent kinase 5; Parkinson's disease; Protein phosphorylation; Raf kinase inhibitor protein
资金
- National Nature Science Foundation of China [30900423, 31071208]
- Specialized Research Fund for the Doctoral Program of Higher Education [20100142110053]
- Program for New Century Excellent Talents in University
Raf kinase inhibitor protein (RKIP) is a major negative mediator of the extracellular signal-related kinase (ERK)/mitogen-activated protein kinase (MAPK) pathway. The downregulation of RKIP is correlated with many cancers, but the mechanisms that underlie this downregulation and its roles in the nervous system remain unclear. Here, we demonstrate that RKIP is a substrate of cyclin-dependent kinase 5 (CDK5) in neurons and that the phosphorylation of RKIP at T42 causes the release of Raf-1. Moreover, T42 phosphorylation promotes the exposure and recognition of the target motif KLYEQ in the C-terminus of RKIP by chaperone Hsc70 and the subsequent degradation of RKIP via chaperone-mediated autophagy (CMA). Furthermore, in the brain sample of Parkinson's disease (PD) patients and in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochlorideeinduced and transgenic PD models, we demonstrate that CDK5-mediated phosphorylation and autophagy of RKIP are involved in the overactivation of the ERK/MAPK cascade, leading to S-phase reentry and neuronal loss. These findings provide evidence for the role of the CDK5/RKIP/ERK pathway in PD pathogenesis and suggest that this pathway may be a suitable therapeutic target in PD. (C) 2014 Elsevier Inc. All rights reserved.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据