Arsenite Stress Down-regulates Phosphorylation and 14-3-3 Binding of Leucine-rich Repeat Kinase 2 (LRRK2), Promoting Self-association and Cellular Redistribution

被引:29
作者
Mamais, Adamantios [1 ,2 ,3 ]
Chia, Ruth [3 ,4 ]
Beilina, Alexandra [3 ]
Hauser, David N. [3 ,5 ]
Hall, Christine [2 ]
Lewis, Patrick A. [2 ,6 ]
Cookson, Mark R. [3 ]
Bandopadhyay, Rina [1 ,2 ]
机构
[1] UCL, Inst Neurol, Reta Lila Weston Inst Neurol Studies, London WC1N 1PJ, England
[2] UCL, Inst Neurol, Dept Mol Neurosci, London WC1N 3BJ, England
[3] NIA, Cell Biol & Gene Express Sect, Neurogenet Lab, NIH, Bethesda, MD 20892 USA
[4] Georgetown Univ, Med Ctr, Dept Neurosci, Washington, DC 20057 USA
[5] Brown Univ, Dept Neurosci, Natl Inst Hlth Grad Partnership Program, Providence, RI 02912 USA
[6] Univ Reading, Sch Pharm, Reading RG6 6AP, Berks, England
基金
英国惠康基金; 美国国家卫生研究院;
关键词
PARKINSONS-DISEASE PATHOLOGY; G2019S MUTATION; GTP-BINDING; ROC DOMAIN; INHIBITION; PROTEINS; LEUCINE-RICH-REPEAT-KINASE-2; LOCALIZATION; DEGRADATION; ACTIVATION;
D O I
10.1074/jbc.M113.528463
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2) are a common genetic cause of Parkinson disease, but the mechanisms whereby LRRK2 is regulated are unknown. Phosphorylation of LRRK2 at Ser(910)/Ser(935) mediates interaction with 14-3-3. Pharmacological inhibition of its kinase activity abolishes Ser(910)/Ser(935) phosphorylation and 14-3-3 binding, and this effect is also mimicked by pathogenic mutations. However, physiological situations where dephosphorylation occurs have not been defined. Here, we show that arsenite or H2O2-induced stresses promote loss of Ser(910)/Ser(935) phosphorylation, which is reversed by phosphatase inhibition. Arsenite-induced dephosphorylation is accompanied by loss of 14-3-3 binding and is observed in wild type, G2019S, and kinase-dead D2017A LRRK2. Arsenite stress stimulates LRRK2 self-association and association with protein phosphatase 1 alpha, decreases kinase activity and GTP binding in vitro, and induces translocation of LRRK2 to centrosomes. Our data indicate that signaling events induced by arsenite and oxidative stress may regulate LRRK2 function.
引用
收藏
页码:21386 / 21400
页数:15
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