期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 289, 期 31, 页码 21386-21400出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M113.528463
关键词
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资金
- National Institutes of Health, NIA, Intramural Research Program
- Michael J. Fox Foundation
- Reta Lila Weston Institute of Neurological Studies
- Wellcome Trust/Medical Research Council Joint Call in Neurodegeneration award [WT089698]
- Medical Research Council [MR/L010933/1, MC_G1000735] Funding Source: researchfish
- Parkinson's UK [F-1002] Funding Source: researchfish
- MRC [MC_G1000735, MR/L010933/1] Funding Source: UKRI
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.
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