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Arsenite Stress Downregulates Phosphorylation and 14-3-3 Binding of Leucine-rich Repeat Kinase 2 (LRRK2) Promoting Self-Association and Cellular Redistribution.

Mamais, A; Chia, R; Beilina, A; Hauser, DN; Hall, C; Lewis, PA; Cookson, MR; (2014) Arsenite Stress Downregulates Phosphorylation and 14-3-3 Binding of Leucine-rich Repeat Kinase 2 (LRRK2) Promoting Self-Association and Cellular Redistribution. J Biol Chem , 289 (31) pp. 21386-21400. 10.1074/jbc.M113.528463. Green open access

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Abstract

Mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2) are a common genetic cause of Parkinson's disease but the mechanisms whereby LRRK2 is regulated are unknown. Phosphorylation of LRRK2 at residues Ser(910) and 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 several pathogenic mutations. However, the physiological or pathological 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 PP1α, decreases kinase activity and GTP binding in vitro and induces translocation of LRRK2 to centrosomes. Our data indicate that signalling events induced by arsenite and oxidative stress may regulate LRRK2 function.

Type: Article
Title: Arsenite Stress Downregulates Phosphorylation and 14-3-3 Binding of Leucine-rich Repeat Kinase 2 (LRRK2) Promoting Self-Association and Cellular Redistribution.
Open access status: An open access version is available from UCL Discovery
DOI: 10.1074/jbc.M113.528463
Publisher version: http://dx.doi.org/10.1074/jbc.M113.528463
Additional information: © 2014 by The American Society for Biochemistry and Molecular Biology, Inc. Author's Choice—Final version full access. Creative Commons Attribution Unported License applies to Author Choice Articles
Keywords: Arsenite, Parkinson disease, leucine-rich repeat kinase 2 (LRRK2), neurodegenerative disease, oxidative stress, phosphorylation
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Clinical and Movement Neurosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Department of Neuromuscular Diseases
URI: http://discovery.ucl.ac.uk/id/eprint/1432973
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