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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.

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J Biol Chem 2014 Jun;

Authors: Adamantios Mamais, Ruth Chia, Alexandra Beilina, David N Hauser, Christine Hall, Patrick A Lewis, Mark R Cookson, Rina Bandopadhyay

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 PP1?, 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.

PMID: 24942733 [PubMed - as supplied by publisher]

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