期刊
JOURNAL OF NEUROCHEMISTRY
卷 112, 期 6, 页码 1593-1604出版社
WILEY
DOI: 10.1111/j.1471-4159.2010.06568.x
关键词
C; elegans; c-Jun kinase; membrane; mitogen-activated protein kinase; p38; phosphorylation
资金
- NIEHS [ES15567]
- NINDS [NS41786]
- Alzheimer Association and the Michael J. Fox Foundation
- Intramural Research Program of the NIH
- National Institute on Aging [Z01AG000948]
P>Mutations in leucine-rich repeat kinase 2 (LRRK2) are prevalent causes of late-onset Parkinson's disease. Here, we show that LRRK2 binds to MAPK kinases (MKK) 3, 6, and 7, and that LRRK2 is able to phosphorylate MKK3, 6 and 7. Over-expression of LRRK2 and MKK6 increased the steady state levels of each protein beyond that observed with over-expression of either protein alone. Co-expression increased levels of MKK6 in the membrane more than in the cytoplasm. The increased expression of LRRK2 and MKK6 requires MKK6 activity. The disease-linked LRRK2 mutations, G2019S, R1441C and I2020T, enhance binding of LRRK2 to MKK6. This interaction was further supported by in vivo studies in C. elegans. RNAi knockdown in C. elegans of the endogenous orthologs for MKK6 or p38, sek-1 and pmk-1, abolishes LRRK2-mediated protection against mitochondrial stress. These results were confirmed by deletion of sek-1 in C. elegans. These data demonstrate that MKKs and LRRK2 function in similar biological pathways, and support a role for LRRK2 in modulating the cellular stress response.
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