MKK6 binds and regulates expression of Parkinson's disease-related protein LRRK2

• Published in: Journal of neurochemistry Vol. 112; no. 6; pp. 1593 - 1604
• Main Authors: Hsu, Cindy H, Chan, Diane, Greggio, Elisa, Saha, Shamol, Guillily, Maria D, Ferree, Andrew, Raghavan, Kesav, Shen, Grace C, Segal, Lilach, Ryu, Hoon, Cookson, Mark R, Wolozin, Benjamin
• Format: Journal Article
• Language: English
• Published: Oxford, UK Oxford, UK : Blackwell Publishing Ltd 01.03.2010; Blackwell Publishing Ltd; Wiley-Blackwell
• Subjects: Amyloid beta-Protein Precursor - metabolism; Animals; Animals, Genetically Modified; Behavior, Animal; Biological and medical sciences; c-Jun kinase; C. elegans; Caenorhabditis elegans; Carrier Proteins - genetics; Carrier Proteins - metabolism; Cell Line, Transformed; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Gene expression; Gene Expression Regulation - genetics; Gene Expression Regulation - physiology; Humans; Immunoprecipitation - methods; Insecticides - toxicity; Kinases; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; MAP Kinase Kinase 6 - genetics; MAP Kinase Kinase 6 - metabolism; Medical sciences; membrane; mitogen-activated protein kinase; Mortality; Mutation; Mutation - genetics; Nervous system (semeiology, syndromes); Nervous system as a whole; Neurology; p38; Parkinson's disease; phosphorylation; Phosphorylation - drug effects; Protein Binding - genetics; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; Protein-Serine-Threonine Kinases - pharmacology; Proteins; RNA Interference - physiology; Rotenone - toxicity; Stress response; Subcellular Fractions - metabolism; Transfection - methods; Phosphorylation; C; membrane; Parkinson disease; Leucine; Mitochondria; Endogenous; p38; Deletion; Degenerative disease; elegans; Nervous system diseases; Enzyme; Transferases; Interaction; Mitogen-activated protein kinase; c-Jun kinase; Steady state; Protein; Stress; Cerebral disorder; Central nervous system disease; Mutation; Cytoplasm; Extrapyramidal syndrome
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/j.1471-4159.2010.06568.x

J. Neurochem. (2010) 112, 1593-1604. 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.