Phosphorylation of LRRK2 by casein kinase 1α regulates trans-Golgi clustering via differential interaction with ARHGEF7

Ruth Chia, Sara Haddock, Alexandra Beilina, Iakov N. Rudenko, Adamantios Mamais, Alice Kaganovich, Yan Li, Ravindran Kumaran, Michael A. Nalls and Mark R. Cookson ()
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Ruth Chia: Cell Biology and Gene Expression Section, Laboratory of Neurogenetics, National Institute on Aging
Sara Haddock: Cell Biology and Gene Expression Section, Laboratory of Neurogenetics, National Institute on Aging
Alexandra Beilina: Cell Biology and Gene Expression Section, Laboratory of Neurogenetics, National Institute on Aging
Iakov N. Rudenko: Cell Biology and Gene Expression Section, Laboratory of Neurogenetics, National Institute on Aging
Adamantios Mamais: Cell Biology and Gene Expression Section, Laboratory of Neurogenetics, National Institute on Aging
Alice Kaganovich: Cell Biology and Gene Expression Section, Laboratory of Neurogenetics, National Institute on Aging
Yan Li: Peptide Sequencing Facility, National Institute of Neurological Disorders and Stroke/NIH
Ravindran Kumaran: Cell Biology and Gene Expression Section, Laboratory of Neurogenetics, National Institute on Aging
Michael A. Nalls: Molecular Genetics Section, Laboratory of Neurogenetics, National Institute on Aging
Mark R. Cookson: Cell Biology and Gene Expression Section, Laboratory of Neurogenetics, National Institute on Aging

Nature Communications, 2014, vol. 5, issue 1, 1-11

Abstract: Abstract LRRK2, a gene relevant to Parkinson's disease, encodes a scaffolding protein with both GTPase and kinase activities. LRRK2 protein is itself phosphorylated and therefore is subject to regulation by cell signalling; however, the kinase(s) responsible for this event have not been definitively identified. Here using an unbiased siRNA kinome screen, we identify and validate casein kinase 1α (CK1α) as being responsible for LRRK2 phosphorylation, including in the adult mouse striatum. We further show that LRRK2 recruitment to TGN46-positive Golgi-derived vesicles is modulated by constitutive LRRK2 phosphorylation by CK1α. These effects are mediated by differential protein interactions of LRRK2 with a guanine nucleotide exchange factor, ARHGEF7. These pathways are therefore likely involved in the physiological maintenance of the Golgi in cells, which may play a role in the pathogenesis of Parkinson’s disease.

Date: 2014
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DOI: 10.1038/ncomms6827

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