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Nat Commun. 2014 Dec 15;5:5827. doi: 10.1038/ncomms6827.

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

Author information

1
Cell Biology and Gene Expression Section, Laboratory of Neurogenetics, National Institute on Aging, 35 Convent Drive, Bethesda, Maryland 20892-3707, USA.
2
Peptide Sequencing Facility, National Institute of Neurological Disorders and Stroke/NIH, 35 Convent Drive, Bethesda, Maryland 20892-3721, USA.
3
Molecular Genetics Section, Laboratory of Neurogenetics, National Institute on Aging, 35 Convent Drive, Bethesda, Maryland 20892-3707, USA.

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.

PMID:
25500533
PMCID:
PMC4268884
DOI:
10.1038/ncomms6827
[Indexed for MEDLINE]
Free PMC Article

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