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

• Published in: Nature communications Vol. 5; no. 1; p. 5827
• Main Authors: Chia, Ruth, Haddock, Sara, Beilina, Alexandra, Rudenko, Iakov N., Mamais, Adamantios, Kaganovich, Alice, Li, Yan, Kumaran, Ravindran, Nalls, Michael A., Cookson, Mark R.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 15.12.2014
• Subjects: 13; 13/89; 14/63; 631/378/1689/1718; 631/45/275; 631/80/86; 82; 82/1; Animals; Benzamides - pharmacology; Casein Kinase Ialpha - antagonists & inhibitors; Casein Kinase Ialpha - genetics; Casein Kinase Ialpha - metabolism; Cerebral Cortex - cytology; Cerebral Cortex - drug effects; Cerebral Cortex - enzymology; Corpus Striatum - cytology; Corpus Striatum - enzymology; Gene Expression Regulation; HEK293 Cells; Humanities and Social Sciences; Humans; Imidazoles - pharmacology; Indoles - pharmacology; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Membrane Glycoproteins - antagonists & inhibitors; Membrane Glycoproteins - genetics; Membrane Glycoproteins - metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; multidisciplinary; Neurons - cytology; Neurons - drug effects; Neurons - enzymology; Phloroglucinol - analogs & derivatives; Phloroglucinol - pharmacology; Phosphorylation; Primary Cell Culture; Protein Kinase Inhibitors - pharmacology; Protein Serine-Threonine Kinases - antagonists & inhibitors; Protein Serine-Threonine Kinases - genetics; Protein Serine-Threonine Kinases - metabolism; Rho Guanine Nucleotide Exchange Factors - antagonists & inhibitors; Rho Guanine Nucleotide Exchange Factors - genetics; Rho Guanine Nucleotide Exchange Factors - metabolism; RNA, Small Interfering - genetics; RNA, Small Interfering - metabolism; Science; Science (multidisciplinary); Signal Transduction; trans-Golgi Network - drug effects; trans-Golgi Network - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms6827

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. The kinase LRRK2 is implicated in Parkinson’s disease progression and is known to be phosphorylated. Chia et al. show that this phosphorylation is mediated by the kinase CK1a, and is required for the recruitment of LRRK2 to Golgi-derived vesicles, suggesting a role for this protein in Golgi maintenance.