title: Phosphorylation of LRRK2 by casein kinase 1α regulates trans-Golgi clustering via differential interaction with ARHGEF7.
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.
authors.affiliation: Cell Biology and Gene Expression Section, Laboratory of Neurogenetics, National Institute on Aging, 35 Convent Drive, Bethesda, Maryland 20892-3707, USA.
authors.forename: Ruth
authors.initials: R
authors.lastname: Chia
authors.affiliation: Cell Biology and Gene Expression Section, Laboratory of Neurogenetics, National Institute on Aging, 35 Convent Drive, Bethesda, Maryland 20892-3707, USA.
authors.forename: Sara
authors.initials: S
authors.lastname: Haddock
authors.affiliation: Cell Biology and Gene Expression Section, Laboratory of Neurogenetics, National Institute on Aging, 35 Convent Drive, Bethesda, Maryland 20892-3707, USA.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Beilina
authors.affiliation: Cell Biology and Gene Expression Section, Laboratory of Neurogenetics, National Institute on Aging, 35 Convent Drive, Bethesda, Maryland 20892-3707, USA.
authors.forename: Iakov N
authors.initials: IN
authors.lastname: Rudenko
authors.affiliation: Cell Biology and Gene Expression Section, Laboratory of Neurogenetics, National Institute on Aging, 35 Convent Drive, Bethesda, Maryland 20892-3707, USA.
authors.forename: Adamantios
authors.initials: A
authors.lastname: Mamais
authors.affiliation: Cell Biology and Gene Expression Section, Laboratory of Neurogenetics, National Institute on Aging, 35 Convent Drive, Bethesda, Maryland 20892-3707, USA.
authors.forename: Alice
authors.initials: A
authors.lastname: Kaganovich
authors.affiliation: Peptide Sequencing Facility, National Institute of Neurological Disorders and Stroke/NIH, 35 Convent Drive, Bethesda, Maryland 20892-3721, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Cell Biology and Gene Expression Section, Laboratory of Neurogenetics, National Institute on Aging, 35 Convent Drive, Bethesda, Maryland 20892-3707, USA.
authors.forename: Ravindran
authors.initials: R
authors.lastname: Kumaran
authors.affiliation: Molecular Genetics Section, Laboratory of Neurogenetics, National Institute on Aging, 35 Convent Drive, Bethesda, Maryland 20892-3707, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Nalls
authors.affiliation: Cell Biology and Gene Expression Section, Laboratory of Neurogenetics, National Institute on Aging, 35 Convent Drive, Bethesda, Maryland 20892-3707, USA.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Cookson
mesh_terms: D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D048128:Casein Kinase Ialpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D003342:Corpus Striatum / Q000166:cytology / Q000201:enzymology*; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D010696:Phloroglucinol / Q000031:analogs & derivatives / Q000494:pharmacology; D010766:Phosphorylation; D061251:Primary Cell Culture; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D064067:Rho Guanine Nucleotide Exchange Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D021601:trans-Golgi Network / Q000187:drug effects / Q000378:metabolism*
chemical_list: C493177:4-(4-(2,3-dihydrobenzo(1,4)dioxin-6-yl)-5-pyridin-2-yl-1H-imidazol-2-yl)benzamide; C576606:ARHGEF7 protein, human; D001549:Benzamides; C411652:IC 261; D007093:Imidazoles; D007211:Indoles; D008562:Membrane Glycoproteins; D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; D064067:Rho Guanine Nucleotide Exchange Factors; C072237:TGOLN2 protein, human; D010696:Phloroglucinol; D048128:Casein Kinase Ialpha; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases