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

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

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.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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
  • 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
  • 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*
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Rho Guanine Nucleotide Exchange Factors / antagonists & inhibitors
  • Rho Guanine Nucleotide Exchange Factors / genetics
  • Rho Guanine Nucleotide Exchange Factors / metabolism*
  • Signal Transduction
  • trans-Golgi Network / drug effects
  • trans-Golgi Network / metabolism*

Substances

  • 4-(4-(2,3-dihydrobenzo(1,4)dioxin-6-yl)-5-pyridin-2-yl-1H-imidazol-2-yl)benzamide
  • ARHGEF7 protein, human
  • Benzamides
  • IC 261
  • Imidazoles
  • Indoles
  • Membrane Glycoproteins
  • Protein Kinase Inhibitors
  • RNA, Small Interfering
  • Rho Guanine Nucleotide Exchange Factors
  • TGOLN2 protein, human
  • Phloroglucinol
  • Casein Kinase Ialpha
  • LRRK2 protein, human
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • Protein-Serine-Threonine Kinases