title: EGFR-dependent phosphorylation of leucine-rich repeat kinase LRRK1 is important for proper endosomal trafficking of EGFR.
abstract: Ligand-induced activation of the epidermal growth factor receptor (EGFR) initiates trafficking events that relocalize the receptors from the cell surface to intracellular endocytic compartments. We recently reported that leucine-rich repeat kinase 1 (LRRK1) is involved in the trafficking of EGFR from early to late endosomes. In this study, we demonstrate that EGFR regulates the kinase activity of LRRK1 via tyrosine phosphorylation and that this is required for proper endosomal trafficking of EGFR. Phosphorylation of LRRK1 at Tyr-944 results in reduced LRRK1 kinase activity. Mutation of LRRK1 Tyr-944 (Y944F) abolishes EGF-stimulated tyrosine phosphorylation, resulting in hyperactivation of LRRK1 kinase activity and enhanced motility of EGF-containing endosomes toward the perinuclear region. The compartments in which EGFR accumulates are mixed endosomes and are defective in the proper formation of intraluminal vesicles of multivesicular bodies. These results suggest that feedback down-regulation of LRRK1 kinase activity by EGFR plays an important role in the appropriate endosomal trafficking of EGFR.
authors.affiliation: Department of Molecular Biology, Graduate School of Science, Nagoya University, Chikusa-ku, Nagoya, Japan.
authors.forename: Kouki
authors.initials: K
authors.lastname: Ishikawa
authors.forename: Atsuki
authors.initials: A
authors.lastname: Nara
authors.forename: Kunihiro
authors.initials: K
authors.lastname: Matsumoto
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Hanafusa
mesh_terms: D019943:Amino Acid Substitution; D001425:Bacterial Outer Membrane Proteins; D001665:Binding Sites / Q000235:genetics; D015536:Down-Regulation; D011992:Endosomes / Q000378:metabolism; D004789:Enzyme Activation; D004815:Epidermal Growth Factor / Q000378:metabolism; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D029968:Escherichia coli Proteins; D025461:Feedback, Physiological; D006160:Guanosine Triphosphate / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D009068:Movement / Q000502:physiology; D016296:Mutagenesis; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport; D012313:RNA / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017384:Sequence Deletion; D014443:Tyrosine / Q000737:chemistry
chemical_list: D001425:Bacterial Outer Membrane Proteins; D029968:Escherichia coli Proteins; C039919:RNA, recombinant; C074745:traN protein, E coli; D014443:Tyrosine; D004815:Epidermal Growth Factor; D012313:RNA; D006160:Guanosine Triphosphate; C512478:EGFR protein, human; D066246:ErbB Receptors; C510751:LRRK1 protein, human; D017346:Protein Serine-Threonine Kinases