title: Α-Dystrobrevin-1 recruits Grb2 and α-catulin to organize neurotransmitter receptors at the neuromuscular junction.
abstract: Neuromuscular junctions (NMJs), the synapses made by motor neurons on muscle fibers, form during embryonic development but undergo substantial remodeling postnatally. Several lines of evidence suggest that α-dystrobrevin, a component of the dystrophin-associated glycoprotein complex (DGC), is a crucial regulator of the remodeling process and that tyrosine phosphorylation of one isoform, α-dystrobrevin-1, is required for its function at synapses. We identified a functionally important phosphorylation site on α-dystrobrevin-1, generated phosphorylation-specific antibodies to it and used them to demonstrate dramatic increases in phosphorylation during the remodeling period, as well as in nerve-dependent regulation in adults. We then identified proteins that bind to this site in a phosphorylation-dependent manner and others that bind to α-dystrobrevin-1 in a phosphorylation-independent manner. They include multiple members of the DGC, as well as α-catulin, liprin-α1, Usp9x, PI3K, Arhgef5 and Grb2. Finally, we show that two interactors, α-catulin (phosphorylation independent) and Grb2 (phosphorylation dependent) are localized to NMJs in vivo, and that they are required for proper organization of neurotransmitter receptors on myotubes.
authors.affiliation: Department of Molecular and Cellular Biology and Center for Brain Science, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Jacinthe
authors.initials: J
authors.lastname: Gingras
authors.affiliation: Laboratory of Synaptogenesis, Dept. of Cell Biology, Nencki Institute of Experimental Biology, Warsaw 02-093, Poland.
authors.forename: Marta
authors.initials: M
authors.lastname: Gawor
authors.affiliation: Laboratory of Synaptogenesis, Dept. of Cell Biology, Nencki Institute of Experimental Biology, Warsaw 02-093, Poland.
authors.forename: Krzysztof M
authors.initials: KM
authors.lastname: Bernadzki
authors.affiliation: Department of Anatomy and Neurobiology, Washington University School of Medicine, St Louis, MO 63110, USA.
authors.forename: R Mark
authors.initials: RM
authors.lastname: Grady
authors.affiliation: Novartis Biomedical Institute, Cambridge, MA 02139, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Hallock
authors.affiliation: Novartis Biomedical Institute, Cambridge, MA 02139, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Glass
authors.affiliation: Department of Molecular and Cellular Biology and Center for Brain Science, Harvard University, Cambridge, MA 02138, USA Department of Anatomy and Neurobiology, Washington University School of Medicine, St Louis, MO 63110, USA.
authors.forename: Joshua R
authors.initials: JR
authors.lastname: Sanes
authors.affiliation: Laboratory of Synaptogenesis, Dept. of Cell Biology, Nencki Institute of Experimental Biology, Warsaw 02-093, Poland t.proszynski@nencki.gov.pl.
authors.forename: Tomasz J
authors.initials: TJ
authors.lastname: Proszynski
mesh_terms: D000818:Animals; D002460:Cell Line; D049029:Dystrophin-Associated Proteins / Q000378:metabolism*; D051380:GRB2 Adaptor Protein / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009469:Neuromuscular Junction / Q000378:metabolism*; D009479:Neuropeptides / Q000378:metabolism*; D010766:Phosphorylation; D060066:Protein Interaction Maps; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D011950:Receptors, Cholinergic / Q000378:metabolism*; D009435:Synaptic Transmission; D051178:alpha Catenin / Q000378:metabolism*
chemical_list: C098884:Dtna protein, mouse; D049029:Dystrophin-Associated Proteins; D051380:GRB2 Adaptor Protein; C495949:Grb2 protein, mouse; D009479:Neuropeptides; D011950:Receptors, Cholinergic; D051178:alpha Catenin
keywords: AChR; Development; Dystrobrevin; Dystrophin-associated glycoprotein complex; Maturation; Neuromuscular junction