title: Rapsyn is required for MuSK signaling and recruits synaptic components to a MuSK-containing scaffold.
abstract: Agrin-induced clustering of acetylcholine receptors (AChRs) in the postsynaptic membrane is a key step in synaptogenesis at the neuromuscular junction. The receptor tyrosine kinase MuSK is a component of the agrin receptor, while the cytoplasmic protein rapsyn is necessary for the clustering of AChRs and all other postsynaptic membrane components studied to date. We show here that MuSK remains concentrated at synaptic sites in rapsyn-deficient mutant mice, suggesting that MuSK forms a primary structural scaffold to which rapsyn attaches other synaptic components. Using nonmuscle cells, we show that rapsyn-MuSK interactions are mediated by the ectodomain of MuSK, suggesting the existence of a transmembrane intermediate. In addition to rapsyn's structural role, we demonstrate that it is required for an early step in MuSK signaling, AChR phosphorylation. This signaling requires the kinase domain of MuSK, but not its ectodomain. Thus, MuSK may interact with rapsyn in multiple ways to play both structural and signaling roles in agrin-induced differentiation.
authors.affiliation: Department of Molecular Biology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
authors.forename: Elizabeth D
authors.initials: ED
authors.lastname: Apel
authors.forename: David J
authors.initials: DJ
authors.lastname: Glass
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Moscoso
authors.forename: George D
authors.initials: GD
authors.lastname: Yancopoulos
authors.forename: Joshua R
authors.initials: JR
authors.lastname: Sanes
mesh_terms: D018171:Agrin / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D003598:Cytoskeletal Proteins / Q000378:metabolism; D049030:Dystroglycans; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D009124:Muscle Proteins / Q000172:deficiency / Q000502:physiology*; D010766:Phosphorylation; D011784:Quail; D051381:Rats; D011940:Receptor Aggregation; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism / Q000502:physiology*; D011950:Receptors, Cholinergic / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000172:deficiency / Q000502:physiology*; D015398:Signal Transduction; D013569:Synapses / Q000378:metabolism / Q000502:physiology*; D014018:Tissue Distribution
chemical_list: D018171:Agrin; D003598:Cytoskeletal Proteins; C483081:DAG1 protein, human; D008562:Membrane Glycoproteins; D009124:Muscle Proteins; D011950:Receptors, Cholinergic; D011978:Receptors, Nicotinic; C051609:peripheral membrane protein 43K; D049030:Dystroglycans; C095714:MUSK protein, human; D020794:Receptor Protein-Tyrosine Kinases