RAPSYN IS REQUIRED FOR MUSK SIGNALING AND RECRUITS SYNAPTIC COMPONENTS TO A MUSK-CONTAINING SCAFFOLD

Agrin-induced clustering of acetylcholine receptors (AChRs) in the pos tsynaptic membrane is a key step in synaptogenesis at the neuromuscula r junction. The receptor tyrosine kinase MuSK is a component of the ag rin receptor, while the cytoplasmic protein rapsyn is necessary for th e clustering of AChRs and all other postsynaptic membrane components s tudied to date. We show here that MuSK remains concentrated at synapti c sites in rapsyn-deficient mutant mice, suggesting that MuSK forms a primary structural scaffold to which rapsyn attaches other synaptic co mponents. 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 M uSK, but not its ectodomain. Thus, MuSK may interact with rapsyn in mu ltiple ways to play both structural and signaling roles in agrin-induc ed differentiation.