KINASE DOMAIN OF THE MUSCLE-SPECIFIC RECEPTOR TYROSINE KINASE (MUSK) IS SUFFICIENT FOR PHOSPHORYLATION BUT NOT CLUSTERING OF ACETYLCHOLINE-RECEPTORS - REQUIRED ROLE FOR THE MUSK ECTODOMAIN

Formation of the neuromuscular junction (NMJ) depends upon a nerve-der ived protein, agrin, acting by means of a muscle-specific receptor tyr osine kinase, MuSK, as well as a required accessory receptor protein k nown as MASC. We report that MuSK does not merely play a structural ro le by demonstrating that MuSK kinase activity is required for inducing acetylcholine receptor (AChR) clustering, We also show that MuSK is n ecessary, and that MuSK kinase domain activation is sufficient, to med iate a key early event in NMJ formation-phosphorylation of the AChR. H owever, MuSK kinase domain activation and the resulting AChR phosphory lation are not sufficient for AChR clustering; thus we show that the M uSK ectodomain is also required. These results indicate that AChR phos phorylation is not the sole trigger of the clustering process, Moreove r, our results suggest that, unlike the ectodomain of all other recept or tyrosine kinases, the MuSK ectodomain plays a required role in addi tion to simply mediating ligand binding and receptor dimerization, per haps by helping to recruit NMJ components to a MuSK-based scaffold.