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-derived protein, agrin, acting by means of a muscle-specific receptor tyrosine kinase, MuSK, as well as a required accessory receptor protein known as MASC. We report that MuSK does not merely play a structural role by demonstrating...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 1997-08, Vol.94 (16), p.8848-8853
Main Authors: Glass, David J., Apel, Elizabeth D., Shah, Sonal, Bowen, David C., DeChiara, Thomas M., Stitt, Trevor N., Sanes, Joshua R., Yancopoulos, George D.
Format: Article
Language:English
Subjects:
Agrin - metabolism
Animals
Antibodies
Biochemistry
Biological Sciences
Cell Line
Chimeras
Cholinergic receptors
Enzymes
Fibroblasts
Humans
Ligands
Muscle fibers
Muscle, Skeletal - metabolism
Muscular system
Neurology
Neurons
Phosphorylation
Rats
Receptor Aggregation
Receptor Protein-Tyrosine Kinases - genetics
Receptor Protein-Tyrosine Kinases - metabolism
Receptors
Receptors, Cholinergic - metabolism
Recombinant Fusion Proteins - metabolism
Scaffolds
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Summary:Formation of the neuromuscular junction (NMJ) depends upon a nerve-derived protein, agrin, acting by means of a muscle-specific receptor tyrosine kinase, MuSK, as well as a required accessory receptor protein known as MASC. We report that MuSK does not merely play a structural role by demonstrating that MuSK kinase activity is required for inducing acetylcholine receptor (AChR) clustering. We also show that MuSK is necessary, and that MuSK kinase domain activation is sufficient, to mediate a key early event in NMJ formation--phosphorylation of the AChR. However, MuSK kinase domain activation and the resulting AChR phosphorylation are not sufficient for AChR clustering; thus we show that the MuSK ectodomain is also required. These results indicate that AChR phosphorylation is not the sole trigger of the clustering process. Moreover, our results suggest that, unlike the ectodomain of all other receptor tyrosine kinases, the MuSK ectodomain plays a required role in addition to simply mediating ligand binding and receptor dimerization, perhaps by helping to recruit NMJ components to a MuSK-based scaffold.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.94.16.8848