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Distinct domains of MuSK mediate its abilities to induce and to associate with postsynaptic specializations.
- Source :
-
The Journal of cell biology [J Cell Biol] 1999 Sep 06; Vol. 146 (5), pp. 1133-46. - Publication Year :
- 1999
-
Abstract
- Agrin released from motor nerve terminals activates a muscle-specific receptor tyrosine kinase (MuSK) in muscle cells to trigger formation of the skeletal neuromuscular junction. A key step in synaptogenesis is the aggregation of acetylcholine receptors (AChRs) in the postsynaptic membrane, a process that requires the AChR-associated protein, rapsyn. Here, we mapped domains on MuSK necessary for its interactions with agrin and rapsyn. Myotubes from MuSK(-/)- mutant mice form no AChR clusters in response to agrin, but agrin-responsiveness is restored by the introduction of rat MuSK or a Torpedo orthologue. Thus, MuSK(-/)- myotubes provide an assay system for the structure-function analysis of MuSK. Using this system, we found that sequences in or near the first of four extracellular immunoglobulin-like domains in MuSK are required for agrin responsiveness, whereas sequences in or near the fourth immunoglobulin-like domain are required for interaction with rapsyn. Analysis of the cytoplasmic domain revealed that a recognition site for the phosphotyrosine binding domain-containing proteins is essential for MuSK activity, whereas consensus binding sites for the PSD-95/Dlg/ZO-1-like domain-containing proteins and phosphatidylinositol-3-kinase are dispensable. Together, our results indicate that the ectodomain of MuSK mediates both agrin- dependent activation of a complex signal transduction pathway and agrin-independent association of the kinase with other postsynaptic components. These interactions allow MuSK not only to induce a multimolecular AChR-containing complex, but also to localize that complex to a primary scaffold in the postsynaptic membrane.
- Subjects :
- Adenosine Triphosphate metabolism
Animals
Binding Sites
Cell Fusion
Cell Line
Enzyme Activation
Ligands
Mice
Muscle, Skeletal cytology
Muscle, Skeletal enzymology
Mutation
Phosphatidylinositol 3-Kinases metabolism
Phosphotyrosine metabolism
Rats
Receptor Protein-Tyrosine Kinases genetics
Receptor, trkC
Receptors, Nerve Growth Factor genetics
Receptors, Nerve Growth Factor metabolism
Signal Transduction
Synaptic Membranes enzymology
Torpedo
Agrin metabolism
Muscle Proteins metabolism
Receptor Protein-Tyrosine Kinases chemistry
Receptor Protein-Tyrosine Kinases metabolism
Receptors, Cholinergic metabolism
Synaptic Membranes metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0021-9525
- Volume :
- 146
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- The Journal of cell biology
- Publication Type :
- Academic Journal
- Accession number :
- 10477765
- Full Text :
- https://doi.org/10.1083/jcb.146.5.1133