Association of muscle-specific kinase MuSK with the acetylcholine receptor in mammalian muscle

Abstract

During synaptogenesis at the neuromuscular junction, a neurally released factor, agrin, causes the clustering of acetylcholine receptors (AChRs) in the muscle membrane beneath the nerve terminal. Agrin acts through a specific receptor which is thought to have a receptor tyrosine kinase, MuSK, as one of its components. In agrin‐treated muscle cells, both MuSK and the AChR become tyrosine phosphorylated. To determine how the activation of MuSK leads to AChR clustering, we have investigated their interaction in cultured C2 myotubes. Immunoprecipitation experiments showed that MuSK is associated with the AChR and that this association is increased by agrin treatment. Agrin also caused a transient activation of the AChR‐associated MuSK, as demonstrated by MuSK phosphorylation. In agrin‐treated myotubes, MuSK phosphorylation increased with the same time course as phosphorylation of the β subunit of the AChR, but declined more quickly. Although both herbimycin and staurosporine blocked agrin‐induced AChR phosphorylation, only herbimycin inhibited the phosphorylation of MuSK. These results suggest that although agrin increases the amount of activated MuSK that is associated with the AChR, MuSK is not directly responsible for AChR phosphorylation but acts through other kinases.

Rapsyn carboxyl terminal domains mediate muscle specific kinase–induced phosphorylation of the muscle acetylcholine receptor

“…Potentially, protein interactions underlying localization could be regulated via posttranslational modifications of the AChR, rapsyn, or additional binding proteins. Consistent with the first possibility, agrin/MuSK signaling induces rapid tyrosine phosphorylation of the AChR β and δ subunits , Mohamed et al, 2001, mediated by an intervening cytoplasmic tyrosine kinase (Fuhrer et al, 1997), perhaps of the src and/or abl families Swope, 1999, Finn et al, 2003). Phosphorylation correlates closely with reduced mobility and detergent extractability of the AChR (Meier et al., 1995, Borges andFerns, 2001), suggesting that it regulates linkage to the cytoskeleton.…”

“…MuSK-induced phosphorylation of the AChR β and δ subunits involves an intervening cytoplasmic tyrosine kinase (Fuhrer et al, 1997), whose activity and/or localization appears to be rapsyn-dependent Swope, 1999, Mittaud et al, 2001). Indeed, agrininduced phosphorylation of the AChR is significantly decreased in rapsyn null myotubes (Apel et al, 1997) and rapsyn activates cytoplasmic kinases in heterologous cells (Qu et al, 1996, Mohamed andSwope, 1999).…”

Spatio‐temporally regulated expression of receptor tyrosine kinases, mRor1, mRor2, during mouse development: implications in development and function of the nervous system

“…It has been shown that MuSK is a critical component of the functional receptor for agrin (Glass & Yancopoulos 1997). Although MuSK itself fails to bind agrin directly, the kinase activity and the extracellular domain of MuSK are required for both the phosphorylation and cluster formation of the acetylcholine receptor (Fuhrer et al 1997;Glass & Yancopoulos 1997). Thus, it is also possible that the Ror-family RTKs are also components of functional receptors for particular ligands.…”

Sperm Epidermal Growth Factor Receptor (EGFR) Mediates α7 Acetylcholine Receptor (AChR) Activation to Promote Fertilization

“…Several proteins are associated with nAChR, including rapsyn, which mediates the association of the receptor to the cytoskeleton (18 -20). Protein tyrosine phosphorylation mediates the cytoskeletal anchoring of the receptor (21,22), and SFK are involved in this phosphorylation (23). Inhibition of Src increases the response of the receptor, and vice versa, when Src is highly activated the receptor activity is inhibited (24).…”