Disease relevance of Musk

• In humans, MuSK maps to chromosome 9q31.3-32, which overlaps with the region reported to contain the Fukuyama muscular dystrophy mutation [1].
• Similarly to AChR, MuSK and several of its partners are the target of mutations responsible for diseases of the NMJ, such as congenital myasthenic syndromes [2].
• Moreover, they show that MuSK is also required for the maintenance of the NMJ, offering a mechanistic explanation for the myasthenia gravis caused by auto-antibodies to MuSK [3].
• To test whether MuSK complexes form stop signals in the absence of myotube signaling, we cultured ciliary ganglion (CG) neurons with nonmuscle cells expressing cell-surface MuSK [4].
• We have searched for modulators of MuSK function using a library of human single chain variable region antibodies (scFv) that can be displayed on M13 phage or expressed as soluble protein [5].

High impact information on Musk

• Here we demonstrate that agrin acts via a receptor complex that includes MuSK as well as a myotube-specific accessory component [6].
• MuSK is a receptor tyrosine kinase localized to the motor endplate, seemingly well positioned to receive a key nerve-derived signal [6].
• We have generated mice with a targeted disruption of the gene encoding MuSK, a receptor tyrosine kinase selectively localized to the postsynaptic muscle surface [7].
• The receptor tyrosine kinase MuSK is required for neuromuscular junction formation in vivo [7].
• We observed CK2-mediated phosphorylation of serine residues within the kinase insert (KI) of MuSK [8].

Chemical compound and disease context of Musk

• Myasthenia gravis can be induced in mice by injecting the extracellular domain of rat muscle-specific kinase (MuSK), a transmembrane receptor tyrosine kinase involved in agrin signaling at the neuromuscular junction [9].

Biological context of Musk

• We produced mice that express a chimeric receptor, containing the juxtamembrane region of Musk and the kinase domain of TrkA, selectively in muscle, and we crossed this transgene into Musk mutant mice [10].
• In addition to rapsyn's structural role, we demonstrate that it is required for an early step in MuSK signaling, AChR phosphorylation [11].
• Distinct phenotypes of mutant mice lacking agrin, MuSK, or rapsyn [12].
• Several lines of evidence suggest that agrin and MuSK stimulate synapse-specific transcription indirectly by regulating the distribution of other cell surface ligands, which stimulate a pathway for synapse-specific gene expression [13].
• We report here that in muscle cells, MuSK interacts with Dishevelled (Dvl), a signaling molecule important for planar cell polarity [14].

Anatomical context of Musk

• Mice lacking either agrin or MuSK have recently been generated and exhibit similarly profound defects in their neuromuscular junctions [6].
• In C2 myotubes, agrin induced tyrosine phosphorylation of these kinases, of AChR-bound MuSK, and of the AChR beta and delta subunits, as observed in phosphotyrosine immunoblotting experiments [15].
• Conversely, in situ activation of MuSK in cultured Xenopus embryonic muscle cells, either focally by anti-MuSK antibody-coated beads or globally by agrin, stimulated downstream tyrosine phosphatases, which could be blocked by pervanadate treatment [16].
• Agrin acts by activating the muscle-specific kinase MuSK and inducing coaggregation of the 43-kDa protein rapsyn with AChRs on muscle cell membrane [17].
• Here we identify a receptor tyrosine kinase (RTK) specific to skeletal muscle, which we term "MuSK" for muscle-specific kinase [1].

Associations of Musk with chemical compounds

• Mice lacking Musk, a muscle-specific receptor tyrosine kinase that is activated by agrin, fail to form neuromuscular synapses and consequently die at birth because of their failure to move or breathe [10].
• These results show that the juxtamembrane region of Musk, including a single phosphotyrosine docking site, even in the context of a different kinase domain, is sufficient to activate the multiple pathways leading to presynaptic and postsynaptic differentiation in vivo [10].
• Tyrosine phosphatase regulation of MuSK-dependent acetylcholine receptor clustering [16].
• We report that inhibition of tyrosine phosphatases in cultured C2 mouse myotubes using pervanadate enhanced MuSK auto-activation and agrin-independent AChR clustering [16].
• Cross-linking and immunoprecipitation experiments in Torpedo postsynaptic membranes together with transfection experiments with muscle-specific kinase (MuSK) constructs in MuSK-deficient myotubes or COS-7 cells provide the first evidence that ColQ binds MuSK [18].

Physical interactions of Musk

• Interestingly, CREB mutants unable to bind to DNA also inhibit MuSK promoter activity, suggesting a CRE-independent inhibitory mechanism [19].

Enzymatic interactions of Musk

• The receptor tyrosine kinase, MuSK, is required for the formation of the neuromuscular junction (NMJ) where MuSK becomes phosphorylated when exposed to neuronally synthesized isoforms of agrin [20].
• In addition, Src and Fyn phosphorylated MuSK [21].

Co-localisations of Musk

• These two proteins are also coordinately regulated on the surfaces of cultured myotubes where MuSK and AChRs colocalize both in spontaneous and agrin-induced clusters [20].

Regulatory relationships of Musk

• Much evidence suggests that the nerve-derived protein agrin activates muscle-specific kinase (MuSK) to cluster AChRs through the synapse-specific cytoplasmic protein rapsyn [22].
• These results imply that rapsyn and signaling components activated by MuSK kinase may be dispensable for some early aspects of postsynaptic differentiation [23].
• Ectopic Musk expression stimulates synapse formation in the absence of Agrin and rescues the lethality of Agrn mutant mice, demonstrating that the postsynaptic cell, and MuSK in particular, has a potent role in regulating the formation of synapses [24].

Other interactions of Musk

• Agrin acts via a MuSK receptor complex [6].
• During neuromuscular synaptogenesis, neurally released agrin induces aggregation and tyrosine phosphorylation of acetylcholine receptors (AChRs) by acting through both the receptor tyrosine kinase MuSK (muscle-specific kinase) and the AChR-associated protein, rapsyn [15].
• Our results suggest that muscle tyrosine phosphatases tightly regulate MuSK activation and signaling and support a novel role of Shp2 in MuSK-dependent AChR clustering [16].
• These data indicate that Nrg-1 is dispensable for clustering AChRs and activating AChR genes in subsynaptic nuclei during development and suggest that these aspects of postsynaptic differentiation are dependent on Agrin/MuSK signaling without a requirement for a secondary signal [13].
• Suppression of CREB expression by small interfering RNA increases MuSK promoter activity [19].

Analytical, diagnostic and therapeutic context of Musk

• Strikingly, MuSK expression is dramatically induced throughout the adult myofiber after denervation, block of electrical activity, or physical immobilization [1].
• Extrajunctional MuSK is first apparent 3 days after denervation and is sharply reduced upon reinnervation [20].
• Immunofluorescence data indicated that MDK4 protein production begins with myoblasts elongation and is maintained throughout myotube formation [25].
• An evaluation of genotoxicity tests with Musk ketone [26].
• Here we investigated the effects of MuSK antibodies or Dex on MURF-1 expression in C2C12 cultures and in mouse muscles after treatment in vivo, using quantitative Western blotting [27].

References