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Musk  -  muscle, skeletal, receptor tyrosine kinase

Mus musculus

Synonyms: MDK4, Mdk4, Mlk, MuSK, Muscle, skeletal receptor tyrosine-protein kinase, ...
 
 
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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

 

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

 

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

 

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

References

  1. Receptor tyrosine kinase specific for the skeletal muscle lineage: expression in embryonic muscle, at the neuromuscular junction, and after injury. Valenzuela, D.M., Stitt, T.N., DiStefano, P.S., Rojas, E., Mattsson, K., Compton, D.L., Nuñez, L., Park, J.S., Stark, J.L., Gies, D.R. Neuron (1995) [Pubmed]
  2. The synaptic muscle-specific kinase (MuSK) complex: new partners, new functions. Strochlic, L., Cartaud, A., Cartaud, J. Bioessays (2005) [Pubmed]
  3. Inhibition of synapse assembly in mammalian muscle in vivo by RNA interference. Kong, X.C., Barzaghi, P., Ruegg, M.A. EMBO Rep. (2004) [Pubmed]
  4. Motor neurite outgrowth is selectively inhibited by cell surface MuSK and agrin. Dimitropoulou, A., Bixby, J.L. Mol. Cell. Neurosci. (2005) [Pubmed]
  5. Direct demonstration of MuSK involvement in acetylcholine receptor clustering through identification of agonist ScFv. Xie, M.H., Yuan, J., Adams, C., Gurney, A. Nat. Biotechnol. (1997) [Pubmed]
  6. Agrin acts via a MuSK receptor complex. Glass, D.J., Bowen, D.C., Stitt, T.N., Radziejewski, C., Bruno, J., Ryan, T.E., Gies, D.R., Shah, S., Mattsson, K., Burden, S.J., DiStefano, P.S., Valenzuela, D.M., DeChiara, T.M., Yancopoulos, G.D. Cell (1996) [Pubmed]
  7. The receptor tyrosine kinase MuSK is required for neuromuscular junction formation in vivo. DeChiara, T.M., Bowen, D.C., Valenzuela, D.M., Simmons, M.V., Poueymirou, W.T., Thomas, S., Kinetz, E., Compton, D.L., Rojas, E., Park, J.S., Smith, C., DiStefano, P.S., Glass, D.J., Burden, S.J., Yancopoulos, G.D. Cell (1996) [Pubmed]
  8. Casein kinase 2-dependent serine phosphorylation of MuSK regulates acetylcholine receptor aggregation at the neuromuscular junction. Cheusova, T., Khan, M.A., Schubert, S.W., Gavin, A.C., Buchou, T., Jacob, G., Sticht, H., Allende, J., Boldyreff, B., Brenner, H.R., Hashemolhosseini, S. Genes Dev. (2006) [Pubmed]
  9. Delayed synapsing muscles are more severely affected in an experimental model of MuSK-induced myasthenia gravis. Xu, K., Jha, S., Hoch, W., Dryer, S.E. Neuroscience (2006) [Pubmed]
  10. Restoration of synapse formation in Musk mutant mice expressing a Musk/Trk chimeric receptor. Herbst, R., Avetisova, E., Burden, S.J. Development (2002) [Pubmed]
  11. Rapsyn is required for MuSK signaling and recruits synaptic components to a MuSK-containing scaffold. Apel, E.D., Glass, D.J., Moscoso, L.M., Yancopoulos, G.D., Sanes, J.R. Neuron (1997) [Pubmed]
  12. Distinct phenotypes of mutant mice lacking agrin, MuSK, or rapsyn. Gautam, M., DeChiara, T.M., Glass, D.J., Yancopoulos, G.D., Sanes, J.R. Brain Res. Dev. Brain Res. (1999) [Pubmed]
  13. Neuromuscular synapse formation in mice lacking motor neuron- and skeletal muscle-derived Neuregulin-1. Jaworski, A., Burden, S.J. J. Neurosci. (2006) [Pubmed]
  14. Regulation of AChR clustering by Dishevelled interacting with MuSK and PAK1. Luo, Z.G., Wang, Q., Zhou, J.Z., Wang, J., Luo, Z., Liu, M., He, X., Wynshaw-Boris, A., Xiong, W.C., Lu, B., Mei, L. Neuron (2002) [Pubmed]
  15. Agrin-induced activation of acetylcholine receptor-bound Src family kinases requires Rapsyn and correlates with acetylcholine receptor clustering. Mittaud, P., Marangi, P.A., Erb-Vögtli, S., Fuhrer, C. J. Biol. Chem. (2001) [Pubmed]
  16. Tyrosine phosphatase regulation of MuSK-dependent acetylcholine receptor clustering. Madhavan, R., Zhao, X.T., Ruegg, M.A., Peng, H.B. Mol. Cell. Neurosci. (2005) [Pubmed]
  17. Regulation of acetylcholine receptor clustering by the tumor suppressor APC. Wang, J., Jing, Z., Zhang, L., Zhou, G., Braun, J., Yao, Y., Wang, Z.Z. Nat. Neurosci. (2003) [Pubmed]
  18. MuSK is required for anchoring acetylcholinesterase at the neuromuscular junction. Cartaud, A., Strochlic, L., Guerra, M., Blanchard, B., Lambergeon, M., Krejci, E., Cartaud, J., Legay, C. J. Cell Biol. (2004) [Pubmed]
  19. Inhibition of MuSK expression by CREB interacting with a CRE-like element and MyoD. Kim, C.H., Xiong, W.C., Mei, L. Mol. Cell. Biol. (2005) [Pubmed]
  20. Localization and regulation of MuSK at the neuromuscular junction. Bowen, D.C., Park, J.S., Bodine, S., Stark, J.L., Valenzuela, D.M., Stitt, T.N., Yancopoulos, G.D., Lindsay, R.M., Glass, D.J., DiStefano, P.S. Dev. Biol. (1998) [Pubmed]
  21. Src-class kinases act within the agrin/MuSK pathway to regulate acetylcholine receptor phosphorylation, cytoskeletal anchoring, and clustering. Mohamed, A.S., Rivas-Plata, K.A., Kraas, J.R., Saleh, S.M., Swope, S.L. J. Neurosci. (2001) [Pubmed]
  22. Distinct roles of nerve and muscle in postsynaptic differentiation of the neuromuscular synapse. Lin, W., Burgess, R.W., Dominguez, B., Pfaff, S.L., Sanes, J.R., Lee, K.F. Nature (2001) [Pubmed]
  23. Kinase- and rapsyn-independent activities of the muscle-specific kinase (MuSK). Bromann, P.A., Zhou, H., Sanes, J.R. Neuroscience (2004) [Pubmed]
  24. MuSK controls where motor axons grow and form synapses. Kim, N., Burden, S.J. Nat. Neurosci. (2008) [Pubmed]
  25. Exclusive expression of the receptor tyrosine kinase MDK4 in skeletal muscle and the decidua. Besser, J., Zahalka, M.A., Ullrich, A. Mech. Dev. (1996) [Pubmed]
  26. An evaluation of genotoxicity tests with Musk ketone. Api, A.M., Pfitzer, E.A., San, R.H. Food Chem. Toxicol. (1996) [Pubmed]
  27. MuSK antibody positive myasthenia gravis plasma modifies MURF-1 expression in C2C12 cultures and mouse muscle in vivo. Benveniste, O., Jacobson, L., Farrugia, M.E., Clover, L., Vincent, A. J. Neuroimmunol. (2005) [Pubmed]
 
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