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Gene Review

MUSK  -  muscle, skeletal, receptor tyrosine kinase

Homo sapiens

Synonyms: MuSK, Muscle, skeletal receptor tyrosine-protein kinase, Muscle-specific kinase receptor, Muscle-specific tyrosine-protein kinase receptor
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Disease relevance of MUSK

  • Here, we summarize briefly the genetic and autoimmune disorders that affect neuromuscular transmission, and the identified targets, including new evidence that antibodies to muscle-specific receptor tyrosine kinase (MuSK) are involved in the pathogenesis of acetylcholine receptor (AChR) antibody-negative myasthenia gravis [1].
  • In the present study, rabbits immunized with MuSK ectodomain protein manifested MG-like muscle weakness with a reduction of AChR clustering at the NMJs [2].
  • We expressed MuSK in insect cells by using a baculovirus expression vector and mapped the tyrosines that are phosphorylated in MuSK in an in vitro kinase assay using matrix-assisted laser desorption ionization MS to sequence tryptic peptides fractionated by HPLC [3].
  • We report on a 56-year-old woman with muscle-specific receptor tyrosine kinase (MuSK) antibody-positive myasthenia with predominant bulbar symptoms and respiratory insufficiency [4].
  • Towards the molecular elucidation of congenital myasthenic syndromes: identification of mutations in MuSK [5].

High impact information on MUSK


Chemical compound and disease context of MUSK


Biological context of MUSK

  • We observed CK2-mediated phosphorylation of serine residues within the kinase insert (KI) of MuSK [11].
  • 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 [12].
  • We have assayed anti-MuSK antibodies in 78 patients with SNMG, who have been followed for many years in our Institution. Here we describe the clinical phenotype of the 37 patients whose results were positive on this assay [13].
  • In contrast, the mechanism by which muscle activity regulates MuSK gene expression is not known [14].
  • MuSK glycosylation restrains MuSK activation and acetylcholine receptor clustering [15].

Anatomical context of MUSK

  • MuSK mediates the agrin-induced clustering of AChRs during synapse formation, and is also expressed at the mature neuromuscular junction [7].
  • MuSK is a receptor tyrosine kinase expressed selectively in skeletal muscle and localized to neuromuscular synapses [16].
  • The N-terminal region of agrin binds tightly to basal lamina, while the C-terminal region interacts with a muscle-specific tyrosine kinase (MuSK) to induce the formation of the postsynaptic apparatus [17].
  • Here, we show that rapsyn induces the clustering of the synapse-specific receptor-tyrosine kinase MuSK in transfected QT-6 fibroblasts [18].
  • In addition, we isolated MuSK from Torpedo electric organ and used nanoelectrospray tandem mass spectrometry and parent ion scanning to identify the tyrosine residues that are phosphorylated in activated, endogenous MuSK in vivo [3].

Associations of MUSK with chemical compounds

  • These data suggest that phosphorylation of the MuSK NPXY site leads to recruitment of a phosphotyrosine-binding domain-containing protein that functions to stimulate phosphorylation and clustering of AChRs [16].
  • Neural agrin activated MuSK in vitro if the lactosamine-containing mucin domain was present, and this activation was blocked in large part by Galbeta1,3GalNAc and Galbeta1,4GIcNAc [19].
  • Agrin, a heparin sulfate proteoglycan, is released from the motor nerve terminal to activate its muscle-specific kinase (MuSK) receptor that leads to a second messenger cascade requiring rapsyn to ultimately bring about AChR clustering in the muscle membrane [20].
  • Last, sialylated and nonsialylated variants of N-acetyllactosamine differentially modulated AChR clustering and agrin activity, and these changes correlated with the ability of MuSK, an agrin-stimulated kinase, to bind to these structures [21].
  • Here we show, using mainly one plasma negative for both AChR and MuSK antibodies, that the inhibitory effect of the non-IgG fraction correlates well with the desensitisation caused by 100 microM nicotine, and is found also when AChRs are expressed in a non-muscle cell line (HEK) [22].

Physical interactions of MUSK

  • Our results support a model in which the tetratricopeptide repeat domains of rapsyn bind directly to the cytoplasmic portion of MuSK, which could thereby serve as an initial scaffold for the clustering of acetylcholine receptors [23].

Regulatory relationships of MUSK


Other interactions of MUSK

  • We then review the development of the NMJ, focusing on the important roles of nerve-derived agrin and MuSK in clustering of AChRs and other essential components of the NMJ [1].
  • Activation of these enzymes requires not only the kinase activity of MuSK, but also its interaction with proteins such as Dishevelled [24].
  • In myotubes, laminin-1 rearranged dystroglycans and syntrophins into a laminin-like network, whereas inducing AChR-containing clusters of dystrobrevin, utrophin, and, to a marginal degree, MuSK [25].
  • In addition, we show that clustering cannot be rescued in myogenin-depleted myotubes by simply overexpressing the essential clustering molecules MuSK, rapsyn, and nAChRs [26].

Analytical, diagnostic and therapeutic context of MUSK

  • Many genes crucial to neuromuscular synapse formation, such as MuSK and nAChRs, are induced before muscle innervation or after muscle denervation, and this induction requires expression of the E-box binding, basic helix-loop-helix muscle-specific transcription factor, myogenin (Mgn) [27].
  • Using immunoprecipitation of (125)I-labelled-human MuSK, 27 of 66 (41%) seronegative patients were positive, but 18 ocular SNMG patients, 105 AChR antibody positive MG patients, and 108 controls were negative [28].
  • RESULTS: Anti-MuSK antibody was detected by radioimmunoassay using highly purified MuSK recombinant antigen [29].
  • Antibodies to MuSK and RyR were measured by immunoassays [30].
  • Single-fiber electromyography (SFEMG) of the extensor digitorum communis was abnormal in 90% of MuSK Ab-positive patients [31].


  1. The agrin/muscle-specific kinase pathway: new targets for autoimmune and genetic disorders at the neuromuscular junction. Liyanage, Y., Hoch, W., Beeson, D., Vincent, A. Muscle Nerve (2002) [Pubmed]
  2. Induction of myasthenia by immunization against muscle-specific kinase. Shigemoto, K., Kubo, S., Maruyama, N., Hato, N., Yamada, H., Jie, C., Kobayashi, N., Mominoki, K., Abe, Y., Ueda, N., Matsuda, S. J. Clin. Invest. (2006) [Pubmed]
  3. The in vitro and in vivo phosphotyrosine map of activated MuSK. Watty, A., Neubauer, G., Dreger, M., Zimmer, M., Wilm, M., Burden, S.J. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  4. Successful treatment of MuSK antibody-positive myasthenia gravis with rituximab. Hain, B., Jordan, K., Deschauer, M., Zierz, S. Muscle Nerve (2006) [Pubmed]
  5. Towards the molecular elucidation of congenital myasthenic syndromes: identification of mutations in MuSK. Chevessier, F., Faraut, B., Ravel-Chapuis, A., Richard, P., Gaudon, K., Bauché, S., Prioleau, C., Herbst, R., Goillot, E., Ioos, C., Azulay, J.P., Attarian, S., Leroy, J.P., Fournier, E., Legay, C., Schaeffer, L., Koenig, J., Fardeau, M., Eymard, B., Pouget, J., Hantaï, D. Acta myologica : myopathies and cardiomyopathies : official journal of the Mediterranean Society of Myology / edited by the Gaetano Conte Academy for the study of striated muscle diseases. (2005) [Pubmed]
  6. Alpha3Na+/K+-ATPase is a neuronal receptor for agrin. Hilgenberg, L.G., Su, H., Gu, H., O'Dowd, D.K., Smith, M.A. Cell (2006) [Pubmed]
  7. Auto-antibodies to the receptor tyrosine kinase MuSK in patients with myasthenia gravis without acetylcholine receptor antibodies. Hoch, W., McConville, J., Helms, S., Newsom-Davis, J., Melms, A., Vincent, A. Nat. Med. (2001) [Pubmed]
  8. A C. elegans Ror receptor tyrosine kinase regulates cell motility and asymmetric cell division. Forrester, W.C., Dell, M., Perens, E., Garriga, G. Nature (1999) [Pubmed]
  9. Diseases of the neuromuscular junction. McConville, J., Vincent, A. Current opinion in pharmacology. (2002) [Pubmed]
  10. High-dose cyclophosphamide in refractory myasthenia gravis with MuSK antibodies. Lin, P.T., Martin, B.A., Weinacker, A.B., So, Y.T. Muscle Nerve (2006) [Pubmed]
  11. 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]
  12. 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? Glass, D.J., Apel, E.D., Shah, S., Bowen, D.C., DeChiara, T.M., Stitt, T.N., Sanes, J.R., Yancopoulos, G.D. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  13. Clinical correlates with anti-MuSK antibodies in generalized seronegative myasthenia gravis. Evoli, A., Tonali, P.A., Padua, L., Monaco, M.L., Scuderi, F., Batocchi, A.P., Marino, M., Bartoccioni, E. Brain (2003) [Pubmed]
  14. Characterization of a muscle-specific enhancer in human MuSK promoter reveals the essential role of myogenin in controlling activity-dependent gene regulation. Tang, H., Veldman, M.B., Goldman, D. J. Biol. Chem. (2006) [Pubmed]
  15. MuSK glycosylation restrains MuSK activation and acetylcholine receptor clustering. Watty, A., Burden, S.J. J. Biol. Chem. (2002) [Pubmed]
  16. The juxtamembrane region of MuSK has a critical role in agrin-mediated signaling. Herbst, R., Burden, S.J. EMBO J. (2000) [Pubmed]
  17. Matrix metalloproteinase-3 removes agrin from synaptic basal lamina. VanSaun, M., Werle, M.J. J. Neurobiol. (2000) [Pubmed]
  18. Rapsyn clusters and activates the synapse-specific receptor tyrosine kinase MuSK. Gillespie, S.K., Balasubramanian, S., Fung, E.T., Huganir, R.L. Neuron (1996) [Pubmed]
  19. N-acetyllactosamine and the CT carbohydrate antigen mediate agrin-dependent activation of MuSK and acetylcholine receptor clustering in skeletal muscle. Parkhomovskiy, N., Kammesheidt, A., Martin, P.T. Mol. Cell. Neurosci. (2000) [Pubmed]
  20. The postsynaptic submembrane machinery at the neuromuscular junction: requirement for rapsyn and the utrophin/dystrophin-associated complex. Banks, G.B., Fuhrer, C., Adams, M.E., Froehner, S.C. J. Neurocytol. (2003) [Pubmed]
  21. Modulation of agrin binding and activity by the CT and related carbohydrate antigens. Xia, B., Martin, P.T. Mol. Cell. Neurosci. (2002) [Pubmed]
  22. Inhibition of acetylcholine receptor function by seronegative myasthenia gravis non-IgG factor correlates with desensitisation. Spreadbury, I., Kishore, U., Beeson, D., Vincent, A. J. Neuroimmunol. (2005) [Pubmed]
  23. The tetratricopeptide repeat domains of rapsyn bind directly to cytoplasmic sequences of the muscle-specific kinase. Antolik, C., Catino, D.H., Resneck, W.G., Bloch, R.J. Neuroscience (2006) [Pubmed]
  24. Signaling complexes for postsynaptic differentiation. Luo, Z., Wang, Q., Dobbins, G.C., Levy, S., Xiong, W.C., Mei, L. J. Neurocytol. (2003) [Pubmed]
  25. Laminin-1 redistributes postsynaptic proteins and requires rapsyn, tyrosine phosphorylation, and Src and Fyn to stably cluster acetylcholine receptors. Marangi, P.A., Wieland, S.T., Fuhrer, C. J. Cell Biol. (2002) [Pubmed]
  26. Myogenin-dependent nAChR clustering in aneural myotubes. Macpherson, P.C., Cieslak, D., Goldman, D. Mol. Cell. Neurosci. (2006) [Pubmed]
  27. Activity-dependent gene regulation in skeletal muscle is mediated by a histone deacetylase (HDAC)-Dach2-myogenin signal transduction cascade. Tang, H., Goldman, D. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  28. Detection and characterization of MuSK antibodies in seronegative myasthenia gravis. McConville, J., Farrugia, M.E., Beeson, D., Kishore, U., Metcalfe, R., Newsom-Davis, J., Vincent, A. Ann. Neurol. (2004) [Pubmed]
  29. Anti-MuSK myasthenia gravis presenting with purely ocular findings. Caress, J.B., Hunt, C.H., Batish, S.D. Arch. Neurol. (2005) [Pubmed]
  30. Patterns and severity of neuromuscular transmission failure in seronegative myasthenia gravis. Nemoto, Y., Kuwabara, S., Misawa, S., Kawaguchi, N., Hattori, T., Takamori, M., Vincent, A. J. Neurol. Neurosurg. Psychiatr. (2005) [Pubmed]
  31. Repetitive nerve stimulation of facial muscles in MuSK antibody-positive myasthenia gravis. Oh, S.J., Hatanaka, Y., Hemmi, S., Young, A.M., Scheufele, M.L., Nations, S.P., Lu, L., Claussen, G.C., Wolfe, G.I. Muscle Nerve (2006) [Pubmed]
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