MuSK protein explained

muscle, skeletal, receptor tyrosine kinase
Hgncid:	7525
Symbol:	MUSK
Entrezgene:	4593
Omim:	601296
Refseq:	NM_005592
Uniprot:	O15146
Chromosome:	9
Arm:	q
Band:	31.3
Locussupplementarydata:	-q32

MuSK (for Muscle-Specific Kinase)^[1] is a receptor tyrosine kinase required for the formation and maintenance of the neuromuscular junction.^[2] It is activated by a nerve-derived proteoglycan called agrin,^[3] which is similarly also required for neuromuscular junction formation.^[4]

MuSK signaling

Upon activation by its ligand agrin,^[5] MuSK signals via the proteins called casein kinase 2 (CK2),^[6] Dok-7^[7] and rapsyn, to induce "clustering" of acetylcholine receptors (AChR). Both CK2 and Dok-7 are required for MuSK-induced formation of the neuromuscular junction, since mice lacking Dok-7 failed to form AChR clusters or neuromuscular synapses, and since downregulation of CK2 also impedes recruitment of AChR to the primary MuSK scaffold. In addition to the proteins mentioned, other proteins are then gathered, to form the endplate to the neuromuscular junction. The nerve terminates onto the endplate, forming the neuromuscular junction - a structure required to transmit nerve impulses to the muscle, and thus initiating muscle contraction.

Role in disease

Antibodies directed against this protein (Anti-MuSK autoantibodies) are found in some people with myasthenia gravis not demonstrating antibodies to the acetylcholine receptor.^[8] The disease still causes loss of acetylcholine receptor activity,^[9] but the symptoms affected people experience may differ from those of people with other causes of myasthenia gravis.

Notes and References

1. Valenzuela DM, Stitt TN, DiStefano PS, Rojas E, Mattsson K, Compton DL, Nunez L, Park JS, Stark JL, Gies DR, Thomas S, LeBeau MM, Fernald AA, Copeland NG, Jenkins NA, Burden SJ, Glass DJ, Yancopoulos GD . Receptor tyrosine kinase specific for the skeletal muscle lineage: expression in embryonic muscle, at the neuromuscular junction, and after injury . Neuron . 15 . 3 . 573–584 . Sep 1995 . 7546737 . 10.1016/0896-6273(95)90146-9 . 17575761 . free .
2. DeChiara TM, Bowen DC, Valenzuela DM, Simmons MV, Poueymirou WT, Thomas S, Kinetz E, Compton DL, Rojas E, Park JS, Smith C, DiStefano PS, Glass DJ, Burden SJ, Yancopoulos GD . The receptor tyrosine kinase MuSK is required for neuromuscular junction formation in vivo . Cell . 85 . 4 . 501–512 . May 1996 . 8653786 . 10.1016/s0092-8674(00)81251-9 . 17455481 . free .
3. Glass DJ, Bowen DC, Stitt TN, Radziejewski C, Bruno J, Ryan TE, Gies DR, Shah S, Mattson K, Burden SJ, DiStefano PS, Valenzuela DM, DeChiara TM, Yancopoulos GD . Agrin acts via a MuSK receptor complex . Cell . 85 . 4 . 513–523 . May 1996 . 8653787 . 10.1016/s0092-8674(00)81252-0 . 14930468 . free .
4. Gautam M, Noakes PG, Moscoso L, Rupp F, Scheller RH, Merlie JP, Sanes JR . Defective neuromuscular synaptogenesis in agrin-deficient mutant mice . Cell . 85 . 4 . 525–535 . May 1996 . 8653788 . 10.1016/s0092-8674(00)81253-2 . 12517490 . free .
5. Glass DJ, Bowen DC, Stitt TN, Radziejewski C, Bruno J, Ryan TE, Gies DR, Shah S, Mattson K, Burden SJ, DiStefano PS, Valenzuela DM, DeChiara TM, Yancopoulos GD . Agrin acts via a MuSK receptor complex . Cell . 85 . 4 . 513–523 . May 1996 . 8653787 . 10.1016/s0092-8674(00)81252-0 . 14930468 . free .
6. Cheusova T, Khan MA, Schubert SW, Gavin AC, Buchou T, Jacob G, Sticht H, Allende J, Boldyreff B, Brenner HR, Hashemolhosseini S . Casein kinase 2-dependent serine phosphorylation of MuSK regulates acetylcholine receptor aggregation at the neuromuscular junction . Genes & Development . 20 . 13 . 1800–16 . Jul 2006 . 16818610 . 1522076 . 10.1101/gad.375206 .
7. Okada K, Inoue A, Okada M, Murata Y, Kakuta S, Jigami T, Kubo S, Shiraishi H, Eguchi K, Motomura M, Akiyama T, Iwakura Y, Higuchi O, Yamanashi Y . The muscle protein Dok-7 is essential for neuromuscular synaptogenesis . Science . 312 . 5781 . 1802–5 . Jun 2006 . 16794080 . 10.1126/science.1127142 . 2006Sci...312.1802O . 45730054 .
8. Hoch W, McConville J, Helms S, Newsom-Davis J, Melms A, Vincent A . Auto-antibodies to the receptor tyrosine kinase MuSK in patients with myasthenia gravis without acetylcholine receptor antibodies . Nature Medicine . 7 . 3 . 365–8 . Mar 2001 . 11231638 . 10.1038/85520 . 18641849 .
9. Barrett-Jolley R, Byrne N, Vincent A, Newsom-Davis J . Plasma from patients with seronegative myasthenia gravis inhibit nAChR responses in the TE671/RD cell line . Pflügers Archiv . 428 . 5–6 . 492–8 . Oct 1994 . 7838671 . 10.1007/BF00374570 . 5611563 .