|muscle, skeletal, receptor tyrosine kinase|
|Locus||Chr. 9 q31.3-q32|
MuSK is required for formation of the Neuromuscular Junction
During development, the growing end of motor neuron axons secrete a protein called agrin. This protein binds to several receptors on the surface of skeletal muscle. The receptor that seems to be required for formation of the neuromuscular junction (NMJ), which comprises the nerve-muscle synapse, is called MuSK (Muscle-specific kinase). MuSK is a receptor tyrosine kinase - meaning that it induces cellular signaling by causing the addition of phosphate molecules to particular tyrosines on itself, and on proteins that bind the cytoplasmic domain of the receptor.
The requirement for MuSK in the formation of the NMJ was demonstrated primarily by mouse ("knockout") studies. In mice that are deficient for either agrin or MuSK, the neuromuscular junction does not form. Many other proteins also comprise the NMJ, and are required to maintain its integrity. For example, MuSK also binds a protein called "downstream-of-tyrosine-kinase-7" (Dok-7). Dok-7's PTB domain binds phosphorylated MuSK, which acts to stabilize active MuSK or alternatively enhance MuSK's own kinase activity.
Upon activation by its ligand agrin, MuSK signals via the proteins called Casein kinase 2 (CK2), Dok-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.
MuSK's role in disease
Antibodies directed against this protein, either Anti-MuSK autoantibodies or anti-AChR, are found in those patients with myasthenia gravis not demonstrating antibodies to the acetylcholine receptor (sero-negative). The disease still appears to result in an autoimmune loss of acetylcholine receptor activity, but the phenotype of these patients appears to be different from those of many other myasthenic patients: more likely women, less eye involvement, more likely to have weakness of neck and oropharynx, and more likely to be African-American in ethnicity.
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