MuSk function during health and disease.

ABSTRACT

The receptor tyrosine kinase MuSK (muscle-specific kinase) is the key signaling molecule during the formation of a mature and functional neuromuscular junction (NMJ). Signal transduction events downstream of MuSK activation induce both pre- and postsynaptic differentiation, which, most prominently, includes the clustering of acetylcholine receptors (AChRs) at synaptic sites. MuSK activation requires a complex interplay between its co-receptor Lrp4 (low-density lipoprotein receptor-related protein-4), the motor neuron-derived heparan-sulfate proteoglycan Agrin and the intracellular adaptor protein Dok-7. A tight regulation of MuSK kinase activity is crucial for proper NMJ development. Defects in MuSK signaling are the cause of muscle weakness as reported in congenital myasthenic syndromes and myasthenia gravis. This review focuses on recent structure-based analyses of MuSK, Agrin, Lrp4 and Dok-7 interactions and their function during MuSK activation. Conclusions about the regulation of the MuSK kinase that were derived from molecular structures will be highlighted. In addition, the role of MuSK during development and disease will be discussed.