The MuSK receptor family

Abstract

MuSK is a receptor tyrosine kinase that plays an essential role in the formation and maintenance of neuromuscular synapses. MuSK is not a muscle-specific kinase, however, as the name implies, since MuSK is expressed in the brain, transiently in the liver, and in additional tissues. MuSK function has been largely studied at the neuromuscular synapse. Neural Agrin, supplied by motor neurons, indirectly stimulates MuSK by binding to Lrp4, a member of the low-density lipoprotein receptor family, promoting formation of an Lrp4/MuSK complex and stimulating MuSK tyrosine phosphorylation. Once tyrosine phosphorylated, MuSK stimulates a pathway for anchoring key proteins in the postsynaptic membrane and a separate pathway for transcribing “synaptic” genes in nearby nuclei. Activated MuSK is also responsible for clustering Lrp4, which functions as a muscle-derived retrograde signal for presynaptic differentiation. MuSK is a type I transmembrane protein, related to ROR kinases, with an extracellular region that is composed of three Ig-like domains and a Frizzled-like domain. One face of the first Ig-like domain has a critical role in MuSK dimerization, whereas the opposing face of this Ig-like domain is essential for association of MuSK with Lrp4. The Frizzled-like domain can bind Wnt proteins, but the role of Wnt-MuSK signaling is poorly understood. Dok-7 is recruited to tyrosine-phosphorylated MuSK and acts both as an inside-out ligand to stabilize and enhance MuSK phosphorylation and as an adapter for downstream signaling. Mutations in Agrin, Lrp4, MuSK, and Dok-7 cause congenital myasthenia, and autoantibodies to Lrp4, MuSK, and Agrin cause myasthenia gravis.