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The MuSK Receptor Family

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Book cover Receptor Tyrosine Kinases: Family and Subfamilies

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.

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Abbreviations

ACh:

Acetylcholine

AChR:

Acetylcholine receptor

ALS:

Amyotrophic lateral sclerosis

CNS:

Central nervous system

Lrp4:

Low-density lipoprotein receptor-related protein 4

MG:

Myasthenia gravis

MuSK:

Muscle-specific kinase

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Authors and Affiliations

  1. Molecular Neurobiology Program, Skirball Institute of Biomolecular Medicine, NYU Medical School, 540 First Avenue, New York, NY, 10016, USA

    Steven J. Burden, Wei Zhang & Norihiro Yumoto

  2. Structural Biology Program, Helen L. and Martin S. Kimmel Center for Biology, NYU Medical School, 540 First Avenue, New York, NY, 10016, USA

    Stevan R. Hubbard

Authors
  1. Steven J. Burden
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  2. Stevan R. Hubbard
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  3. Wei Zhang
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  4. Norihiro Yumoto
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Corresponding author

Correspondence to Steven J. Burden .

Editor information

Editors and Affiliations

  1. School of Medicine and Public Health Department of Human Oncology, University of Wisconsin, Madison, Wisconsin, USA

    Deric L. Wheeler

  2. Department of Biological Regulation, Rehovot, Israel

    Yosef Yarden

Receptor at a glance: MuSK

Receptor at a glance: MuSK

Chromosome location

Mouse, chromosome 4, 31.87 cM

Gene size (bp)

Approx. 88–108 kb (depends on source)

Intron/ exon numbers

15/16

mRNA size (5′, ORF, 3′)

3422 (150 nt 5′; 2629 ORF; 593 3′)

Amino acid number

893

Kda

99.7

Posttranslational modifications

N-linked glycosylation

Domains

Ig-like domain, Frizzled-like domain, protein kinase domain

Ligands

Lrp4, Wnts (Wnt11, 4, 9a)

Known dimerizing partners

Lrp4, Dok-7, MuSK

Pathways activated

 

Tissues expressed

Skeletal muscle, brain

Human diseases

Congenital myasthenia, myasthenia gravis

Knockout mouse phenotype

Failure to form neuromuscular synapses

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© 2015 Springer International Publishing Switzerland

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Burden, S.J., Hubbard, S.R., Zhang, W., Yumoto, N. (2015). The MuSK Receptor Family. In: Wheeler, D., Yarden, Y. (eds) Receptor Tyrosine Kinases: Family and Subfamilies. Springer, Cham. https://doi.org/10.1007/978-3-319-11888-8_9

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