LRP4 serves as a coreceptor of agrin.

Full Abstract

Neuromuscular junction (NMJ) formation requires agrin, a factor released from motoneurons, and MuSK, a transmembrane tyrosine kinase that is activated by agrin. However, how signal is transduced from agrin to MuSK remains unclear. We report that LRP4, a low-density lipoprotein receptor (LDLR)-related protein, is expressed specifically in myotubes and binds to neuronal agrin. Its expression enables agrin binding and MuSK signaling in cells that otherwise do not respond to agrin. Suppression of LRP4 expression in muscle cells attenuates agrin binding, agrin-induced MuSK tyrosine phosphorylation, and AChR clustering. LRP4 also forms a complex with MuSK in a manner that is stimulated by agrin. Finally, we showed that LRP4 becomes tyrosine-phosphorylated in agrin-stimulated muscle cells. These observations indicate that LRP4 is a coreceptor of agrin that is necessary for MuSK signaling and AChR clustering and identify a potential target protein whose mutation and/or autoimmunization may cause muscular dystrophies.

Author information

Author/s: Zhang, Bin (B); Luo, Shiwen (S); Wang, Qiang (Q); Suzuki, Tatsuo (T); Xiong, Wen C (WC); Mei, Lin (L);

Affiliation: Program of Developmental Neurobiology, Institute of Molecular Medicine and Genetics, Department of Neurology, Medical College of Georgia, Augusta, GA 30912, USA.

Journal and publication information

Publication Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't

Journal: Neuron (Neuron), published in United States. (Language: eng)

Reference: 2008-Oct; vol 60 (issue 2) : pp 285-97

Dates: Created 2008/10/29; Completed 2008/11/26; Revised 2009/10/26;

PMID: 18957220, status: MEDLINE (last retrieval date: 10/27/2009, IMS Date: )

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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MeSH headings (categories)

This article was linked to the MESH Headings shown below.

Agrin - genetics; metabolism
Animals
Cell Line
Humans
Mice
Motor Neurons - metabolism; ultrastructure
Muscle Fibers, Skeletal - metabolism; ultrastructure
Neuromuscular Junction - embryology; genetics; metabolism
Phosphorylation
Presynaptic Terminals - metabolism; ultrastructure

Presynaptic Terminals - metabolism; ultrastructure
Protein Binding - physiology
Receptor Aggregation - genetics
Receptor Protein-Tyrosine Kinases - genetics; metabolism
Receptors, Cholinergic - genetics; metabolism; ultrastructure
Receptors, LDL - genetics; metabolism
Signal Transduction - genetics
Synaptic Membranes - genetics; metabolism; ultrastructure
Synaptic Transmission - genetics
Tyrosine - metabolism

Associated Chemicals: Agrin (0) ; Lrp4 protein, mouse (0) ; Receptors, Cholinergic (0) ; Receptors, LDL (0) ; Tyrosine (55520-40-6) ; Receptor Protein-Tyrosine Kinases (EC 2.7.1.112) ; MuSK protein, mouse (EC 2.7.10.1)

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