LRP4 serves as a coreceptor of Agrin
Open accessAbstract
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.
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At the neuromuscular junction, Lrp4, APP, and MuSK form a complex that prepatterns the muscle.
“at the NMJ, Lrp4, APP and muscle-specific kinase (MuSK) form a complex to prepattern the muscle [88–90]”
From ApoE, ApoE Receptors, and the Synapse in Alzheimer's Disease (2017) · cites this paper as [90]
Agrin released from motor neurons signals through APP, MuSK, and Lrp4 to recruit nicotinic acetylcholine receptors.
“Agrin is released from the motor neuron and signals through APP, MuSK and Lrp4 to recruit nicotinic acetylcholine receptors (AChRs).”
From ApoE, ApoE Receptors, and the Synapse in Alzheimer's Disease (2017) · cites this paper as [90]
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Lrp4 domains differentially regulate limb/brain development and synaptic plasticity
Pohlkamp, T., Durakoglugil, M., Lane-Donovan, C., Xian, X., Johnson, E. B., Hammer, R. E., & Herz, J. (2015) · PLOS ONE · doi:10.1371/journal.pone.0116701 · Cited by 28 · see citing works
- Authors
- Zhang, B., Luo, S., Wang, Q., Suzuki, T., Xiong, W. C., & Mei, L.
- Affiliations
- Augusta University (US)
- Shinshu University (JP)
- Corresponding author
- Mei, Lin
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2008-10
- Volume
- 60
- Issue
- 2
- Pages
- 285-297
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC2743173
- OpenAlex
- W1991623532
- Cited by
- 525
- References
- 86
- Citations by year
- 2026: 12 · 2025: 27 · 2024: 24 · 2023: 20 · 2022: 27 · 2021: 24 · 2020: 40 · 2019: 27 · 2018: 26 · 2017: 23 · 2016: 32 · 2015: 23 · 2014: 30 · 2013: 46 · 2012: 46
- FWCI
- 13.32
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 1781 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- Muscular Dystrophy Association
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Health Sciences › Medicine › Neurology › Myasthenia Gravis and Thymoma
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
- Keywords
- LRP4, agrin, musk, neuromuscular junction formation, co-receptors, low density lipoprotein receptor-related protein, tyrosine phosphorylation, acetylcholine receptor clustering, myotubes, muscular dystrophy, autoimmunization
- MeSH terms
- Animals, Cell Line, Humans, Motor Neurons, Synaptic Transmission, Neuromuscular Junction, Phosphorylation, Protein Binding, Receptor Aggregation, Receptors, Cholinergic, Receptors, LDL, Synaptic Membranes, Tyrosine, Signal Transduction, Presynaptic Terminals, Agrin, Muscle Fibers, Skeletal, Receptor Protein-Tyrosine Kinases, LDL-Receptor Related Proteins, Mice
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