The Function of Cortactin in the Clustering of Acetylcholine Receptors at the Vertebrate Neuromuscular Junction

Hdl Handle:
http://hdl.handle.net/10675.2/574
Title:
The Function of Cortactin in the Clustering of Acetylcholine Receptors at the Vertebrate Neuromuscular Junction
Authors:
Madhavan, Raghavan; Gong, Zhuolin L.; Ma, Jin Jin; Chan, Ariel W. S.; Peng, H. Benjamin
Abstract:
Background: Postsynaptic enrichment of acetylcholine receptors (AChRs) at the vertebrate neuromuscular junction (NMJ) depends on the activation of the muscle receptor tyrosine MuSK by neural agrin. Agrin-stimulation of MuSK is known to initiate an intracellular signaling cascade that leads to the clustering of AChRs in an actin polymerization-dependent manner, but the molecular steps which link MuSK activation to AChR aggregation remain incompletely defined.; Methodology/Principal Findings: In this study we used biochemical, cell biological and molecular assays to investigate a possible role in AChR clustering of cortactin, a protein which is a tyrosine kinase substrate and a regulator of F-actin assembly and which has also been previously localized at AChR clustering sites. We report that cortactin was co-enriched at AChR clusters in situ with its target the Arp2/3 complex, which is a key stimulator of actin polymerization in cells. Cortactin was further preferentially tyrosine phosphorylated at AChR clustering sites and treatment of myotubes with agrin significantly enhanced the tyrosine phosphorylation of cortactin. Importantly, forced expression in myotubes of a tyrosine phosphorylation-defective cortactin mutant (but not wild-type cortactin) suppressed agrin-dependent AChR clustering, as did the reduction of endogenous cortactin levels using RNA interference, and introduction of the mutant cortactin into muscle cells potently inhibited synaptic AChR aggregation in response to innervation.; Conclusion: Our results suggest a novel function of phosphorylation-dependent cortactin signaling downstream from agrin/MuSK in facilitating AChR clustering at the developing NMJ.
Editors:
Mei, Lin
Citation:
PLoS One. 2009 Dec 29; 4(12):e8478
Issue Date:
29-Dec-2009
URI:
http://hdl.handle.net/10675.2/574
DOI:
10.1371/journal.pone.0008478
PubMed ID:
20041195
PubMed Central ID:
PMC2793544
Type:
Article
ISSN:
1932-6203
Appears in Collections:
Department of Neurology: Faculty Research and Presentations

Full metadata record

DC FieldValue Language
dc.contributor.authorMadhavan, Raghavanen_US
dc.contributor.authorGong, Zhuolin L.en_US
dc.contributor.authorMa, Jin Jinen_US
dc.contributor.authorChan, Ariel W. S.en_US
dc.contributor.authorPeng, H. Benjaminen_US
dc.contributor.editorMei, Lin-
dc.date.accessioned2012-10-26T16:26:46Z-
dc.date.available2012-10-26T16:26:46Z-
dc.date.issued2009-12-29en_US
dc.identifier.citationPLoS One. 2009 Dec 29; 4(12):e8478en_US
dc.identifier.issn1932-6203en_US
dc.identifier.pmid20041195en_US
dc.identifier.doi10.1371/journal.pone.0008478en_US
dc.identifier.urihttp://hdl.handle.net/10675.2/574-
dc.description.abstractBackground: Postsynaptic enrichment of acetylcholine receptors (AChRs) at the vertebrate neuromuscular junction (NMJ) depends on the activation of the muscle receptor tyrosine MuSK by neural agrin. Agrin-stimulation of MuSK is known to initiate an intracellular signaling cascade that leads to the clustering of AChRs in an actin polymerization-dependent manner, but the molecular steps which link MuSK activation to AChR aggregation remain incompletely defined.en_US
dc.description.abstractMethodology/Principal Findings: In this study we used biochemical, cell biological and molecular assays to investigate a possible role in AChR clustering of cortactin, a protein which is a tyrosine kinase substrate and a regulator of F-actin assembly and which has also been previously localized at AChR clustering sites. We report that cortactin was co-enriched at AChR clusters in situ with its target the Arp2/3 complex, which is a key stimulator of actin polymerization in cells. Cortactin was further preferentially tyrosine phosphorylated at AChR clustering sites and treatment of myotubes with agrin significantly enhanced the tyrosine phosphorylation of cortactin. Importantly, forced expression in myotubes of a tyrosine phosphorylation-defective cortactin mutant (but not wild-type cortactin) suppressed agrin-dependent AChR clustering, as did the reduction of endogenous cortactin levels using RNA interference, and introduction of the mutant cortactin into muscle cells potently inhibited synaptic AChR aggregation in response to innervation.en_US
dc.description.abstractConclusion: Our results suggest a novel function of phosphorylation-dependent cortactin signaling downstream from agrin/MuSK in facilitating AChR clustering at the developing NMJ.en_US
dc.rightsMadhavan et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.en_US
dc.subjectResearch Articleen_US
dc.subjectCell Biology/Cell Signalingen_US
dc.subjectCell Biology/Cytoskeletonen_US
dc.subjectCell Biology/Neuronal Signaling Mechanismsen_US
dc.subjectNeuroscience/Neurodevelopmenten_US
dc.subjectNeuroscience/Neuronal Signaling Mechanismsen_US
dc.titleThe Function of Cortactin in the Clustering of Acetylcholine Receptors at the Vertebrate Neuromuscular Junctionen_US
dc.typeArticleen_US
dc.identifier.pmcidPMC2793544en_US
dc.contributor.corporatenameDepartment of Neurology-

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