title: Muscle-specific receptor tyrosine kinase endocytosis in acetylcholine receptor clustering in response to agrin.
abstract: Agrin, a factor used by motoneurons to direct acetylcholine receptor (AChR) clustering at the neuromuscular junction, initiates signal transduction by activating the muscle-specific receptor tyrosine kinase (MuSK). However, the underlying mechanisms remain poorly defined. Here, we demonstrated that MuSK became rapidly internalized in response to agrin, which appeared to be required for induced AChR clustering. Moreover, we provided evidence for a role of N-ethylmaleimide sensitive factor (NSF) in regulating MuSK endocytosis and subsequent signaling in response to agrin stimulation. NSF interacts directly with MuSK with nanomolar affinity, and treatment of muscle cells with the NSF inhibitor N-ethylmaleimide, mutation of NSF, or suppression of NSF expression all inhibited agrin-induced AChR clustering. Furthermore, suppression of NSF expression and NSF mutation attenuate MuSK downstream signaling. Our study reveals a potentially novel mechanism that regulates agrin/MuSK signaling cascade.
authors.affiliation: Program of Developmental Neurobiology, Institute of Molecular Medicine and Genetics, Medical College of Georgia, Augusta, Georgia 30912, USA.
authors.forename: Dan
authors.initials: D
authors.lastname: Zhu
authors.forename: Zhihua
authors.initials: Z
authors.lastname: Yang
authors.forename: Zhenge
authors.initials: Z
authors.lastname: Luo
authors.forename: Shiwen
authors.initials: S
authors.lastname: Luo
authors.forename: Wen C
authors.initials: WC
authors.lastname: Xiong
authors.forename: Lin
authors.initials: L
authors.lastname: Mei
mesh_terms: D018171:Agrin / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D004705:Endocytosis / Q000502:physiology; D051379:Mice; D009154:Mutation; D052066:N-Ethylmaleimide-Sensitive Proteins / Q000235:genetics / Q000378:metabolism; D009469:Neuromuscular Junction / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D011950:Receptors, Cholinergic / Q000502:physiology*; D015398:Signal Transduction
chemical_list: D018171:Agrin; D011950:Receptors, Cholinergic; C511695:MuSK protein, mouse; D020794:Receptor Protein-Tyrosine Kinases; D052066:N-Ethylmaleimide-Sensitive Proteins