Muscle-specific receptor tyrosine kinase endocytosis in acetylcholine receptor clustering in response to agrin.
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.
Zhu
Dan
D
Program of Developmental Neurobiology, Institute of Molecular Medicine and Genetics, Medical College of Georgia, Augusta, Georgia 30912, USA.
Yang
Zhihua
Z
Luo
Zhenge
Z
Luo
Shiwen
S
Xiong
Wen C
WC
Mei
Lin
L
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
D018171:Agrin; D011950:Receptors, Cholinergic; C511695:MuSK protein, mouse; D020794:Receptor Protein-Tyrosine Kinases; D052066:N-Ethylmaleimide-Sensitive Proteins