TY - JOUR
T1 - Muscle-specific receptor tyrosine kinase endocytosis in acetylcholine receptor clustering in response to agrin
AU - Zhu, Dan
AU - Yang, Zhihua
AU - Luo, Zhenge
AU - Luo, Shiwen
AU - Xiong, Wen C.
AU - Mei, Lin
PY - 2008/2/13
Y1 - 2008/2/13
N2 - 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.
AB - 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.
KW - Agrin
KW - Endocytosis
KW - MuSK
KW - NSF
KW - Neuromuscular junction
KW - Nicotinic acetylcholine receptors
UR - http://www.scopus.com/inward/record.url?scp=39549114805&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=39549114805&partnerID=8YFLogxK
U2 - 10.1523/JNEUROSCI.4130-07.2008
DO - 10.1523/JNEUROSCI.4130-07.2008
M3 - Article
C2 - 18272689
AN - SCOPUS:39549114805
SN - 0270-6474
VL - 28
SP - 1688
EP - 1696
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 7
ER -