PT  - JOURNAL ARTICLE
AU  - Dan Zhu
AU  - Zhihua Yang
AU  - Zhenge Luo
AU  - Shiwen Luo
AU  - Wen C. Xiong
AU  - Lin Mei
TI  - Muscle-Specific Receptor Tyrosine Kinase Endocytosis in Acetylcholine Receptor Clustering in Response to Agrin
AID  - 10.1523/JNEUROSCI.4130-07.2008
DP  - 2008 Feb 13
TA  - The Journal of Neuroscience
PG  - 1688--1696
VI  - 28
IP  - 7
4099  - http://www.jneurosci.org/content/28/7/1688.short
4100  - http://www.jneurosci.org/content/28/7/1688.full
SO  - J. Neurosci.2008 Feb 13; 28
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.