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Dok-7 activates the muscle receptor kinase MuSK and shapes synapse formation

Science Signaling 2: ra7, 2009
Akane Inoue1, Kiyoko Setoguchi2, Yosuke Matsubara2, Kumiko Okada2, Nozomi Sato3, Yoichiro Iwakura3, Osamu Higuchi1, Yuji Yamanashi1.
1Division of Genetics, Department of Cancer Biology, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan. 2Department of Cell Regulation, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 113-8510, Japan. 3Division of Cell Biology, Center for Experimental Medicine, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan.

The formation of the neuromuscular junction (NMJ) is orchestrated by the muscle-specific receptor tyrosine kinase MuSK and by neural Agrin, an extracellular activator of MuSK. We previously showed that the MuSK-interacting protein Dok-7 is essential for neuromuscular synaptogenesis, although the mechanisms by which Dok-7 regulates MuSK activity and promotes synapse formation have been unclear. Here, we show that Dok-7 directly interacts with the cytoplasmic portion of MuSK and activates the receptor tyrosine kinase, and that neural Agrin requires Dok-7 to activate MuSK. In vivo overexpression of Dok-7 increased MuSK activation and promoted NMJ formation. Furthermore, Dok-7 was required for the localization of MuSK in the central region of muscle, which is essential for the correct formation of NMJs in this region. These observations indicate that Dok-7 positively regulates neuromuscular synaptogenesis by controlling MuSK activity, its distribution, and its responsiveness to neural Agrin.