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Sci. Signal., 24 February 2009
Vol. 2, Issue 59, p. ra7
[DOI: 10.1126/scisignal.2000113]

RESEARCH

Dok-7 Activates the Muscle Receptor Kinase MuSK and Shapes Synapse Formation

Akane Inoue1*, Kiyoko Setoguchi2*, Yosuke Matsubara2, Kumiko Okada2, Nozomi Sato3, Yoichiro Iwakura3, Osamu Higuchi1, and Yuji Yamanashi1{dagger}

1 Division of Genetics and Department of Cancer Biology, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan.
2 Department of Cell Regulation, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.
3 Division of Cell Biology, Center for Experimental Medicine, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan.

* These authors contributed equally to this work.

Abstract: 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.

{dagger} To whom correspondence should be addressed. E-mail: yyamanas{at}ims.u-tokyo.ac.jp

Citation: A. Inoue, K. Setoguchi, Y. Matsubara, K. Okada, N. Sato, Y. Iwakura, O. Higuchi, Y. Yamanashi, Dok-7 Activates the Muscle Receptor Kinase MuSK and Shapes Synapse Formation. Sci. Signal. 2, ra7 (2009).

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