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Sci. Signal., 25 September 2012
Vol. 5, Issue 243, p. ra69
[DOI: 10.1126/scisignal.2002802]

RESEARCH ARTICLES

Phosphorylation of Cytohesin-1 by Fyn Is Required for Initiation of Myelination and the Extent of Myelination During Development

Junji Yamauchi1,2,3,4*, Yuki Miyamoto1, Tomohiro Torii1, Shou Takashima1, Kazumi Kondo5, Katsumasa Kawahara3, Noriko Nemoto6, Jonah R. Chan7, Gozoh Tsujimoto8, and Akito Tanoue1

1 Department of Pharmacology, National Research Institute for Child Health and Development, Setagaya, Tokyo 157-8535, Japan.
2 Department of Biological Sciences, Tokyo Institute of Technology, Midori, Yokohama 226-8501, Japan.
3 Department of Physiology, Kitasato University School of Medicine, Sagamihara, Kanagawa 252-0374, Japan.
4 The Japan Human Health Sciences Foundation, Chuo, Tokyo 103-0001, Japan.
5 Otsuka Pharmaceutical Co. Ltd., Kawauchi, Tokushima 771-0192, Japan.
6 Bioimaging Research Center, Kitasato University School of Medicine, Sagamihara, Kanagawa 252-0374, Japan.
7 Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA.
8 Department of Pharmacogenomics, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo, Kyoto 606-8501, Japan.

Abstract: Schwann cells respond to cues from axons by transforming their cellular morphology and forming myelin. We demonstrated that the guanine nucleotide exchange factor (GEF) cytohesin-1 promoted myelination by activating the small guanosine triphosphatase (GTPase) Arf6. In mice, ablating cytohesin-1 delayed myelination and diminished the amount of myelin produced. We determined that the Src-family kinase Fyn phosphorylated tyrosine 382 (Y382) of cytohesin-1, and we generated transgenic mice that expressed a Schwann cell–specific phosphorylation mutant of cytohesin-1 (Y382F) that could not be targeted by Fyn. During development, these transgenic mice displayed delayed myelination compared to that of wild-type mice, as well as a decrease in the amount of myelin produced, similar to that observed in cytohesin-1–/– mice. These findings demonstrate that phosphorylation of cytohesin-1 by Fyn is required for full myelination and suggest that tyrosine phosphorylation of GEFs may be a mechanism to activate small GTPases engaged in cell morphogenesis.

* To whom correspondence should be addressed. E-mail: jyamauchi{at}nch.go.jp

Citation: J. Yamauchi, Y. Miyamoto, T. Torii, S. Takashima, K. Kondo, K. Kawahara, N. Nemoto, J. R. Chan, G. Tsujimoto, A. Tanoue, Phosphorylation of Cytohesin-1 by Fyn Is Required for Initiation of Myelination and the Extent of Myelination During Development. Sci. Signal. 5, ra69 (2012).

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