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Sci. Signal., 26 April 2011
Vol. 4, Issue 170, p. ra26
[DOI: 10.1126/scisignal.2001127]

RESEARCH ARTICLES

Thioredoxin Mediates Oxidation-Dependent Phosphorylation of CRMP2 and Growth Cone Collapse

Akifumi Morinaka1, Mayumi Yamada2,3, Rurika Itofusa4, Yosuke Funato1, Yuta Yoshimura1, Fumio Nakamura5, Takeshi Yoshimura6*, Kozo Kaibuchi6, Yoshio Goshima5, Mikio Hoshino2, Hiroyuki Kamiguchi4, and Hiroaki Miki1{dagger}

1 Laboratory of Intracellular Signaling, Institute for Protein Research, Osaka University, 3-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
2 Department of Biochemistry and Cellular Biology, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo 187-8502, Japan.
3 Department of Pathology and Tumor Biology, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto 606-8501, Japan.
4 Laboratory for Neuronal Growth Mechanisms, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
5 Department of Molecular Pharmacology and Neurobiology, Graduate School of Medicine, Yokohama City University, Yokohama, Kanagawa 236-0004, Japan.
6 Department of Cell Pharmacology, Graduate School of Medicine, Nagoya University, 65 Tsurumai, Showa, Nagoya, Aichi 466-8550, Japan.

* Present address: Division of Neurobiology and Bioinformatics, National Institute for Physiological Sciences, Institutes of Natural Sciences, 5-1 Higashiyama, Myodaiji, Okazaki, Aichi 444-8787, Japan.

Abstract: Semaphorin3A (Sema3A) is a repulsive guidance molecule for axons, which acts by inducing growth cone collapse through phosphorylation of CRMP2 (collapsin response mediator protein 2). Here, we show a role for CRMP2 oxidation and thioredoxin (TRX) in the regulation of CRMP2 phosphorylation and growth cone collapse. Sema3A stimulation generated hydrogen peroxide (H2O2) through MICAL (molecule interacting with CasL) and oxidized CRMP2, enabling it to form a disulfide-linked homodimer through cysteine-504. Oxidized CRMP2 then formed a transient disulfide-linked complex with TRX, which stimulated CRMP2 phosphorylation by glycogen synthase kinase–3, leading to growth cone collapse. We also reconstituted oxidation-dependent phosphorylation of CRMP2 in vitro, using a limited set of purified proteins. Our results not only clarify the importance of H2O2 and CRMP2 oxidation in Sema3A-induced growth cone collapse but also indicate an unappreciated role for TRX in linking CRMP2 oxidation to phosphorylation.

{dagger} To whom correspondence should be addressed. E-mail: hmiki{at}protein.osaka-u.ac.jp

Citation: A. Morinaka, M. Yamada, R. Itofusa, Y. Funato, Y. Yoshimura, F. Nakamura, T. Yoshimura, K. Kaibuchi, Y. Goshima, M. Hoshino, H. Kamiguchi, H. Miki, Thioredoxin Mediates Oxidation-Dependent Phosphorylation of CRMP2 and Growth Cone Collapse. Sci. Signal. 4, ra26 (2011).

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