Thioredoxin mediates oxidation-dependent phosphorylation of CRMP2 and growth cone collapse

Akifumi Morinaka, Mayumi Yamada, Rurika Itofusa, Yosuke Funato, Yuta Yoshimura, Fumio Nakamura, Takeshi Yoshimura, Kozo Kaibuchi, Yoshio Goshima, Mikio Hoshino, Hiroyuki Kamiguchi, Hiroaki Miki

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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 (H 2O2) 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.

Original languageEnglish
Article numberra26
JournalScience Signaling
Volume4
Issue number170
DOIs
Publication statusPublished - 26-04-2011

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Morinaka, A., Yamada, M., Itofusa, R., Funato, Y., Yoshimura, Y., Nakamura, F., Yoshimura, T., Kaibuchi, K., Goshima, Y., Hoshino, M., Kamiguchi, H., & Miki, H. (2011). Thioredoxin mediates oxidation-dependent phosphorylation of CRMP2 and growth cone collapse. Science Signaling, 4(170), [ra26]. https://doi.org/10.1126/scisignal.2001127