Nature Cell Biology 8, 501 - 508 (2006)
Published online: 2 April 2006; | doi:10.1038/ncb1405
The thioredoxin-related redox-regulating protein nucleoredoxin inhibits Wnt– -catenin signalling through DishevelledYosuke Funato1, 2, Tatsuo Michiue3, Makoto Asashima3, 4
& Hiroaki Miki1, 51
Division of Cancer Genomics, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan. 2
Division of Biochemistry, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan. 3
Department of Life Sciences (Biology), Graduate School of Arts and Sciences, University of Tokyo, 3-8-1, Komaba, Meguro-ku, Tokyo 153-8902, Japan. 4
ICORP, Japan Science and Technology Agency (JST), 3-8-1, Komaba, Meguro-ku, Tokyo 153-8902, Japan. 5
PRESTO, JST, 4-1-8 Honcho, Kawaguchi-shi, Saitama 332-0012, Japan.
Correspondence should be addressed to Hiroaki Miki miki@ims.u-tokyo.ac.jp Wnt -cateninTCFLEFnucleoredoxinRasproteinsDvl1c-MycCyclin D1sFRP-1Dishevelled (Dvl) transduces signals from the Wnt receptor, Frizzled, to downstream components, leading to the stabilization of -catenin and subsequent activation of the transcription factor T cell factor (TCF) and/or lymphoid enchancer factor (LEF)1,
2,
3. However, the mechanism of Dvl action remains unclear. Here, we report that nucleoredoxin (NRX)4, a thioredoxin (TRX) family protein, interacts with Dvl. Overexpression of NRX selectively suppresses the Wnt–-catenin pathway and ablation of NRX by RNA-interference (RNAi) results in activation of TCF, accelerated cell proliferation and enhancement of oncogenicity through cooperation with mitogen-activated extracellular signal regulated kinase kinase (MEK) or Ras. We find that cells respond to H2O2 stimulation by activating TCF. Redox-dependent activation of the Wnt–-catenin pathway occurs independently of extracellular Wnts and is impaired by RNAi of NRX . In addition, association between Dvl and NRX is inhibited by H2O2 treatment. These data suggest a relationship between the Wnt–-catenin pathway and redox signalling through redox-sensitive association of NRX with Dvl.
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