The thioredoxin-related redox-regulating protein nucleoredoxin inhibits Wnt-β-catenin signalling through Dishevelled

• Published in: Nature cell biology Vol. 8; no. 5; pp. 501 - 508
• Main Authors: Miki, Hiroaki, Funato, Yosuke, Michiue, Tatsuo, Asashima, Makoto
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01.05.2006
• Subjects: Adaptor Proteins, Signal Transducing - metabolism; Animals; beta Catenin - antagonists & inhibitors; Cell Proliferation; Cells, Cultured; Cellular signal transduction; Cercopithecus aethiops; COS Cells; Culture Media, Conditioned; Dishevelled Proteins; DNA binding proteins; Embryo, Nonmammalian - cytology; Embryo, Nonmammalian - embryology; Genetic aspects; Humans; Hydrogen Peroxide - pharmacology; Mice; NIH 3T3 Cells; Nuclear Proteins - metabolism; Oxidation-Reduction; Oxidoreductases - metabolism; Phosphoproteins - metabolism; Physiological aspects; Protein Binding; RNA Interference; Signal Transduction; TCF Transcription Factors - metabolism; Thioredoxin; Thioredoxins - metabolism; Transcriptional Activation - drug effects; Wnt Proteins - antagonists & inhibitors; Xenopus; Xenopus Proteins
• ISSN: 1465-7392; 1476-4679; 1476-4679
• DOI: 10.1038/ncb1405

Dishevelled (Dvl) transduces signals from the Wnt receptor, Frizzled, to downstream components, leading to the stabilization of β-catenin and subsequent activation of the transcription factor T cell factor (TCF) and/or lymphoid enchancer factor (LEF). However, the mechanism of Dvl action remains unclear. Here, we report that nucleoredoxin (NRX), a thioredoxin (TRX) family protein, interacts with Dvl. Overexpression of NRX selectively suppresses the Wnt-β-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-β-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-β-catenin pathway and redox signalling through redox-sensitive association of NRX with Dvl.