The thioredoxin-related redox-regulating protein nucleoredoxin inhibits Wnt-beta-catenin signalling through dishevelled.
Dishevelled (Dvl) transduces signals from the Wnt receptor, Frizzled, to downstream components, leading to the stabilization of beta-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-beta-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 H(2)O(2) stimulation by activating TCF. Redox-dependent activation of the Wnt-beta-catenin pathway occurs independently of extracellular Wnts and is impaired by RNAi of NRX . In addition, association between Dvl and NRX is inhibited by H(2)O(2) treatment. These data suggest a relationship between the Wnt-beta-catenin pathway and redox signalling through redox-sensitive association of NRX with Dvl.
Funato
Yosuke
Y
Division of Cancer Genomics, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
Michiue
Tatsuo
T
Asashima
Makoto
M
Miki
Hiroaki
H
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D019556:COS Cells; D049109:Cell Proliferation; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D017077:Culture Media, Conditioned; D000072261:Dishevelled Proteins; D004625:Embryo, Nonmammalian / Q000166:cytology / Q000196:embryology; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D051379:Mice; D041681:NIH 3T3 Cells; D009687:Nuclear Proteins / Q000378:metabolism*; D010084:Oxidation-Reduction; D010088:Oxidoreductases / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism*; D011485:Protein Binding; D034622:RNA Interference; D015398:Signal Transduction; D051820:TCF Transcription Factors / Q000378:metabolism; D013879:Thioredoxins / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects; D051153:Wnt Proteins / Q000037:antagonists & inhibitors*; D014981:Xenopus; D029867:Xenopus Proteins; D051176:beta Catenin / Q000037:antagonists & inhibitors*
D048868:Adaptor Proteins, Signal Transducing; D017077:Culture Media, Conditioned; C000606586:DVL1 protein, Xenopus; D000072261:Dishevelled Proteins; D009687:Nuclear Proteins; D010750:Phosphoproteins; D051820:TCF Transcription Factors; D051153:Wnt Proteins; D029867:Xenopus Proteins; D051176:beta Catenin; D013879:Thioredoxins; D006861:Hydrogen Peroxide; D010088:Oxidoreductases; C105231:nucleoredoxin