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

Abstract

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.

The disruption of the rod-derived cone viability gene leads to photoreceptor dysfunction and susceptibility to oxidative stress

“…26 We also observed a gene dose-dependent reduction of two regulators of the Wnt pathway: Btrc and Porcupine (Porcn), a pathway related to that of nucleoredoxin, the distant homolog of Nxnl1. 31 Finally, the Srpk2, Cugbp2, Son and Donson involved in alternative splicing, support the interesting possibility that RdCVF and/or RdCVFL are able to regulate their own relative expression by controlling the expression of specific splicing factors.…”

Redox-based regulation of signal transduction: Principles, pitfalls, and promises

“…Upon oxidation of reactive cysteines of Nrx1, its association with Dishevelled is lost which promotes stabilization of β-catenin and subsequent activation of the transcription factor T cell factor (TCF). In support of the redox dependence of the DishevelledNrx1 interaction, exposure to H 2 O 2 also resulted in disruption of the complex, leading to subsequent accumulation of β-catenin and activation of TCF [186]. It is worthwhile to mention that these conclusions were reached based upon mutagenesis experiments that encompassed mutations of cysteines 205 and 208 of Nrx, and that direct evidence for oxidation of those sites was not provided.…”

A genome-wide association study implicates diacylglycerol kinase eta (DGKH) and several other genes in the etiology of bipolar disorder

“…32 The phosphatidylinositol and Wnt pathways, which connect via protein kinase C (PKC), have been hypothesized to play an important role in the mechanism of action of mood-stabilizing medications. 33 These results illustrate how a genome-wide association study can highlight the potential etiologic importance of specific components of even wellunderstood pathways.…”