Critical Scaffolding Regions of the Tumor Suppressor Axin1 Are Natively Unfolded

Noutsou, Maria; Duarte, Afonso M.S.; Anvarian, Zeinab; Didenko, Tatiana; Minde, David-Paul; Kuper, Ineke; Ridder, I De; Oikonomou, Christina; Friedler, Assaf; Boelens, Rolf; Rüdiger, Stefan; Maurice, Madelon M.

doi:10.1016/j.jmb.2010.11.013

Cited by 53 publications

(64 citation statements)

References 68 publications

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“…We mapped the region of interaction between NRF2 and Axin1 to the exon 6 of Axin1. This is a critical scaffolding segment of Axin1, termed the central region, that enables Axin1 to interact with several proteins, including transcription factors b-Catenin, MYC, Smad3, and p53 as well as protein kinases GSK-3b, CK1, MKK1, and MKK4, among others (36). This region is natively unfolded, and it has been suggested to undergo a sort of ''induced fit'' to accommodate specific groups of proteins.…”

Section: Discussionmentioning

confidence: 99%

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WNT-3A Regulates an Axin1/NRF2 Complex That Regulates Antioxidant Metabolism in Hepatocytes

Rada

Rojo

Offergeld

et al. 2015

Antioxidants & Redox Signaling

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Aims: Nuclear factor (erythroid-derived 2)-like 2 (NRF2) is a master regulator of oxidant and xenobiotic metabolism, but it is unknown how it is regulated to provide basal expression of this defense system. Here, we studied the putative connection between NRF2 and the canonical WNT pathway, which modulates hepatocyte metabolism. Results: WNT-3A increased the levels of NRF2 and its transcriptional signature in mouse hepatocytes and HEK293T cells. The use of short interfering RNAs in hepatocytes and mouse embryonic fibroblasts which are deficient in the redox sensor Kelch-like ECH-associated protein 1 (KEAP1) indicated that WNT-3A activates NRF2 in a b-Catenin-and KEAP1-independent manner. WNT-3A stabilized NRF2 by preventing its GSK-3-dependent phosphorylation and subsequent SCF/b-TrCP-dependent ubiquitination and proteasomal degradation. Axin1 and NRF2 were physically associated in a protein complex that was regulated by WNT-3A, involving the central region of Axin1 and the Neh4/Neh5 domains of NRF2. Axin1 knockdown increased NRF2 protein levels, while Axin1 stabilization with Tankyrase inhibitors blocked WNT/NRF2 signaling. The relevance of this novel pathway was assessed in mice with a conditional deletion of Axin1 in the liver, which showed upregulation of the NRF2 signature in hepatocytes and disruption of liver zonation of antioxidant metabolism. Innovation: NRF2 takes part in a protein complex with Axin1 that is regulated by the canonical WNT pathway. This new WNT-NRF2 axis controls the antioxidant metabolism of hepatocytes. Conclusion: These results uncover the participation of NRF2 in a WNT-regulated signalosome that participates in basal maintenance of hepatic antioxidant metabolism. Antioxid. Redox Signal. 22, 555-571.

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Section: Discussionmentioning

confidence: 99%

“…Axin1 is an essential element of the WNT signalosome that scaffolds specific kinases and substrates together (36). To study the possible connection between NRF2 and Axin1, first we knocked down the expression of Axin1 in Keap1 -/ -MEFs.…”

Section: Axin1 Is Involved In the Regulation Of Nrf2mentioning

confidence: 99%

WNT-3A Regulates an Axin1/NRF2 Complex That Regulates Antioxidant Metabolism in Hepatocytes

Rada

Rojo

Offergeld

et al. 2015

Antioxidants & Redox Signaling

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“…Alanine substitutions were generated by site-directed mutagenesis. Flag-or His-Dvl1 constructs were PCR-subcloned into pcDNA3 or a modified pET-24a(+) vector (Novagen), as described previously (48). For immunoblotting and immunofluorescence, mouse antiFlag (M2; Sigma), mouse anti-actin (C4; MP Biomedicals), mouse anti-V5 (Invitrogen), or rabbit anti-V5 (Sigma) was used.…”

Section: Methodsmentioning

confidence: 99%

Wnt/β-catenin signaling requires interaction of the Dishevelled DEP domain and C terminus with a discontinuous motif in Frizzled

Tauriello

Jordens

Kirchner

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

191

218

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Wnt binding to members of the seven-span transmembrane Frizzled (Fz) receptor family controls essential cell fate decisions and tissue polarity during development and in adulthood. The Fzmediated membrane recruitment of the cytoplasmic effector Dishevelled (Dvl) is a critical step in Wnt/β-catenin signaling initiation, but how Fz and Dvl act together to drive downstream signaling events remains largely undefined. Here, we use an Fz peptide-based microarray to uncover a mechanistically important role of the bipartite Dvl DEP domain and C terminal region (DEP-C) in binding a three-segmented discontinuous motif in Fz. We show that cooperative use of two conserved motifs in the third intracellular loop and the classic C-terminal motif of Fz is required for DEP-C binding and Wnt-induced β-catenin activation in cultured cells and Xenopus embryos. Within the complex, the Dvl DEP domain mainly binds the Fz C-terminal tail, whereas a short region at the Dvl C-terminal end is required to bind the Fz third loop and stabilize the Fz-Dvl interaction. We conclude that Dvl DEP-C binding to Fz is a key event in Wnt-mediated signaling relay to β-catenin. The discontinuous nature of the Fz-Dvl interface may allow for precise regulation of the interaction in the control of Wnt-dependent cellular responses.peptide microarray | protein-protein interaction | Wingless signaling

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“…Axin is a largely unstructured, flexible protein (Spink et al 2000;Noutsou et al 2011) that contains CK1, GSK-3, and b-catenin-binding sites ( Fig. 2) (Ikeda et al 1998;Yamamoto et al 1999;Rubinfeld et al 2001;Liu et al 2002).…”

Section: Axin the Central Phosphorylation Scaffoldmentioning

confidence: 99%

The -Catenin Destruction Complex

Stamos

Weis

2012

Cold Spring Harbor Perspectives in Biology

871

783

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The Wnt/b-catenin pathway is highly regulated to insure the correct temporal and spatial activation of its target genes. In the absence of a Wnt stimulus, the transcriptional coactivator b-catenin is degraded by a multiprotein "destruction complex" that includes the tumor suppressors Axin and adenomatous polyposis coli (APC), the Ser/Thr kinases GSK-3 and CK1, protein phosphatase 2A (PP2A), and the E3-ubiquitin ligase b-TrCP. The complex generates a b-TrCP recognition site by phosphorylation of a conserved Ser/Thr-rich sequence near the b-catenin amino terminus, a process that requires scaffolding of the kinases and bcatenin by Axin. Ubiquitinated b-catenin is degraded by the proteasome. The molecular mechanisms that underlie several aspects of destruction complex function are poorly understood, particularly the role of APC. Here we review the molecular mechanisms of destruction complex function and discuss several potential roles of APC in b-catenin destruction.

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Critical Scaffolding Regions of the Tumor Suppressor Axin1 Are Natively Unfolded

Cited by 53 publications

References 68 publications

WNT-3A Regulates an Axin1/NRF2 Complex That Regulates Antioxidant Metabolism in Hepatocytes

WNT-3A Regulates an Axin1/NRF2 Complex That Regulates Antioxidant Metabolism in Hepatocytes

Wnt/β-catenin signaling requires interaction of the Dishevelled DEP domain and C terminus with a discontinuous motif in Frizzled

The -Catenin Destruction Complex

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