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The inhibitory effects of Disabled-2 (Dab2) on Wnt signaling are mediated through Axin

Oncogene volume 27, pages 1865–1875 (2008)Cite this article

Abstract

β-Catenin-mediated Wnt signaling is essential in embryonic development and in adult tissues. Recent studies have demonstrated that Axin not only plays an important inhibitory role in coordinating β-catenin degradation, but is itself degraded by the low-density-lipoprotein receptor-related protein (LRP)5/6 Wnt co-receptor. Here, we demonstrate that the endocytic adaptor molecule Disabled-2 (Dab2), which we have previously demonstrated to act as an inhibitor of β-catenin signaling, interacts with Axin and prevents its interaction with and degradation by the LRP5 co-receptor, thereby increasing its half-life and stabilization. Dab2 levels induced during retinoic acid-induced differentiation of F9, or during transforming growth factor-β-induced epithelial–mesenchymal transdifferentiation of mouse mammary epithelial cells result in the stabilization of Axin and concomitant inhibition of β-catenin signaling. Ectopic expression of Dab2 in F9 cells as well as in transformed cell lines results in increased Axin expression and attenuation of Wnt-mediated signaling. We conclude that Dab2 may play an important role in the maintenance of the differentiated state and restrain Wnt-mediated proliferation through its association with and modulation of Axin.

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Acknowledgements

We thank Dr S Takada for the generous provision of control Wnt-3A-producing mouse L-cells and Drs Furuhashi, Wu, Zeng and He for generous provision of the Myc–Axin, Flag-tagged LRP5 plasmids and LRP5/6 antibody, respectively. We also thank Dr Gary Wildey for helpful discussion and also thank Dr S Ledbetter at Genzyme Inc. for generous provision of TGFβ This work was supported by Grants CA55536 and CA80095 from the National Cancer Institute to PHH.

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Authors and Affiliations

  1. Department of Cell Biology, The Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA

    Y Jiang & P H Howe

  2. INSERM U673, Hopital St-Antoine, Paris, France

    C Prunier

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  1. Y Jiang
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  3. P H Howe
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Correspondence to P H Howe.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Jiang, Y., Prunier, C. & Howe, P. The inhibitory effects of Disabled-2 (Dab2) on Wnt signaling are mediated through Axin. Oncogene 27, 1865–1875 (2008). https://doi.org/10.1038/sj.onc.1210829

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