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Dab2 stabilizes Axin and attenuates Wnt/β-catenin signaling by preventing protein phosphatase 1 (PP1)–Axin interactions

Oncogene volume 28, pages 2999–3007 (2009)Cite this article

Abstract

Wnt/β-catenin signaling plays a pivotal role in modulating cellular proliferation, differentiation, tissue organization and embryonic development. Earlier, we found that the endocytic adaptor disabled-2 (Dab2) could attenuate Wnt/β-catenin signaling by stabilizing Axin and preventing its translocation to the membrane. Recently, protein phosphatase 1 (PP1) has been shown to interact with, and dephosphorylate Axin, leading to its destabilization. Here, we show that Dab2 functions upstream of PP1 to block the interaction between Axin and PP1, inhibiting Axin dephosphorylation and thereby stabilizing its expression, ultimately leading to inhibition of Wnt/β-catenin. We show that Dab2 acts as a competitive inhibitor of PP1 by binding to the same C-terminal domain of Axin. Both PP1 and Axin bind to the N-terminus of Dab2 and a Dab2 truncation mutant consisting of the N-terminal phosphotyrosine binding domain blocks PP1–Axin interactions and inhibits Wnt signaling. We confirm the inhibitory effect of Dab2 on Wnt/β-catenin signaling in zebrafish embryos, showing that its ectopic expression phenocopies Axin overexpression resulting in altered dorsoventral patterning. We conclude that Dab2 stabilizes Axin and attenuates Wnt/β-catenin signaling by preventing PP1 from binding 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 David Virshup and Dr Sheng-Cai Lin for generous provision of PP1 and Axin reagents. We are also grateful to Drs Sanjay Pimplikar and Ping Song for all their help with the zebrafish studies. This work was supported by Grant CA55536 and CA80095 from the National Cancer Institute to PHH.

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Authors and Affiliations

  1. Department of Cancer Biology NB4, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA

    Y Jiang & P H Howe

  2. Department of Oncological Sciences, Center for Children, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA

    W Luo

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  1. Y Jiang
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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., Luo, W. & Howe, P. Dab2 stabilizes Axin and attenuates Wnt/β-catenin signaling by preventing protein phosphatase 1 (PP1)–Axin interactions. Oncogene 28, 2999–3007 (2009). https://doi.org/10.1038/onc.2009.157

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