Abstract

The stability of the Wnt pathway transcription factor β-catenin is tightly regulated by the multi-subunit destruction complex. Deregulated Wnt pathway activity has been implicated in many cancers, making this pathway an attractive target for anticancer therapies. However, the development of targeted Wnt pathway inhibitors has been hampered by the limited number of pathway components that are amenable to small molecule inhibition. Here, we used a chemical genetic screen to identify a small molecule, XAV939, which selectively inhibits β-catenin-mediated transcription. XAV939 stimulates β-catenin degradation by stabilizing axin, the concentration-limiting component of the destruction complex. Using a quantitative chemical proteomic approach, we discovered that XAV939 stabilizes axin by inhibiting the poly-ADP-ribosylating enzymes tankyrase 1 and tankyrase 2. Both tankyrase isoforms interact with a highly conserved domain of axin and stimulate its degradation through the ubiquitin-proteasome pathway. Thus, our study provides new mechanistic insights into the regulation of axin protein homeostasis and presents new avenues for targeted Wnt pathway therapies.

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Acknowledgements

We thank D. Patel, F. Harbinski, J. Leighton-Davies, R. de Beaumont, X. Xiang, K. Bean, C. Xin, S. Zhao, B. Zhang and M. Xu for technical assistance, G. Wussler, H. Urquiza and W. Dai for zebrafish maintenance, and I. Cornella Taracido, S. Cleaver, A. Hernandez and Y. Ben-Neriah for comments and advice. In addition we are indebted to B. Kuster, J. Rick, M. Raida and A. Scholten for continued support and discussion.

Author Contributions S.-M.A.H., A.C., F.St., G.A.M., E.W., V.M., S.F., C.Lu, D.C., M.W.K., C.Le., P.M.F., J.A.T., T.B., J.A.P., A.B. and F.C. conceived and designed the study. S.-M.A.H., Y.M.M., S.L., A.C., F.St., G.A.M., O.C., E.W., Y.Z., S.W., M.H., X.S., C.W., C.M., A.F., R.T., F.Se., W.S., H.C., M.Sh., C.R., M.Sc., J.S., S.G., A.B. and F.C. designed and implemented experiments. S.-M.A.H., F.St., A.B., Y.M.M. and F.C. wrote the paper.

Author information

Author notes

    • Markus Schirle
    • , Christoph Lengauer
    • , Tewis Bouwmeester
    •  & Andreas Bauer

    Present addresses: Novartis Institutes for Biomedical Research, CH-4002 Basel, Switzerland (T.B., A.B.); Novartis Institutes for Biomedical Research, Cambridge, Massachusetts 02139, USA (M. Sc.); Sanofi-Aventis, 94403 Vitry-sur-Seine, France (C.L.).

Affiliations

  1. Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA

    • Shih-Min A. Huang
    • , Yuji M. Mishina
    • , Shanming Liu
    • , Atwood Cheung
    • , Frank Stegmeier
    • , Gregory A. Michaud
    • , Olga Charlat
    • , Elizabeth Wiellette
    • , Yue Zhang
    • , Stephanie Wiessner
    • , Marc Hild
    • , Xiaoying Shi
    • , Christopher J. Wilson
    • , Craig Mickanin
    • , Vic Myer
    • , Aleem Fazal
    • , Ronald Tomlinson
    • , Fabrizio Serluca
    • , Wenlin Shao
    • , Hong Cheng
    • , Michael Shultz
    • , Stephen Fawell
    • , Chris Lu
    • , Daniel Curtis
    • , Christoph Lengauer
    • , Peter M. Finan
    • , John A. Tallarico
    • , Jeffery A. Porter
    •  & Feng Cong
  2. Cellzome AG, Meyerhofstrasse 1, D-69117 Heidelberg, Germany

    • Christina Rau
    • , Markus Schirle
    • , Judith Schlegl
    • , Sonja Ghidelli
    • , Tewis Bouwmeester
    •  & Andreas Bauer
  3. Department of Systems Biology, Harvard Medical School, Boston, Massachusetts 02115, USA

    • Marc W. Kirschner

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Corresponding author

Correspondence to Feng Cong.

Supplementary information

PDF files

  1. 1.

    Supplementary Information

    This file contains Supplementary Methods, Supplementary Figures S1-S9 with Legends, and a Legend for Table S1 (see separate file s2).

  2. 2.

    Supplementary Methods

    This file contains the methods for the synthesis of XAV939.

Excel files

  1. 1.

    Supplementary Table 1

    This file contains the competition data for all 699 identified proteins (see file s1 for full Legend).

About this article

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DOI

https://doi.org/10.1038/nature08356

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