Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling


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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Figure 1: XAV939 inhibits Wnt/β-catenin signalling by increasing axin protein levels.
Figure 2: Identification of the cellular efficacy targets of XAV939.
Figure 3: Tankyrase modulates axin protein levels.
Figure 4: Tankyrase physically and functionally interacts with axin.
Figure 5: XAV939 stabilizes axin protein and inhibits ubiquitination of axin.
Figure 6: XAV939 inhibits DLD-1 colony formation in an axin-dependent manner.

Similar content being viewed by others


  1. Clevers, H. Wnt/β-catenin signaling in development and disease. Cell 127, 469–480 (2006)

    Article  CAS  Google Scholar 

  2. Polakis, P. The many ways of Wnt in cancer. Curr. Opin. Genet. Dev. 17, 45–51 (2007)

    Article  CAS  Google Scholar 

  3. Barker, N. & Clevers, H. Mining the Wnt pathway for cancer therapeutics. Nature Rev. Drug Discov. 5, 997–1014 (2006)

    Article  CAS  Google Scholar 

  4. Miyaki, M. et al. Characteristics of somatic mutation of the adenomatous polyposis coli gene in colorectal tumors. Cancer Res. 54, 3011–3020 (1994)

    CAS  PubMed  Google Scholar 

  5. Mori, Y. et al. Somatic mutations of the APC gene in colorectal tumors: mutation cluster region in the APC gene. Hum. Mol. Genet. 1, 229–233 (1992)

    Article  Google Scholar 

  6. Powell, S. M. et al. APC mutations occur early during colorectal tumorigenesis. Nature 359, 235–237 (1992)

    Article  ADS  CAS  Google Scholar 

  7. Salic, A., Lee, E., Mayer, L. & Kirschner, M. W. Control of β-catenin stability: reconstitution of the cytoplasmic steps of the Wnt pathway in Xenopus egg extracts. Mol. Cell 5, 523–532 (2000)

    Article  CAS  Google Scholar 

  8. Lee, E., Salic, A., Kruger, R., Heinrich, R. & Kirschner, M. W. The roles of APC and axin derived from experimental and theoretical analysis of the Wnt pathway. PLoS Biol. 1, E10 (2003)

    Article  Google Scholar 

  9. Behrens, J. et al. Functional interaction of an axin homolog, conductin, with β-catenin, APC, and GSK3β. Science 280, 596–599 (1998)

    Article  ADS  CAS  Google Scholar 

  10. Kishida, M. et al. Axin prevents Wnt-3a-induced accumulation of β-catenin. Oncogene 18, 979–985 (1999)

    Article  CAS  Google Scholar 

  11. Hart, M. J., de los Santos, R., Albert, I. N., Rubinfeld, B. & Polakis, P. Downregulation of β-catenin by human axin and its association with the APC tumor suppressor, β-catenin and GSK3β. Curr. Biol. 8, 573–581 (1998)

    Article  CAS  Google Scholar 

  12. Leung, J. Y. et al. Activation of AXIN2 expression by β-catenin-T cell factor. A feedback repressor pathway regulating Wnt signaling. J. Biol. Chem. 277, 21657–21665 (2002)

    Article  CAS  Google Scholar 

  13. Willert, K., Shibamoto, S. & Nusse, R. Wnt-induced dephosphorylation of axin releases β-catenin from the axin complex. Genes Dev. 13, 1768–1773 (1999)

    Article  CAS  Google Scholar 

  14. Donawho, C. K. et al. ABT-888, an orally active poly(ADP-ribose) polymerase inhibitor that potentiates DNA-damaging agents in preclinical tumor models. Clin. Cancer Res. 13, 2728–2737 (2007)

    Article  CAS  Google Scholar 

  15. Poss, K. D., Shen, J. & Keating, M. T. Induction of lef1 during zebrafish fin regeneration. Dev. Dyn. 219, 282–286 (2000)

    Article  CAS  Google Scholar 

  16. Stoick-Cooper, C. L. et al. Distinct Wnt signaling pathways have opposing roles in appendage regeneration. Development 134, 479–489 (2007)

    Article  CAS  Google Scholar 

  17. Chen, B. et al. Small molecule-mediated disruption of Wnt-dependent signaling in tissue regeneration and cancer. Nature Chem. Biol. 5, 100–107 (2009)

    Article  ADS  CAS  Google Scholar 

  18. Hsiao, S. J. & Smith, S. Tankyrase function at telomeres, spindle poles, and beyond. Biochimie 90, 83–92 (2008)

    Article  CAS  Google Scholar 

  19. Sbodio, J. I., Lodish, H. F. & Chi, N. W. Tankyrase-2 oligomerizes with tankyrase-1 and binds to both TRF1 (telomere-repeat-binding factor 1) and IRAP (insulin-responsive aminopeptidase). Biochem. J. 361, 451–459 (2002)

    Article  CAS  Google Scholar 

  20. Yeh, T.-Y. et al. Tankyrase recruitment to the lateral membrane in polarized epithelial cells: regulation by cell–cell contact and protein poly(ADP-ribosyl)ation. Biochem. J. 399, 415–425 (2006)

    Article  CAS  Google Scholar 

  21. Chang, W., Dynek, J. N. & Smith, S. TRF1 is degraded by ubiquitin-mediated proteolysis after release from telomeres. Genes Dev. 17, 1328–1333 (2003)

    Article  CAS  Google Scholar 

  22. Chang, P., Coughlin, M. & Mitchison, T. J. Tankyrase-1 polymerization of poly(ADP-ribose) is required for spindle structure and function. Nature Cell Biol. 7, 1133–1139 (2005)

    Article  CAS  Google Scholar 

  23. Dynek, J. N. & Smith, S. Resolution of sister telomere association is required for progression through mitosis. Science 304, 97–100 (2004)

    Article  ADS  CAS  Google Scholar 

  24. Winston, J. T. et al. The SCFβ-TRCP-ubiquitin ligase complex associates specifically with phosphorylated destruction motifs in IκBα and β-catenin and stimulates IκBα ubiquitination in vitro . Genes Dev. 13, 270–283 (1999)

    Article  CAS  Google Scholar 

  25. Koepp, D. M. et al. Phosphorylation-dependent ubiquitination of cyclin E by the SCFFbw7 ubiquitin ligase. Science 294, 173–177 (2001)

    Article  ADS  CAS  Google Scholar 

  26. Hsiao, S. J., Poitras, M. F., Cook, B. D., Liu, Y. & Smith, S. Tankyrase 2 poly(ADP-ribose) polymerase domain-deleted mice exhibit growth defects but have normal telomere length and capping. Mol. Cell. Biol. 26, 2044–2054 (2006)

    Article  CAS  Google Scholar 

  27. Chiang, Y. J. et al. Tankyrase 1 and tankyrase 2 are essential but redundant for mouse embryonic development. PLoS ONE 3, e2639 (2008)

    Article  ADS  Google Scholar 

  28. Bantscheff, M. et al. Quantitative chemical proteomics reveals mechanisms of action of clinical ABL kinase inhibitors. Nature Biotechnol. 25, 1035–1044 (2007)

    Article  CAS  Google Scholar 

  29. Bantscheff, M. et al. Robust and sensitive iTRAQ quantification on an LTQ Orbitrap mass spectrometer. Mol. Cell. Proteomics 7, 1702–1713 (2008)

    Article  CAS  Google Scholar 

Download references


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

Authors and Affiliations


Corresponding author

Correspondence to Feng Cong.

Supplementary information

Supplementary Information

This file contains Supplementary Methods, Supplementary Figures S1-S9 with Legends, and a Legend for Table S1 (see separate file s2). (PDF 2084 kb)

Supplementary Table 1

This file contains the competition data for all 699 identified proteins (see file s1 for full Legend). (XLS 98 kb)

Supplementary Methods

This file contains the methods for the synthesis of XAV939. (PDF 88 kb)

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

Huang, SM., Mishina, Y., Liu, S. et al. Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling. Nature 461, 614–620 (2009).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing