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Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling

Author

Listed:
  • Shih-Min A. Huang

    (Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA)

  • Yuji M. Mishina

    (Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA)

  • Shanming Liu

    (Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA)

  • Atwood Cheung

    (Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA)

  • Frank Stegmeier

    (Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA)

  • Gregory A. Michaud

    (Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA)

  • Olga Charlat

    (Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA)

  • Elizabeth Wiellette

    (Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA)

  • Yue Zhang

    (Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA)

  • Stephanie Wiessner

    (Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA)

  • Marc Hild

    (Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA)

  • Xiaoying Shi

    (Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA)

  • Christopher J. Wilson

    (Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA)

  • Craig Mickanin

    (Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA)

  • Vic Myer

    (Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA)

  • Aleem Fazal

    (Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA)

  • Ronald Tomlinson

    (Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA)

  • Fabrizio Serluca

    (Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA)

  • Wenlin Shao

    (Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA)

  • Hong Cheng

    (Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA)

  • Michael Shultz

    (Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA)

  • Christina Rau

    (Cellzome AG, Meyerhofstrasse 1, D-69117 Heidelberg, Germany)

  • Markus Schirle

    (Cellzome AG, Meyerhofstrasse 1, D-69117 Heidelberg, Germany
    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.).)

  • Judith Schlegl

    (Cellzome AG, Meyerhofstrasse 1, D-69117 Heidelberg, Germany)

  • Sonja Ghidelli

    (Cellzome AG, Meyerhofstrasse 1, D-69117 Heidelberg, Germany)

  • Stephen Fawell

    (Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA)

  • Chris Lu

    (Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA)

  • Daniel Curtis

    (Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA)

  • Marc W. Kirschner

    (Harvard Medical School, Boston, Massachusetts 02115, USA)

  • Christoph Lengauer

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

  • Peter M. Finan

    (Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA)

  • John A. Tallarico

    (Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA)

  • Tewis Bouwmeester

    (Cellzome AG, Meyerhofstrasse 1, D-69117 Heidelberg, Germany
    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.).)

  • Jeffery A. Porter

    (Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA)

  • Andreas Bauer

    (Cellzome AG, Meyerhofstrasse 1, D-69117 Heidelberg, Germany
    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.).)

  • Feng Cong

    (Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA)

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.

Suggested Citation

  • 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 S, 2009. "Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling," Nature, Nature, vol. 461(7264), pages 614-620, October.
    • Handle: RePEc:nat:nature:v:461:y:2009:i:7264:d:10.1038_nature08356
    DOI: 10.1038/nature08356
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    Cited by:

    1. Victoria H. Ng & Zachary Spencer & Leif R. Neitzel & Anmada Nayak & Matthew A. Loberg & Chen Shen & Sara N. Kassel & Heather K. Kroh & Zhenyi An & Christin C. Anthony & Jamal M. Bryant & Amanda Lawson, 2023. "The USP46 complex deubiquitylates LRP6 to promote Wnt/β-catenin signaling," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    2. Sivakamasundari Vijayakumar & Roberta Sala & Gugene Kang & Angela Chen & Michelle Ann Pablo & Abidemi Ismail Adebayo & Andrea Cipriano & Jonas L. Fowler & Danielle L. Gomes & Lay Teng Ang & Kyle M. Lo, 2023. "Monolayer platform to generate and purify primordial germ-like cells in vitro provides insights into human germline specification," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    3. Liviu Aron & Chenxi Qiu & Zhen Kai Ngian & Marianna Liang & Derek Drake & Jaejoon Choi & Marty A. Fernandez & Perle Roche & Emma L. Bunting & Ella K. Lacey & Sara E. Hamplova & Monlan Yuan & Michael S, 2023. "A neurodegeneration checkpoint mediated by REST protects against the onset of Alzheimer’s disease," Nature Communications, Nature, vol. 14(1), pages 1-22, December.
    4. Jun Li & Jie Ma & Qiyu Zhang & Huizi Gong & Dunqin Gao & Yujie Wang & Biyou Li & Xiao Li & Heyi Zheng & Zhihong Wu & Yunping Zhu & Ling Leng, 2022. "Spatially resolved proteomic map shows that extracellular matrix regulates epidermal growth," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    5. Balazs V. Varga & Maryam Faiz & Helena Pivonkova & Gabriel Khelifi & Huijuan Yang & Shangbang Gao & Emma Linderoth & Mei Zhen & Ragnhildur Thora Karadottir & Samer M. Hussein & Andras Nagy, 2022. "Signal requirement for cortical potential of transplantable human neuroepithelial stem cells," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    6. Jerome Perrard & Susan Smith, 2023. "Multiple E3 ligases control tankyrase stability and function," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    7. Timo N. Kohler & Joachim Jonghe & Anna L. Ellermann & Ayaka Yanagida & Michael Herger & Erin M. Slatery & Antonia Weberling & Clara Munger & Katrin Fischer & Carla Mulas & Alex Winkel & Connor Ross & , 2023. "Plakoglobin is a mechanoresponsive regulator of naive pluripotency," Nature Communications, Nature, vol. 14(1), pages 1-19, December.

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