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ZNRF3 promotes Wnt receptor turnover in an R-spondin-sensitive manner

Author

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  • Huai-Xiang Hao

    (Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue)

  • Yang Xie

    (Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue)

  • Yue Zhang

    (Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue
    Present address: AstraZeneca, 35 Gatehouse Drive, Waltham, Massachusetts 02451, USA.)

  • Olga Charlat

    (Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue)

  • Emma Oster

    (Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue)

  • Monika Avello

    (Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue)

  • Hong Lei

    (Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue)

  • Craig Mickanin

    (Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue)

  • Dong Liu

    (Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue)

  • Heinz Ruffner

    (Novartis Institutes for Biomedical Research, Novartis Pharma AG, Postfach CH-4002 Basel, Switzerland)

  • Xiaohong Mao

    (Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue)

  • Qicheng Ma

    (Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue)

  • Raffaella Zamponi

    (Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue)

  • Tewis Bouwmeester

    (Novartis Institutes for Biomedical Research, Novartis Pharma AG, Postfach CH-4002 Basel, Switzerland)

  • Peter M. Finan

    (Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue)

  • Marc W. Kirschner

    (Harvard Medical School)

  • Jeffery A. Porter

    (Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue)

  • Fabrizio C. Serluca

    (Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue)

  • Feng Cong

    (Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue)

Abstract

R-spondin proteins strongly potentiate Wnt signalling and function as stem-cell growth factors. Despite the biological and therapeutic significance, the molecular mechanism of R-spondin action remains unclear. Here we show that the cell-surface transmembrane E3 ubiquitin ligase zinc and ring finger 3 (ZNRF3) and its homologue ring finger 43 (RNF43) are negative feedback regulators of Wnt signalling. ZNRF3 is associated with the Wnt receptor complex, and inhibits Wnt signalling by promoting the turnover of frizzled and LRP6. Inhibition of ZNRF3 enhances Wnt/β-catenin signalling and disrupts Wnt/planar cell polarity signalling in vivo. Notably, R-spondin mimics ZNRF3 inhibition by increasing the membrane level of Wnt receptors. Mechanistically, R-spondin interacts with the extracellular domain of ZNRF3 and induces the association between ZNRF3 and LGR4, which results in membrane clearance of ZNRF3. These data suggest that R-spondin enhances Wnt signalling by inhibiting ZNRF3. Our study provides new mechanistic insights into the regulation of Wnt receptor turnover, and reveals ZNRF3 as a tractable target for therapeutic exploration.

Suggested Citation

  • Huai-Xiang Hao & Yang Xie & Yue Zhang & Olga Charlat & Emma Oster & Monika Avello & Hong Lei & Craig Mickanin & Dong Liu & Heinz Ruffner & Xiaohong Mao & Qicheng Ma & Raffaella Zamponi & Tewis Bouwmee, 2012. "ZNRF3 promotes Wnt receptor turnover in an R-spondin-sensitive manner," Nature, Nature, vol. 485(7397), pages 195-200, May.
    • Handle: RePEc:nat:nature:v:485:y:2012:i:7397:d:10.1038_nature11019
    DOI: 10.1038/nature11019
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    Cited by:

    1. Lishan Fang & Dane Ford-Roshon & Max Russo & Casey O’Brien & Xiaozhe Xiong & Carino Gurjao & Maximilien Grandclaudon & Srivatsan Raghavan & Steven M. Corsello & Steven A. Carr & Namrata D. Udeshi & Ja, 2022. "RNF43 G659fs is an oncogenic colorectal cancer mutation and sensitizes tumor cells to PI3K/mTOR inhibition," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    2. 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.
    3. Christina M. Termini & Amara Pang & Tiancheng Fang & Martina Roos & Vivian Y. Chang & Yurun Zhang & Nicollette J. Setiawan & Lia Signaevskaia & Michelle Li & Mindy M. Kim & Orel Tabibi & Paulina K. Li, 2021. "Neuropilin 1 regulates bone marrow vascular regeneration and hematopoietic reconstitution," Nature Communications, Nature, vol. 12(1), pages 1-17, December.
    4. Jong Hoon Won & Jacob S. Choi & Joon-Il Jun, 2022. "CCN1 interacts with integrins to regulate intestinal stem cell proliferation and differentiation," Nature Communications, Nature, vol. 13(1), pages 1-15, December.

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