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

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 Bouwmeester, Peter M. Finan, Marc W. Kirschner, Jeffery A. Porter, Fabrizio C. Serluca and Feng Cong ()
Additional contact information
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
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

Nature, 2012, vol. 485, issue 7397, 195-200

Abstract: 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.

Date: 2012
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DOI: 10.1038/nature11019

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