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

Nature
Huai-Xiang HaoFeng Cong

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.

References

Aug 20, 2005·Science·Kyung-Ah KimKazuma Tomizuka
Sep 12, 2006·Developmental Biology·Motoko AokiHitoshi Okamoto
Oct 17, 2006·Nature Genetics·Pietro ParmaGiovanna Camerino
Apr 6, 2007·Genesis : the Journal of Genetics and Development·Jana KreslovaZbynek Kozmik
Sep 7, 2007·Proceedings of the National Academy of Sciences of the United States of America·Minke E BinnertsArie Abo
Apr 11, 2008·Molecular Biology of the Cell·Kyung-Ah KimArie Abo
Aug 20, 2008·Annual Review of Genetics·Matias Simons, Marek Mlodzik
Oct 10, 2008·Development·Olga KazanskayaChristof Niehrs
Jan 31, 2009·Proceedings of the National Academy of Sciences of the United States of America·Jingsong ZhaoArie Abo
Jul 22, 2009·Developmental Cell·Bryan T MacDonaldXi He
Sep 18, 2009·Nature·Shih-Min A HuangFeng Cong
Dec 17, 2009·Molecular Cell·Lea Goentoro, Marc W Kirschner
Jun 23, 2011·Proceedings of the National Academy of Sciences of the United States of America·Kendra S CarmonQingyun Liu
Dec 14, 2011·Proceedings of the National Academy of Sciences of the United States of America·Jian WuBert Vogelstein

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Citations

Mar 19, 2013·Journal of Molecular Histology·Yehui ZhouHonggeng Guan
Jun 13, 2012·Cell Research·Bryan T MacDonald, Xi He
Sep 12, 2012·Nature Biotechnology·Arie Abo, Hans Clevers
Nov 16, 2012·Nature Reviews. Molecular Cell Biology·Christof Niehrs
Dec 12, 2013·Nature Reviews. Molecular Cell Biology·Nick Barker
Jul 13, 2013·Proceedings of the National Academy of Sciences of the United States of America·Xiaomo JiangFeng Cong
Jun 13, 2013·Genes & Development·Dongli WangXinquan Wang
Jun 13, 2013·Genes & Development·Po-Han ChenXiaolin He
Aug 28, 2012·Science·Lawrence Lum, Hans Clevers
Dec 13, 2012·Science Signaling·Folkert VerkaarRenée van Amerongen
Jan 31, 2014·Nature Communications·Changjie WuXincheng Lu
Jul 11, 2013·Journal of Ophthalmology·Stefan SiwkoMingyao Liu
Feb 13, 2013·Annual Review of Physiology·Hans C Clevers, Charles L Bevins
Jul 2, 2014·Nature Reviews. Drug Discovery·Michael Kahn
Nov 28, 2013·Proceedings of the National Academy of Sciences of the United States of America·Jun LiuJennifer L Harris
Dec 1, 2015·Laboratory Investigation; a Journal of Technical Methods and Pathology·Ke YangTong-Chuan He
Jan 12, 2016·Laboratory Investigation; a Journal of Technical Methods and Pathology·Christina Bergmann, Jörg H W Distler
Oct 2, 2015·Carcinogenesis·Kate LawrensonJoellen M Schildkraut
Mar 24, 2016·Proceedings of the National Academy of Sciences of the United States of America·Haruna TakedaNeal G Copeland
Jan 15, 2015·RNA Biology·Vijay Suresh AkhadeManchanahalli R Satyanarayana Rao
Oct 6, 2015·Annual Review of Cell and Developmental Biology·Shoichi Date, Toshiro Sato
Oct 7, 2015·Frontiers in Endocrinology·Emma J PetriePaul R Gooley
Aug 1, 2015·Molecular Biology of the Cell·Tirthadipa Pradhan-Sundd, Esther M Verheyen
Sep 18, 2015·Frontiers in Endocrinology·Ziru LiMichael W Mulholland
Dec 22, 2012·Growth Factors·Kenyi Saito-DiazEthan Lee
May 30, 2015·Proceedings of the National Academy of Sciences of the United States of America·Bon-Kyoung KooHans Clevers
Sep 12, 2014·Bioscience Reports·Jia Yu, David M Virshup

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