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

被引：733

作者：

Hao, Huai-Xiang ^{[1
]}

Xie, Yang ^{[1
]}

Zhang, Yue ^{[1
]}

Charlat, Olga ^{[1
]}

Oster, Emma ^{[1
]}

Avello, Monika ^{[1
]}

Lei, Hong ^{[1
]}

Mickanin, Craig ^{[1
]}

Liu, Dong ^{[1
]}

Ruffner, Heinz ^{[2
]}

Mao, Xiaohong ^{[1
]}

Ma, Qicheng ^{[1
]}

Zamponi, Raffaella ^{[1
]}

Bouwmeester, Tewis ^{[2
]}

Finan, Peter M. ^{[1
]}

Kirschner, Marc W. ^{[3
]}

Porter, Jeffery A. ^{[1
]}

Serluca, Fabrizio C. ^{[1
]}

Cong, Feng ^{[1
]}

机构：

[1] Novartis Inst Biomed Res, Cambridge, MA 02139 USA

[2] Novartis Pharma AG, Novartis Inst Biomed Res, CH-4002 Basel, Switzerland

[3] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA 02115 USA

来源：

NATURE | 2012年 / 485卷 / 7397期

关键词：

BETA-CATENIN FUNCTION; WNT/BETA-CATENIN; LENS MORPHOGENESIS; R-SPONDIN1; PATHWAY; LRP6; LGR5; PHOSPHORYLATION; INHIBITION; DISRUPTION;

D O I：

10.1038/nature11019

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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/beta-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.

引用

页码：195 / U76

页数：8

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