LRP5/6 directly bind to Frizzled and prevent Frizzled-regulated tumour metastasis

Dan-ni Ren, Jinxiao Chen, Zhi Li, Hongwei Yan, Yan Yin, Da Wo, Jiankang Zhang, Luoquan Ao, Bo Chen, Takashi K. Ito, Yihan Chen, Zhongmin Liu, Yongyong Li, Jianhua Yang, Xiaoling Lu, Yi Peng, Linghui Pan, Yongxiang Zhao (), Shangfeng Liu () and Weidong Zhu ()
Additional contact information
Dan-ni Ren: Clinical and Translational Research Center Shanghai East Hospital, Key Laboratory of Arrhythmias of Ministry of Education
Jinxiao Chen: Tongji University School of Medicine
Zhi Li: Chiba University Graduate School of Medicine
Hongwei Yan: Tongji University School of Medicine
Yan Yin: Clinical and Translational Research Center Shanghai East Hospital, Key Laboratory of Arrhythmias of Ministry of Education
Da Wo: Tongji University School of Medicine
Jiankang Zhang: Tongji University School of Medicine
Luoquan Ao: Tongji University School of Medicine
Bo Chen: Clinical and Translational Research Center Shanghai East Hospital, Key Laboratory of Arrhythmias of Ministry of Education
Takashi K. Ito: Chiba University Graduate School of Medicine
Yihan Chen: Clinical and Translational Research Center Shanghai East Hospital, Key Laboratory of Arrhythmias of Ministry of Education
Zhongmin Liu: Clinical and Translational Research Center Shanghai East Hospital, Key Laboratory of Arrhythmias of Ministry of Education
Yongyong Li: Tongji University School of Medicine
Jianhua Yang: Tongji University School of Medicine
Xiaoling Lu: Biological Targeting Diagnosis and Therapy Research Center, Guangxi Medical University
Yi Peng: Biological Targeting Diagnosis and Therapy Research Center, Guangxi Medical University
Linghui Pan: The Affiliated Tumor Hospital, Guangxi Medical University
Yongxiang Zhao: Biological Targeting Diagnosis and Therapy Research Center, Guangxi Medical University
Shangfeng Liu: Clinical and Translational Research Center Shanghai East Hospital, Key Laboratory of Arrhythmias of Ministry of Education
Weidong Zhu: Clinical and Translational Research Center Shanghai East Hospital, Key Laboratory of Arrhythmias of Ministry of Education

Nature Communications, 2015, vol. 6, issue 1, 1-13

Abstract: Abstract How Wnt signalling including canonical and non-canonical pathways are initiated at the cell surface is not completely understood. Here we report that Wnt receptor Frizzled (Frz) and theco-receptors LRP5 and LRP6 (LRP5/6) directly interact with each other and this interaction is regulated by the LRP6 ectodomain. Importantly, through direct binding to Frz, LRP5/6 are able to prevent Frz-regulated non-canonical pathway activation and further non-canonical pathway-mediated tumour metastasis. Knockdown of endogenous LRP5/6 promotes otherwise-nonaggressive tumour cells to migrate in vitro, whereas a soluble recombinant protein of LRP6 ectodomain suppresses migration and metastasis of otherwise-aggressive tumour cells in vitro and in vivo. Furthermore, the expression level of membrane LRP5/6 correlates inversely with metastasis in mouse and human breast cancer. Our study suggests a previously unrecognized mode of receptor interaction, revealing the mechanism of LRP5/6 in inhibition of non-canonical pathway, and a possible clinical use of the LRP6 ectodomain to impede metastasis.

Date: 2015
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DOI: 10.1038/ncomms7906

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