title: LRP5/6 directly bind to Frizzled and prevent Frizzled-regulated tumour metastasis.
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.
authors.affiliation: Clinical and Translational Research Center Shanghai East Hospital, Key Laboratory of Arrhythmias of Ministry of Education, Shanghai, China.
authors.forename: Dan-Ni
authors.initials: DN
authors.lastname: Ren
authors.affiliation: Tongji University School of Medicine, Shanghai, China.
authors.forename: Jinxiao
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, Chiba, Japan.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Li
authors.affiliation: Tongji University School of Medicine, Shanghai, China.
authors.forename: Hongwei
authors.initials: H
authors.lastname: Yan
authors.affiliation: Clinical and Translational Research Center Shanghai East Hospital, Key Laboratory of Arrhythmias of Ministry of Education, Shanghai, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Yin
authors.affiliation: Tongji University School of Medicine, Shanghai, China.
authors.forename: Da
authors.initials: D
authors.lastname: Wo
authors.affiliation: Tongji University School of Medicine, Shanghai, China.
authors.forename: Jiankang
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Tongji University School of Medicine, Shanghai, China.
authors.forename: Luoquan
authors.initials: L
authors.lastname: Ao
authors.affiliation: Clinical and Translational Research Center Shanghai East Hospital, Key Laboratory of Arrhythmias of Ministry of Education, Shanghai, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Chen
authors.affiliation: Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, Chiba, Japan.
authors.forename: Takashi K
authors.initials: TK
authors.lastname: Ito
authors.affiliation: 1] Clinical and Translational Research Center Shanghai East Hospital, Key Laboratory of Arrhythmias of Ministry of Education, Shanghai, China [2] Tongji University School of Medicine, Shanghai, China.
authors.forename: Yihan
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Clinical and Translational Research Center Shanghai East Hospital, Key Laboratory of Arrhythmias of Ministry of Education, Shanghai, China.
authors.forename: Zhongmin
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Tongji University School of Medicine, Shanghai, China.
authors.forename: Yongyong
authors.initials: Y
authors.lastname: Li
authors.affiliation: Tongji University School of Medicine, Shanghai, China.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Yang
authors.affiliation: Biological Targeting Diagnosis and Therapy Research Center, Guangxi Medical University, Nanning, Guangxi, China.
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Lu
authors.affiliation: Biological Targeting Diagnosis and Therapy Research Center, Guangxi Medical University, Nanning, Guangxi, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Peng
authors.affiliation: Department of Oncology Research, The Affiliated Tumor Hospital, Guangxi Medical University, Nanning, Guangxi, China.
authors.forename: Linghui
authors.initials: L
authors.lastname: Pan
authors.affiliation: Biological Targeting Diagnosis and Therapy Research Center, Guangxi Medical University, Nanning, Guangxi, China.
authors.forename: Yongxiang
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: 1] Clinical and Translational Research Center Shanghai East Hospital, Key Laboratory of Arrhythmias of Ministry of Education, Shanghai, China [2] Tongji University School of Medicine, Shanghai, China.
authors.forename: Shangfeng
authors.initials: S
authors.lastname: Liu
authors.affiliation: 1] Clinical and Translational Research Center Shanghai East Hospital, Key Laboratory of Arrhythmias of Ministry of Education, Shanghai, China [2] Tongji University School of Medicine, Shanghai, China.
authors.forename: Weidong
authors.initials: W
authors.lastname: Zhu
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics*; D002465:Cell Movement / Q000235:genetics*; D051157:Frizzled Receptors / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006801:Humans; D066298:In Vitro Techniques; D060492:Low Density Lipoprotein Receptor-Related Protein-5 / Q000235:genetics*; D060488:Low Density Lipoprotein Receptor-Related Protein-6 / Q000235:genetics*; D051379:Mice; D016513:Mice, SCID; D009362:Neoplasm Metastasis / Q000235:genetics
chemical_list: D051157:Frizzled Receptors; C555482:LRP5 protein, human; C555475:LRP6 protein, human; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D060488:Low Density Lipoprotein Receptor-Related Protein-6; C555483:Lrp5 protein, mouse; C555476:Lrp6 protein, mouse