title: LRP6 dimerization through its LDLR domain is required for robust canonical Wnt pathway activation.
abstract: Canonical Wnt/β-catenin signaling pathway plays important roles in multiple aspects of cellular responses in development and diseases. It is currently thought that Wnt receptor Frizzled (Frz) exists separately to Wnt coreceptors LRP5 and LRP6 (LRP5/6), and that Wnt-Frz-LRP5/6 triple complex formation bridged by Wnt ligand is needed for canonical pathway activation. We recently showed that Frz and LRP5/6 interact with each other in the absence of Wnt ligand binding and this interaction maintains the Frz-LRP5/6 complex in an inactive state. Here, we further show that Wnt ligand stimulation induces conformational change of the Frz-LRP6 complex and leads to hexamer formation containing the core LDLR domain-mediated LRP6 homodimer that is stabilized by two pairs of Wnt3a and Frz8, that is, Wnt3a-Frz8-LRP6-LRP6-Frz8-Wnt3a. This LDLR-mediated LRP6 dimerization is essential for robust canonical Wnt pathway activation. Our study thus suggests a previously unrecognized mode of receptor interaction in Wnt signal initiation.
authors.affiliation: Tongji University School of Medicine, Shanghai, China.
authors.forename: Jinxiao
authors.initials: J
authors.lastname: Chen
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: Dan-Ni
authors.initials: DN
authors.lastname: Ren
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: 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: Qingqing
authors.initials: Q
authors.lastname: He
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: Margaret Su-Chun
authors.initials: MS
authors.lastname: Ho
authors.affiliation: Clinical and Translational Research Center Shanghai East Hospital, Key Laboratory of Arrhythmias of Ministry of Education, Shanghai, China; 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: Jianhua
authors.initials: J
authors.lastname: Yang
authors.affiliation: Translational Center for Stem Cell Research, Tongji Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Shangfeng
authors.initials: S
authors.lastname: Liu
authors.affiliation: Clinical and Translational Research Center Shanghai East Hospital, Key Laboratory of Arrhythmias of Ministry of Education, Shanghai, China; Tongji University School of Medicine, Shanghai, China. Electronic address: wzhu@tongji.edu.cn.
authors.forename: Weidong
authors.initials: W
authors.lastname: Zhu
mesh_terms: D000595:Amino Acid Sequence; D019281:Dimerization; D051157:Frizzled Receptors / Q000378:metabolism; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006801:Humans; D008024:Ligands; D060492:Low Density Lipoprotein Receptor-Related Protein-5 / Q000378:metabolism; D060488:Low Density Lipoprotein Receptor-Related Protein-6 / Q000378:metabolism*; D008969:Molecular Sequence Data; D011973:Receptors, LDL / Q000737:chemistry / Q000378:metabolism*; D060449:Wnt Signaling Pathway; D060509:Wnt3A Protein / Q000737:chemistry / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism
chemical_list: D051157:Frizzled Receptors; C573412:LDLR protein, human; C555482:LRP5 protein, human; C555475:LRP6 protein, human; D008024:Ligands; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D011973:Receptors, LDL; D060509:Wnt3A Protein; D051176:beta Catenin
keywords: Canonical Wnt pathway; Dimer; FPLC; Frizzled; LRP5/6