JOURNAL ARTICLE

LRP6 dimerization through its LDLR domain is required for robust canonical Wnt pathway activation

Jinxiao Chen, Hongwei Yan, Dan-Ni Ren, Yan Yin, Zhi Li, Qingqing He, Da Wo, Margaret Su-Chun Ho, Yihan Chen, Zhongmin Liu, Jianhua Yang, Shangfeng Liu, Weidong Zhu
Cellular Signalling 2014, 26 (5): 1068-74
24412751
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.

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