1. LRP6 dimerization through its LDLR domain is required for robust canonical Wnt pathway activation.
- Author
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Chen J, Yan H, Ren DN, Yin Y, Li Z, He Q, Wo D, Ho MS, Chen Y, Liu Z, Yang J, Liu S, and Zhu W
- Subjects
- Amino Acid Sequence, Dimerization, Frizzled Receptors metabolism, HEK293 Cells, Hep G2 Cells, Humans, Ligands, Low Density Lipoprotein Receptor-Related Protein-5 metabolism, Molecular Sequence Data, Receptors, LDL chemistry, Wnt Signaling Pathway, Wnt3A Protein chemistry, beta Catenin metabolism, Low Density Lipoprotein Receptor-Related Protein-6 metabolism, Receptors, LDL metabolism, Wnt3A Protein metabolism
- 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., (Copyright © 2014 Elsevier Inc. All rights reserved.)
- Published
- 2014
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