Initiation of Wnt signaling: control of Wnt coreceptor Lrp6 phosphorylation/activation via frizzled, dishevelled and axin functions
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Canonical Wnt/β-catenin signaling has central roles in development and diseases, and is initiated by the action of the frizzled (Fz) receptor, its coreceptor LDL receptor-related protein 6 (Lrp6), and the cytoplasmic dishevelled (Dvl) protein. The functional relationships among Fz, Lrp6 and Dvl have long been enigmatic. We demonstrated previously that Wnt-induced Lrp6 phosphorylation via glycogen synthase kinase 3 (Gsk3) initiates Wnt/β-catenin signaling. Here we show that both Fz and Dvl functions are critical for Wnt-induced Lrp6 phosphorylation through Fz-Lrp6 interaction. We also show that axin, a key scaffolding protein in the Wnt pathway, is required for Lrp6 phosphorylation via its ability to recruit Gsk3, and inhibition of Gsk3 at the plasma membrane blocks Wnt/β-catenin signaling. Our results suggest a model that upon Wnt-induced Fz-Lrp6 complex formation, Fz recruitment of Dvl in turn recruits the axin-Gsk3 complex, thereby promoting Lrp6 phosphorylation to initiate β-catenin signaling. We discuss the dual roles of the axin-Gsk3 complex and signal amplification by Lrp6-axin interaction during Wnt/β-catenin signaling.
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The binding of Wnt to the Fz/LRP5/6 complex induces the membrane translocation of a key negative regulator of signaling Axin, which binds to a conserved sequence in the cytoplasmic tail of LRP5/6.
“The binding of Wnt to the Fz/LRP5/6 complex induces the membrane translocation of a key negative regulator of signaling Axin, which binds to a conserved sequence in the cytoplasmic tail of LRP5/6.27,28”
From Wnt signal transduction pathways (2008) · cites this paper as [28]
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- Authors
- Zeng, X., Huang, H., Tamai, K., Zhang, X., Harada, Y., Yokota, C., Almeida, K., Wang, J., Doble, B., Woodgett, J., Wynshaw-Boris, A., Hsieh, J.-C., & He, X.
- Affiliations
- Boston Children's Hospital (US)
- University of California San Diego (US)
- Samuel Lunenfeld Research Institute, 600 University Avenue, Toronto, Ontario,M5G 1X5, Canada.
- Stony Brook University (US)
- Corresponding author
- He, Xi
- Venue
- Development
- Publisher
- The Company of Biologists
- Published
- 2008-01-15
- Volume
- 135
- Issue
- 2
- Pages
- 367-375
- ISSN
- 0950-1991 (ISSN-L)
- 1477-9129
- PMC
- PMC5328672
- OpenAlex
- W1837463574
- Cited by
- 492
- References
- 56
- Citations by year
- 2026: 8 · 2025: 16 · 2024: 35 · 2023: 15 · 2022: 20 · 2021: 18 · 2020: 19 · 2019: 18 · 2018: 29 · 2017: 27 · 2016: 21 · 2015: 24 · 2014: 41 · 2013: 26 · 2012: 32
- FWCI
- 12.46
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by
- Locations
- Development (publishedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Journal of Cell Science
- Funders
- Canadian Institutes of Health Research (12043)
- National Institute of Neurological Disorders and Stroke (R01NS073159)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Hedgehog Signaling Pathway Studies
- Keywords
- Wnt/β-catenin signaling, LRP6 phosphorylation, Frizzled receptors, Dishevelled, Axin, glycogen synthase kinase-3, signal amplification, co-receptors
- MeSH terms
- Dishevelled Proteins, Animals, Cell Line, Cell Membrane, Embryo, Nonmammalian, Enzyme Inhibitors, Humans, Models, Biological, Phosphoproteins, Phosphorylation, Protein Binding, Receptors, LDL, Repressor Proteins, Xenopus, Signal Transduction, Protein Structure, Tertiary, Xenopus Proteins, Glycogen Synthase Kinase 3, Adaptor Proteins, Signal Transducing, Wnt Proteins, Frizzled Receptors, beta Catenin, Mice, Axin Protein, Low Density Lipoprotein Receptor-Related Protein-6
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