Cited by 772Wnt/β-catenin signaling in development and cancerHedgehog Signaling Pathway StudiesDevelopmental Biology and Gene Regulation

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Novel mechanism of Wnt signalling inhibition mediated by Dickkopf-1 interaction with LRP6/Arrow

Bafico, Anna, Liu, Guizhong, Yaniv, Abraham, Gazit, Arnona, Aaronson, Stuart A.·2001·Nature Cell Biology

DOI 10.1038/35083081

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Abstract

Wnt signalling has an important role in cell fate determination, tissue patterning and tumorigenesis. Secreted antagonists of Wnt include Frizzled (Fz)-related proteins (FRPs), Cerberus, Wnt inhibitory factor (WIF) and Dickkopf (Dkk). FRPs, Cerberus and WIF have all been shown to act by binding and sequestering Wnt. We report a novel mechanism of Wnt-signalling inhibition by human Dkk-1. Dkk-1 demonstrated no interaction with Wnt but bound a single cell surface site with high affinity (K(D) = 0.39 nM). Its receptor was detectable in a complex with a relative molecular mass of 240,000 (M(r) 240K) with [(125)I] Dkk-1 by covalent affinity cross-linking. Wnt signalling through beta-catenin is mediated by the Fz receptor and a recently identified low-density-lipoprotein-receptor-related co-receptor, LRP6/Arrow. Overproduction of the 200K LRP6 protein, but not of Fz, strikingly increased Dkk-1 binding as well as the amount of the 240K cross-linked complex, which was shown to be composed of Dkk-1 and LRP6. Moreover, Dkk-1 function was completely independent of Fz but LRP6 dramatically interfered with the Dkk-1 inhibition of Wnt signalling. Thus, unlike Wnt antagonists, which exert their effects by molecular mimicry of Fz or Wnt sequestration through other mechanisms, Dkk-1 specifically inhibits canonical Wnt signalling by binding to the LRP6 component of the receptor complex.

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Authors: Bafico, A., Liu, G., Yaniv, A., Gazit, A., & Aaronson, S. A.
Affiliations: Icahn School of Medicine at Mount Sinai (US)
Tel Aviv University (IL)
Corresponding author: Aaronson, Stuart A.
ORCID: Liu, Guizhong
Aaronson, Stuart A.
Venue: Nature Cell Biology
Publisher: Springer Science and Business Media LLC
Published: 2001-06-12
Volume: 3
Issue: 7
Pages: 683-686
ISSN: 1465-7392 (ISSN-L)
1476-4679
DOI: 10.1038/35083081
OpenAlex: W1557541313
Cited by: 772
References: 27
Citations by year: 2026: 12 · 2025: 6 · 2024: 7 · 2023: 26 · 2022: 26 · 2021: 34 · 2020: 27 · 2019: 20 · 2018: 32 · 2017: 37 · 2016: 37 · 2015: 39 · 2014: 34 · 2013: 33 · 2012: 51
FWCI: 9.80
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
Locations: Nature Cell Biology (publishedVersion)
PubMed (publishedVersion)
Funders: National Cancer Institute (R01CA071672, CA71672-04)
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 › Hedgehog Signaling Pathway Studies
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
Keywords: Wnt signaling, DKK1, LRP6, arrows, Wnt antagonists, Frizzled receptors, β-catenin, receptor complex, ligand binding, cell surface receptors
MeSH terms: Cell Line, Cytoskeletal Proteins, Drug Interactions, Humans, Kinetics, Protein Binding, Proteins, Proto-Oncogene Proteins, Receptors, LDL, Transfection, Immunoblotting, Signal Transduction, Trans-Activators, Zebrafish Proteins, Intercellular Signaling Peptides and Proteins, Wnt Proteins, beta Catenin, Low Density Lipoprotein Receptor-Related Protein-6

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Novel mechanism of Wnt signalling inhibition mediated by Dickkopf-1 interaction with LRP6/Arrow

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