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Novel mechanism of Wnt signalling inhibition mediated by Dickkopf-1 interaction with LRP6/Arrow
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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“When comparing Fig 6 and S1 Fig, we find that the wet-lab data from just three studies, namely from [105–107], have been reused by simulation studies.”
From Relating simulation studies by provenance—Developing a family of Wnt signaling models (2021) · cites this paper as [105]
In the citing paper
“A second cluster forms around the simulation studies [45, 46, 51, 56, 57] and either includes the same wet-lab data from [105, 106], the Cell cycle [46] or ROS [51, 57].”
From Relating simulation studies by provenance—Developing a family of Wnt signaling models (2021) · cites this paper as [105]
In the citing paper
“DKK1 is a high-affinity ligand for LRP6 (Wu et al., 2000;Bafico et al., 2001;Bo et al., 2001;Semenov et al., 2001;Brott and Sokol, 2002) and a member of the dickkopf gene family which including DKK1, DKK2, DKK3 and DKK4.”
From Mesd binds to mature LDL-receptor-related protein-6 and antagonizes ligand binding (2005) · cites this paper as Bafico et al., 2001
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Metadata
- 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.
- Venue
- Nature Cell Biology
- Published
- 2001-06-12
- Volume
- 3
- Issue
- 7
- Pages
- 683-686
- ISSN
- 1465-7392 (ISSN-L)
- 1476-4679
- 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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