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

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

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.

Integrity signals

Registry

Crossref · 10.1038/35083081

Cites

27 of 27 references verified0 citation errors · 0 not checkable

Statistics

Recomputing p-values needs the paper’s full text.

Claims the paper makes

We couldn’t retrieve this paper’s full text, so its claims and self-check weren’t run. The registry and citation checks still apply.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Wet-lab data from just three studies, [105-107], have been reused by simulation studies.

    “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.”
  • 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].

    “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].”

Cites

Flagged first, then by citations

Cited by

Sorted by citations

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
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

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review