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

A Bafico1, G Liu, A Yaniv

  • 1Derald H. Ruttenberg Cancer Center, Mount Sinai School of Medicine, Box 1130, One Gustave L. Levy Place, New York, New York 10029, USA.

Nature Cell Biology
|July 4, 2001
PubMed

Insights

Dickkopf-1 (Dkk-1) inhibits Wnt signaling not by binding Wnt, but by targeting the LRP6 receptor. This novel mechanism reveals Dkk-1

Area of Science:

  • Molecular Biology
  • Cell Signaling
  • Developmental Biology

Background:

  • Wnt signaling is crucial for cell fate, tissue patterning, and cancer.
  • Known Wnt antagonists include Frizzled-related proteins (FRPs), Cerberus, Wnt inhibitory factor (WIF), and Dickkopf (Dkk).
  • FRPs, Cerberus, and WIF inhibit Wnt by binding and sequestering Wnt itself.

Purpose of the Study:

  • To elucidate the novel mechanism of Wnt-signaling inhibition by human Dickkopf-1 (Dkk-1).
  • To determine the specific molecular interactions and receptor involvement in Dkk-1 mediated Wnt pathway inhibition.

Main Methods:

  • Covalent affinity cross-linking using [(125)I] Dkk-1 to identify binding partners.
  • Analysis of Dkk-1 binding affinity and receptor complex formation.
  • Investigating the role of Frizzled (Fz) and Low-density-lipoprotein-receptor-related protein 6 (LRP6) in Dkk-1 function.

Main Results:

  • Dkk-1 binds to a single cell surface site with high affinity (K(D) = 0.39 nM) and does not interact with Wnt.
  • A 240,000 molecular mass (M(r) 240K) complex of Dkk-1 and LRP6 was identified.
  • Dkk-1 binding and complex formation were enhanced by LRP6 overproduction, independent of Fz.
  • LRP6, not Fz, was shown to be the critical component for Dkk-1 inhibition of Wnt signaling.

Conclusions:

  • Dkk-1 specifically inhibits canonical Wnt signaling through a novel mechanism.
  • Unlike other antagonists, Dkk-1 targets the LRP6 co-receptor component of the Wnt receptor complex.
  • This distinct mechanism highlights the complexity of Wnt pathway regulation.

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