Novel Mechanism of Wnt Signalling Inhibition Mediated by Dickkopf-1 Interaction With LRP6/Arrow

Nat Cell Biol. 2001 Jul;3(7):683-6. doi: 10.1038/35083081.

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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Cell Line
  • Cytoskeletal Proteins / pharmacology
  • Drug Interactions
  • Humans
  • Immunoblotting
  • Intercellular Signaling Peptides and Proteins
  • Kinetics
  • Low Density Lipoprotein Receptor-Related Protein-6
  • Protein Binding
  • Proteins / metabolism
  • Proteins / pharmacology*
  • Proto-Oncogene Proteins / antagonists & inhibitors
  • Proto-Oncogene Proteins / physiology*
  • Receptors, LDL / metabolism*
  • Signal Transduction / drug effects*
  • Trans-Activators*
  • Transfection
  • Wnt Proteins
  • Zebrafish Proteins*
  • beta Catenin

Substances

  • CTNNB1 protein, human
  • Cytoskeletal Proteins
  • DKK1 protein, human
  • Intercellular Signaling Peptides and Proteins
  • LRP6 protein, human
  • Low Density Lipoprotein Receptor-Related Protein-6
  • Proteins
  • Proto-Oncogene Proteins
  • Receptors, LDL
  • Trans-Activators
  • Wnt Proteins
  • Zebrafish Proteins
  • beta Catenin
  • dkk1b protein, zebrafish