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 tumorigenesis1,2,3,4. Secreted antagonists of Wnt include Frizzled (Fz)-related proteins (FRPs)5,6,7, Cerberus8, Wnt inhibitory factor (WIF)9 and Dickkopf (Dkk)10,11. 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 (KD = 0.39 nM). Its receptor was detectable in a complex with a relative molecular mass of 240,000 (Mr 240K) with [125I] Dkk-1 by covalent affinity cross-linking. Wnt signalling through β-catenin is mediated by the Fz receptor12 and a recently identified low-density-lipoprotein-receptor-related co-receptor, LRP6/Arrow13,14,15. 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 Fz5,6,7 or Wnt sequestration through other mechanisms8,9, Dkk-1 specifically inhibits canonical Wnt signalling by binding to the LRP6 component of the receptor complex.

Cite this article

Bafico, A., Liu, G., Yaniv, A. et al. Novel mechanism of Wnt signalling inhibition mediated by Dickkopf-1 interaction with LRP6/Arrow. Nat Cell Biol 3, 683–686 (2001). https://doi.org/10.1038/35083081

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