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

Nature Cell Biology volume 3, pages 683–686 (2001)Cite this article

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.

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Figure 1: Analysis of DKK-1 inhibitory function.
Figure 2: DKK-1 purification and characterization.
Figure 3: DKK-1 binds specifically to LRP5/6.
Figure 4: Effects of LRP6 on Dkk-1 functional inhibition of Wnt signalling.

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Acknowledgements

This work has been supported by an NCI grant (CA71672-04). We thank F. Hess for generously providing LRP5 and LRP6 cDNAs, and R. Kohansky and T. Moran for helpful advice.

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Authors and Affiliations

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

    Anna Bafico, Guizhong Liu & Stuart A. Aaronson

  2. Department of Human Microbiology, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, 69978, Israel

    Abraham Yaniv & Arnona Gazit

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  1. Anna Bafico
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  2. Guizhong Liu
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Correspondence to Stuart A. Aaronson.

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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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