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LDL-receptor-related protein 6 is a receptor for Dickkopf proteins

Nature volume 411, pages 321–325 (2001)Cite this article

Abstract

Wnt glycoproteins have been implicated in diverse processes during embryonic patterning in metazoa. They signal through frizzled-type seven-transmembrane-domain receptors to stabilize β-catenin1,2. Wnt signalling is antagonized by the extracellular Wnt inhibitor dickkopf1 (dkk1), which is a member of a multigene family3. dkk1 was initially identified as a head inducer in Xenopus embryos but the mechanism by which it blocks Wnt signalling is unknown. LDL-receptor-related protein 6 (LRP6) is required during Wnt/β-catenin signalling in Drosophila, Xenopus and mouse, possibly acting as a co-receptor for Wnt4,5,6. Here we show that LRP6 (ref. 7) is a specific, high-affinity receptor for Dkk1 and Dkk2. Dkk1 blocks LRP6-mediated Wnt/β-catenin signalling by interacting with domains that are distinct from those required for Wnt/Frizzled interaction. dkk1 and LRP6 interact antagonistically during embryonic head induction in Xenopus where LRP6 promotes the posteriorizing role of Wnt/β-catenin signalling. Thus, DKKs inhibit Wnt co-receptor function, exemplifying the modulation of LRP signalling by antagonists.

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Figure 1: Dkk1 binds to LRP6-transfected cells.
Figure 2: Dkk1 and Dkk2 are high-affinity ligands for LRP6.
Figure 3: LRP6 and dkk1 functionally interact.
Figure 4: LRP6 and dkk1 functionally interact in Xenopus head induction.
Figure 5: Distinct domains of LRP6 interact with Wnt–fz and Dkk1.

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Acknowledgements

We thank X. He for reagents and advice; J. Nathans and P. Ramulu for the unpublished pRKdkk1–AP and other plasmids; and H. Clevers, S. Cohen, J. Flanagan, J. Herz, R. Moon, S. Sokol and N. Ueno for other materials. This work was supported in part by the Deutsche Forschungsgemeinschaft.

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Author notes

  1. Bingyu Mao and Wei Wu: These authors contributed equally to this work

  2. Christof Niehrs: Correspondence and requests for materials should be addressed to C.N.

Authors and Affiliations

  1. Division of Molecular Embryology, Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 280, Heidelberg, D-69120, Germany

    Bingyu Mao, Wei Wu, Yan Li, Dana Hoppe, Peter Stannek, Andrei Glinka & Christof Niehrs

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  1. Bingyu Mao
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Correspondence to Christof Niehrs.

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Mao, B., Wu, W., Li, Y. et al. LDL-receptor-related protein 6 is a receptor for Dickkopf proteins. Nature 411, 321–325 (2001). https://doi.org/10.1038/35077108

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