Kremen proteins are Dickkopf receptors that regulate Wnt/β-catenin signalling

Abstract

The Wnt family of secreted glycoproteins mediate cell–cell interactions during cell growth and differentiation in both embryos and adults1,2. Canonical Wnt signalling by way of the β-catenin pathway is transduced by two receptor families. Frizzled proteins and lipoprotein-receptor-related proteins 5 and 6 (LRP5/6) bind Wnts and transmit their signal by stabilizing intracellular β-catenin3,4,5,6. Wnt/β-catenin signalling is inhibited by the secreted protein Dickkopf1 (Dkk1), a member of a multigene family, which induces head formation in amphibian embryos7. Dkk1 has been shown to inhibit Wnt signalling by binding to and antagonizing LRP5/68,9,10. Here we show that the transmembrane proteins Kremen1 and Kremen2 are high-affinity Dkk1 receptors that functionally cooperate with Dkk1 to block Wnt/β-catenin signalling. Kremen2 forms a ternary complex with Dkk1 and LRP6, and induces rapid endocytosis and removal of the Wnt receptor LRP6 from the plasma membrane. The results indicate that Kremen1 and Kremen2 are components of a membrane complex modulating canonical Wnt signalling through LRP6 in vertebrates.

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Figure 1: Kremens are high-affinity Dkk receptors.
Figure 2: Kremens co-operate with Dkk1 in Wnt/LRP6 signalling inhibition.
Figure 3: Deletion analysis of Kremen.
Figure 4: Kremens, Dkk1 and LRP6 form a ternary complex.
Figure 5: Dkk1 and Kremen trigger removal of LRP6 from the cell surface.

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Acknowledgements

We thank X. He for providing reagents and advice, and J. Nathans and P. Ramulu for pRKdkk1-AP and other plasmids. Other materials were provided by H. Clevers, S. Cohen, S. Di Nardo, J. Flanagan, R. Moon and R. Nusse. We thank S. Cohen for advice with fly work and fly stocks, H. Spring for confocal microscopy and U. Hebling for sequencing. This work was supported by the Deutsche Forschungsgemeinschaft.

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Correspondence to Christof Niehrs.

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Mao, B., Wu, W., Davidson, G. et al. Kremen proteins are Dickkopf receptors that regulate Wnt/β-catenin signalling. Nature 417, 664–667 (2002). https://doi.org/10.1038/nature756

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