Kremen proteins are Dickkopf receptors that regulate Wnt/β-catenin signalling (original) (raw)
- Letter
- Published: 26 May 2002
- Wei Wu1,
- Gary Davidson1,
- Joachim Marhold2,
- Mingfa Li2,
- Bernard M. Mechler2,
- Hajo Delius3,
- Dana Hoppe1,
- Peter Stannek1,
- Carmen Walter1,
- Andrei Glinka1 &
- …
- Christof Niehrs1
Nature volume 417, pages 664–667 (2002)Cite this article
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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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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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Authors and Affiliations
- Molecular Embryology Division, Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 280, D-69120, Heidelberg, Germany
Bingyu Mao, Wei Wu, Gary Davidson, Dana Hoppe, Peter Stannek, Carmen Walter, Andrei Glinka & Christof Niehrs - Developmental Genetics Division, Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 280, D-69120, Heidelberg, Germany
Joachim Marhold, Mingfa Li & Bernard M. Mechler - Applied Tumor Virology Division, Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 280, D-69120, Heidelberg, Germany
Hajo Delius
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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
- Received: 15 February 2002
- Accepted: 11 April 2002
- Published: 26 May 2002
- Issue Date: 06 June 2002
- DOI: https://doi.org/10.1038/nature756