Kremen proteins are Dickkopf receptors that regulate Wnt/β-catenin signalling (original) (raw)

Nature volume 417, pages 664–667 (2002)Cite this article

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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References

  1. Wodarz, A. & Nusse, R. Mechanisms of Wnt signalling in development. Annu. Rev. Cell Dev. Biol. 14, 59–88 (1998)
    Article CAS PubMed Google Scholar
  2. Miller, J. R., Hocking, A. M., Brown, J. D. & Moon, R. T. Mechanism and function of signal transduction by the Wnt/β-catenin and Wnt/Ca2+ pathways. Oncogene 18, 7860–7872 (1999)
    Article CAS PubMed Google Scholar
  3. Bhanot, P. et al. A new member of the frizzled family from Drosophila functions as a Wingless receptor. Nature 382, 225–230 (1996)
    Article ADS CAS PubMed Google Scholar
  4. Tamai, K. et al. LDL-receptor-related proteins in Wnt signal transduction. Nature 407, 530–535 (2000)
    Article ADS CAS PubMed Google Scholar
  5. Wehrli, M. et al. arrow encodes an LDL-receptor-related protein essential for Wingless signalling. Nature 407, 527–530 (2000)
    Article ADS CAS PubMed Google Scholar
  6. Pinson, K. I., Brennan, J., Monkley, S., Avery, B. J. & Skarnes, W. C. An LDL-receptor-related protein mediates Wnt signalling in mice. Nature 407, 535–538 (2000)
    Article ADS CAS PubMed Google Scholar
  7. Glinka, A. et al. Dickkopf-1 is a member of a new family of secreted proteins and functions in head induction. Nature 391, 357–362 (1998)
    Article ADS CAS PubMed Google Scholar
  8. Bafico, A., Liu, G., Yaniv, A., Gazit, A. & Aaronson, S. A. Novel mechanism of Wnt signalling inhibition mediated by Dickkopf-1 interaction with LRP6/Arrow. Nature Cell Biol. 3, 683–686 (2001)
    Article CAS PubMed Google Scholar
  9. Semenov, M. V. et al. Head inducer Dickkopf-1 is a ligand for Wnt coreceptor LRP6. Curr. Biol. 11, 951–961 (2001)
    Article CAS PubMed Google Scholar
  10. Mao, B. et al. LDL-receptor-related protein 6 is a receptor for Dickkopf proteins. Nature 411, 321–325 (2001)
    Article ADS CAS PubMed Google Scholar
  11. Nakamura, T., Aoki, S., Kitajima, K., Takahashi, T. & Matsumoto, K. Molecular cloning and characterization of Kremen, a novel kringle-containing transmembrane protein. Biochim. Biophys. Acta 1518, 63–72 (2001)
    Article CAS PubMed Google Scholar
  12. Hsieh, J. C., Rattner, A., Smallwood, P. M. & Nathans, J. Biochemical characterization of Wnt-frizzled interactions using a soluble, biologically active vertebrate Wnt protein. Proc. Natl Acad. Sci. USA 96, 3546–3551 (1999)
    Article ADS CAS PubMed PubMed Central Google Scholar
  13. Korinek, V. et al. Constitutive transcriptional activation by a β-catenin-Tcf complexes in APC/ colon carcinoma. Science 275, 1784–1787 (1997)
    Article CAS PubMed Google Scholar
  14. Brand, A. H. & Perrimon, N. Targeted gene expression as a means of altering cell fates and generating dominant phenotypes. Development 118, 401–415 (1993)
    CAS PubMed Google Scholar
  15. Couso, J. P., Bishop, S. A. & Martinez Arias, A. The wingless signalling pathway and the patterning of the wing margin in Drosophila. Development 120, 621–636 (1994)
    CAS PubMed Google Scholar
  16. Angers, S. et al. Detection of β 2-adrenergic receptor dimerization in living cells using bioluminescence resonance energy transfer (BRET). Proc. Natl Acad. Sci. USA 97, 3684–3689 (2000)
    ADS CAS PubMed PubMed Central Google Scholar
  17. Xu, Y., Piston, D. W. & Johnson, C. H. A bioluminescence resonance energy transfer (BRET) system: application to interacting circadian clock proteins. Proc. Natl Acad. Sci. USA 96, 151–156 (1999)
    Article ADS CAS PubMed PubMed Central Google Scholar
  18. Rupp, R. A., Snider, L. & Weintraub, H. Xenopus embryos regulate the nuclear localization of XMyoD. Genes Dev. 8, 1311–1323 (1994)
    Article CAS PubMed Google Scholar
  19. Wu, W., Glinka, A., Delius, H. & Niehrs, C. Mutual antagonism between dickkopf1 and -2 regulates Wnt/β-catenin signalling. Curr. Biol. 10, 1611–1614 (2000)
    Article CAS PubMed Google Scholar

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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

  1. 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
  2. Developmental Genetics Division, Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 280, D-69120, Heidelberg, Germany
    Joachim Marhold, Mingfa Li & Bernard M. Mechler
  3. Applied Tumor Virology Division, Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 280, D-69120, Heidelberg, Germany
    Hajo Delius

Authors

  1. Bingyu Mao
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  2. Wei Wu
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  3. Gary Davidson
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  4. Joachim Marhold
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  5. Mingfa Li
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  6. Bernard M. Mechler
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  7. Hajo Delius
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  8. Dana Hoppe
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  9. Peter Stannek
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  10. Carmen Walter
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  11. Andrei Glinka
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  12. Christof Niehrs
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Correspondence toChristof 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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