Letter | Published:

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


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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


  1. 1

    Wodarz, A. & Nusse, R. Mechanisms of Wnt signalling in development. Annu. Rev. Cell Dev. Biol. 14, 59–88 (1998)

  2. 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)

  3. 3

    Bhanot, P. et al. A new member of the frizzled family from Drosophila functions as a Wingless receptor. Nature 382, 225–230 (1996)

  4. 4

    Tamai, K. et al. LDL-receptor-related proteins in Wnt signal transduction. Nature 407, 530–535 (2000)

  5. 5

    Wehrli, M. et al. arrow encodes an LDL-receptor-related protein essential for Wingless signalling. Nature 407, 527–530 (2000)

  6. 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)

  7. 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)

  8. 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)

  9. 9

    Semenov, M. V. et al. Head inducer Dickkopf-1 is a ligand for Wnt coreceptor LRP6. Curr. Biol. 11, 951–961 (2001)

  10. 10

    Mao, B. et al. LDL-receptor-related protein 6 is a receptor for Dickkopf proteins. Nature 411, 321–325 (2001)

  11. 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)

  12. 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)

  13. 13

    Korinek, V. et al. Constitutive transcriptional activation by a β-catenin-Tcf complexes in APC/ colon carcinoma. Science 275, 1784–1787 (1997)

  14. 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)

  15. 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)

  16. 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)

  17. 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)

  18. 18

    Rupp, R. A., Snider, L. & Weintraub, H. Xenopus embryos regulate the nuclear localization of XMyoD. Genes Dev. 8, 1311–1323 (1994)

  19. 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)

Download references


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.

Author information

Correspondence to Christof Niehrs.

Ethics declarations

Competing interests

The authors declare that they have no competing financial interests.

Rights and permissions

Reprints and Permissions

About this article

Further reading

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.


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.