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Molecular and Cellular Biology, September 2002, p. 6100-6110, Vol. 22, No. 17
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.17.6100-6110.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Regulation of Wnt/LRP Signaling by Distinct Domains of Dickkopf Proteins

Barbara K. Brott1,2 and Sergei Y. Sokol1,2*

Department of Microbiology and Molecular Genetics, Harvard Medical School,1 Molecular Medicine Unit, Beth Israel Deaconess Medical Center, Boston, Massachusetts 022152

Received 14 January 2002/ Returned for modification 5 March 2002/ Accepted 4 June 2002

Dickkopfs (Dkks) are secreted developmental regulators composed of two cysteine-rich domains. We report that the effects of Dkks depend on molecular context. Although Wnt8 signaling is inhibited by both Dkk1 and Dkk2 in Xenopus embryos, the same pathway is activated upon interaction of Dkk2 with the Wnt coreceptor LRP6. Analysis of individual Dkk domains and chimeric Dkks shows that the carboxy-terminal domains of both Dkks associate with LRP6 and are necessary and sufficient for Wnt8 inhibition, whereas the amino-terminal domain of Dkk1 plays an inhibitory role in Dkk-LRP interactions. Our study illustrates how an inhibitor of a pathway may be converted into an activator and is the first study to suggest a molecular mechanism for how a ligand other than Wnt can positively regulate ß-catenin signaling.

* Corresponding author. Mailing address: Department of Microbiology and Molecular Genetics, Harvard Medical School, and Molecular Medicine Unit, Beth Israel Deaconess Medical Center, 330 Brookline Ave., Boston, MA 02215. Phone: (617) 667-3894. Fax: (617) 667-2913. E-mail: ssokol{at}caregroup.harvard.edu.

Molecular and Cellular Biology, September 2002, p. 6100-6110, Vol. 22, No. 17
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.17.6100-6110.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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