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Molecular and Cellular Biology, March 2004, p. 2000-2011, Vol. 24, No. 5
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.5.2000-2011.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Casein Kinase I{varepsilon} Modulates the Signaling Specificities of Dishevelled

Feng Cong,* Liang Schweizer, and Harold Varmus

Program in Cell Biology, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, New York 10021

Received 1 July 2003/ Returned for modification 1 August 2003/ Accepted 25 November 2003

Wnt signaling is critical to many aspects of development, and aberrant activation of the Wnt signaling pathway can cause cancer. Dishevelled (Dvl) protein plays a central role in this pathway by transducing the signal from the Wnt receptor complex to the ß-catenin destruction complex. Dvl also plays a pivotal role in the planar cell polarity pathway that involves the c-Jun N-terminal kinase (JNK). How functions of Dvl are regulated in these two distinct pathways is not clear. We show that deleting the C-terminal two-thirds of Dvl, which includes the PDZ and DEP domains and is essential for Dvl-induced JNK activation, rendered the molecule a much more potent activator of the ß-catenin pathway. We also found that casein kinase I{varepsilon} (CKI{varepsilon}), a previously identified positive regulator of Wnt signaling, stimulated Dvl activity in the Wnt pathway, but dramatically inhibited Dvl activity in the JNK pathway. Consistent with this, overexpression of CKI{varepsilon} in Drosophila melanogaster stimulated Wnt signaling and disrupted planar cell polarity. We also observed a correlation between the localization and the signaling activity of Dvl in the ß-catenin pathway and the JNK pathway. Furthermore, by using RNA interference, we demonstrate that the Drosophila CKI{varepsilon} homologue Double time positively regulates the ß-catenin pathway through Dvl and negatively regulates the Dvl-induced JNK pathway. We suggest that CKI{varepsilon} functions as a molecular switch to direct Dvl from the JNK pathway to the ß-catenin pathway, possibly by altering the conformation of the C terminus of Dvl.

* Corresponding author. Mailing address: Memorial Sloan-Kettering Cancer Center, 430 East 67th St., RRL 711, New York, NY 10021. Phone: (212) 639-7317. Fax: (212) 717-3125. E-mail: congf{at}mskcc.org.

Molecular and Cellular Biology, March 2004, p. 2000-2011, Vol. 24, No. 5
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.5.2000-2011.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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