Inhibition of the Wnt Signaling Pathway by Idax, a Novel Dvl-Binding Protein

Abstract

In attempting to clarify the roles of Dvl in the Wnt signaling pathway, we identified a novel protein which binds to the PDZ domain of Dvl and named it Idax (for inhibition of the Dvl and Axin complex). Idax and Axin competed with each other for the binding to Dvl. Immunocytochemical analyses showed that Idax was localized to the same place as Dvl in cells and that expression of Axin inhibited the colocalization of Dvl and Idax. Further, Wnt-induced accumulation of β-catenin and activation of T-cell factor in mammalian cells were suppressed by expression of Idax. Expression of Idax in Xenopus embryos induced ventralization with a reduction in the expression of siamois, a Wnt-inducible gene. Idax inhibited Wnt- and Dvl- but not β-catenin-induced axis duplication. It is known that Dvl is a positive regulator in the Wnt signaling pathway and that the PDZ domain is important for this activity. Therefore, these results suggest that Idax functions as a negative regulator of the Wnt signaling pathway by directly binding to the PDZ domain of Dvl.

ACKNOWLEDGMENTS

We are grateful to H. Clevers, D. Kimelman, B. Dallapiccola, A. Nagafuchi, and M. Nakata for donating plasmids and antibodies. We thank the Research Center for Molecular Medicine and Research Facilities for Laboratory Animal Sciences, Hiroshima University School of Medicine, for the use of their facilities.

This work was supported by grants-in-aid for scientific research (B) and for scientific research on priority areas (A) from the Ministry of Education, Science, and Culture, Japan (1999 and 2000), by grants from the Yamanouchi Foundation for Research on Metabolic Disorders (1999 and 2000), by the Uehara Memorial Foundation (1998), by a Research Grant of the Princess Takamatsu Cancer Research Fund (1999; 99-23195), and by the Public Trust Haraguchi Memorial Cancer Research Fund (1999).