1. ¹Department of Cell Biology, The Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
2. ²INSERM U673, Hopital St-Antoine, Paris, France

Correspondence: Dr PH Howe, Department of Cancer Biology, NB4, The Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA. E-mail: howep@ccf.org

Received 1 May 2007; Revised 17 August 2007; Accepted 1 September 2007; Published online 8 October 2007.

Abstract

-Catenin-mediated Wnt signaling is essential in embryonic development and in adult tissues. Recent studies have demonstrated that Axin not only plays an important inhibitory role in coordinating -catenin degradation, but is itself degraded by the low-density-lipoprotein receptor-related protein (LRP)5/6 Wnt co-receptor. Here, we demonstrate that the endocytic adaptor molecule Disabled-2 (Dab2), which we have previously demonstrated to act as an inhibitor of -catenin signaling, interacts with Axin and prevents its interaction with and degradation by the LRP5 co-receptor, thereby increasing its half-life and stabilization. Dab2 levels induced during retinoic acid-induced differentiation of F9, or during transforming growth factor--induced epithelial–mesenchymal transdifferentiation of mouse mammary epithelial cells result in the stabilization of Axin and concomitant inhibition of -catenin signaling. Ectopic expression of Dab2 in F9 cells as well as in transformed cell lines results in increased Axin expression and attenuation of Wnt-mediated signaling. We conclude that Dab2 may play an important role in the maintenance of the differentiated state and restrain Wnt-mediated proliferation through its association with and modulation of Axin.