Journal
EMBO JOURNAL
Volume 22, Issue 12, Pages 3084-3094Publisher
OXFORD UNIV PRESS
DOI: 10.1093/emboj/cdg286
Keywords
axin; beta-catenin; Disabled 2 (Dab2); Dishevelled-3 (Dvl-3); Wnt
Categories
Funding
- NCI NIH HHS [CA55536, CA80095, R01 CA055536, R01 CA080095] Funding Source: Medline
Ask authors/readers for more resources
The adaptor molecule Disabled-2 (Dab2) has been shown to link cell surface receptors to downstream signaling pathways. Using a small-pool cDNA screening strategy, we identify that the N-terminal domain of Dab2 interacts with Dishevelled-3 (Dvl-3), a signaling mediator of the Wnt pathway. Ectopic expression of Dab2 in NIH-3T3 mouse fibroblasts attenuates canonical Wnt/beta-catenin-mediated signaling, including accumulation of P-catenin, activation of beta-catenin/ T-cell-specific factor/lymphoid enhancer-binding factor 1-dependent reporter constructs, and endogenous cyclin D1 induction. Wnt stimulation leads to a time-dependent dissociation of endogenous Dab2-Dvl-3 and Dvl-3-axin interactions in NIH-3T3 cells, while Dab2 overexpression leads to maintenance of Dab2-Dvl-3 association and subsequent loss of Dvl-3-axin interactions. In addition, we find that Dab2 can associate with axin in vitro and stabilize axin expression in vivo. Mouse embryo fibroblasts which lack Dab2 exhibit constitutive Wnt signaling as evidenced by increased levels of nuclear beta-catenin and cyclin D1 protein levels. Based on these results, we propose that Dab2 functions as a negative regulator of canonical Wnt signaling by stabilizing the beta-catenin degradation complex, which may contribute to its proposed role as a tumor suppressor.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available