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Regulation of the Wnt signaling pathway by disabled-2 (Dab2)

Hocevar, B.A., Mou, F., Rennolds, J.L., Morris, S.M., Cooper, J.A., Howe, P.H.·2003·The EMBO Journal
DOI 10.1093/emboj/cdg286
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Abstract

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 beta-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.

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Crossref · 10.1093/emboj/cdg286

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  • Through endocytosis of signaling components such as Axin or LRP6, Dab2 is suggested to play roles in regulation of the Wnt pathways.

    “Through its functions in endocytosis of signaling components such as Axin or LRP6, Dab2 is also suggested to plays roles in the regulation of the Wnt pathways”

    From Endocytosis and Physiology: Insights from Disabled-2 Deficient Mice (2016) · cites this paper as Hocevar et al., 2003

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Metadata

Authors
Hocevar, B. A., Mou, F., Rennolds, J. L., Morris, S. M., Cooper, J. A., & Howe, P. H.
Venue
The EMBO Journal
Publisher
Springer Science and Business Media LLC
Published
2003-06-16
Volume
22
Issue
12
Pages
3084-3094
ISSN
  • 0261-4189
  • 1460-2075
DOI
10.1093/emboj/cdg286
Cited by
117
References
6
Language
en
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