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PMID: 12805222 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

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

The EMBO journal ·Vol. 22 ·No. 12 ·2003-06-16 ·Pages 3084-94

Hocevar BA, Mou F, Rennolds JL, Morris SM, Cooper JA, Howe PH

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.

MeSH Terms
Adaptor Proteins, Signal Transducing Adaptor Proteins, Vesicular Transport Animals Apoptosis Regulatory Proteins Axin Protein Cell Line Culture Media, Conditioned Cytoskeletal Proteins/metabolism Dishevelled Proteins Enzyme Activation Fibroblasts/cytology,metabolism Genes, Reporter Genes, Tumor Suppressor JNK Mitogen-Activated Protein Kinases Mice Mice, Knockout Mitogen-Activated Protein Kinases/metabolism Phosphoproteins Protein Structure, Tertiary Proteins/genetics,metabolism Proto-Oncogene Proteins/genetics,metabolism Recombinant Fusion Proteins/metabolism Repressor Proteins Signal Transduction/physiology Trans-Activators/metabolism Tumor Suppressor Proteins Wnt Proteins Wnt-5a Protein Wnt3 Protein Zebrafish Proteins beta Catenin
Chemicals
Adaptor Proteins, Signal Transducing Adaptor Proteins, Vesicular Transport Apoptosis Regulatory Proteins Axin Protein CTNNB1 protein, mouse Culture Media, Conditioned Cytoskeletal Proteins DAB2 protein, human DVL3 protein, human Dishevelled Proteins Dvl3 protein, mouse Phosphoproteins Proteins Proto-Oncogene Proteins Recombinant Fusion Proteins Repressor Proteins Trans-Activators Tumor Suppressor Proteins WNT5A protein, human Wnt Proteins Wnt-5a Protein Wnt3 Protein Zebrafish Proteins beta Catenin JNK Mitogen-Activated Protein Kinases Mitogen-Activated Protein Kinases
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Hocevar B A
Department of Cell Biology, The Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
Mou F
Rennolds J L
Morris S M
Cooper J A
Howe P H
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Article Info
Journal
The EMBO journal
Abbr.
EMBO J
ISSN
0261-4189
DOI
10.1093/emboj/cdg286
Published
2003-06-16
Pages
3084-94
Language
English
Region
England
NLM ID
8208664
PMCID
PMC162138
Subset
IM
Grants
NCI NIH HHS · R01 CA055536 · United States
NCI NIH HHS · R01 CA080095 · United States
NCI NIH HHS · CA55536 · United States
NCI NIH HHS · CA80095 · United States
External Links
PubMed source DOI: 10.1093/emboj/cdg286 PMC Full Text View journal details
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