Functional domains of axin. Importance of the C terminus as an oligomerization domain.

To understand the mechanism of how Axin acts as an inhibitory molecule in the Wnt pathway, we generated a series of mutated forms of Axin. From the binding experiments, we defined the domains of Axin that bind glycogen synthase kinase-3beta (GSK-3beta) and beta-catenin. We also examined the ability of each ...
Axin mutant to inhibit lymphoid enhancer factor-1 (Lef-1) reporter activity in a cell line expressing high levels of beta-catenin. Axin mutants that did not bind GSK-3beta or beta-catenin were ineffective in suppressing Lef-1 reporter activity. Binding GSK-3beta and beta-catenin was not sufficient for this inhibitory effect of Axin. Axin mutants with C-terminal truncations lacked the ability to inhibit Lef-1 reporter activity, even though they bound GSK-3beta and beta-catenin. The C-terminal region was required for binding to Axin itself. Substitution of the C-terminal region with an unrelated dimerizing molecule, the retinoid X receptor restored its inhibitory effect on Lef-1-dependent transcription. The oligomerization of Axin through its C terminus is important for its function in regulation of beta-catenin-mediated response.
Mesh Terms:
Animals, Binding Sites, COS Cells, Calcium-Calmodulin-Dependent Protein Kinases, Colonic Neoplasms, Cytoskeletal Proteins, DNA-Binding Proteins, Glycogen Synthase Kinase 3, Glycogen Synthase Kinases, Humans, Lymphoid Enhancer-Binding Factor 1, Mice, Mutagenesis, Site-Directed, Protein Conformation, Proteins, Repressor Proteins, Structure-Activity Relationship, Trans-Activators, Transcription Factors, Transcription, Genetic, Tumor Cells, Cultured, beta Catenin
J. Biol. Chem.
Date: May. 14, 1999
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