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

http://www.ncbi.nlm.nih.gov/pubmed/10318824

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.

Pubmed ID: 10318824 RIS Download

Mesh terms: Animals | Axin Protein | 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

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