β-Catenin Binds to the Activation Function 2 Region of the Androgen Receptor and Modulates the Effects of the N-Terminal Domain and TIF2 on Ligand-Dependent Transcription
Open accessAbstract
Beta-catenin is a multifunctional molecule that is activated by signaling through WNT receptors. beta-Catenin can also enhance the transcriptional activity of some steroid hormone receptors such as the androgen receptor and retinoic acid receptor alpha. Androgens can affect nuclear translocation of beta-catenin and influence its subcellular distribution. Using mammalian two-hybrid binding assays, analysis of reporter gene transcription, and coimmunoprecipitation, we now show that beta-catenin binds to the androgen receptor ligand-binding domain (LBD) and modulates the transcriptional effects of TIF2 and the androgen receptor N-terminal domain (NTD). In functional assays, beta-catenin bound to androgen receptor only in the presence of ligand agonists, not antagonists. Beta-catenin binding to the androgen receptor LBD was independent of and cooperative with the androgen receptor NTD and the p160 coactivator TIF2, both of which bind to the activation function 2 (AF-2) region of the androgen receptor. Different mutations of androgen receptor helix 3 amino acids disrupted binding of androgen receptor NTD and beta-catenin. beta-Catenin, androgen receptor NTD, and TIF2 binding to the androgen receptor LBD were affected similarly by a subset of helix 12 mutations, but disruption of two sites on helix 12 affected only binding of beta-catenin and not of TIF2 or the androgen receptor NTD. Mutational disruption of each of five LXXLL peptide motifs in the beta-catenin armadillo repeats did not disrupt either binding to androgen receptor or transcriptional coactivation. ICAT, an inhibitor of T-cell factor 4 (TCF-4), and E-cadherin binding to beta-catenin also blocked binding of the androgen receptor LBD. We also demonstrated cross talk between the WNT and androgen receptor signaling pathways because excess androgen receptor could interfere with WNT signaling and excess TCF-4 inhibited the interaction of beta-catenin and androgen receptor. Taken together, the data show that beta-catenin can bind to the androgen receptor LBD and modulate the effects of the androgen receptor NTD and TIF2 on transcription.
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β-catenin binds the AR AF2.
“While previous studies suggested that β-catenin binds the AR AF2 [18], a co-crystal structure of β-catenin in complex with the LBD of the orphan nuclear receptor LRH-1 suggests involvement between the fifth armadillo repeat of β-catenin and a surface that overlaps with a region analogous to the AR BF3 surface (Fig 1).”
From The FKBP52 Cochaperone Acts in Synergy with β-Catenin to Potentiate Androgen Receptor Signaling (2015) · cites this paper as [18]
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References 65 · Cited by 169
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- Authors
- Song, L.-N., Herrell, R., Byers, S., Shah, S., Wilson, E. M., & Gelmann, E. P.
- Affiliations
- Georgetown University (US)
- University of North Carolina at Chapel Hill (US)
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2003-03-01
- Volume
- 23
- Issue
- 5
- Pages
- 1674-1687
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC151689
- OpenAlex
- W2164404916
- Cited by
- 169
- References
- 65
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 2 · 2023: 4 · 2022: 3 · 2021: 6 · 2020: 5 · 2019: 6 · 2018: 1 · 2017: 9 · 2016: 4 · 2015: 4 · 2014: 7 · 2013: 9 · 2012: 9
- FWCI
- 5.53
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular and Cellular Biology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Canadian Institute for Theoretical Astrophysics
- National Institutes of Health (5r21ca087855-02)
- National Cancer Institute (R01CA096854, CA 96854, CA87855)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Prostate Cancer Treatment and Research
- Keywords
- β-catenin, androgen receptor, ligand-binding domain, AF-2, TIF2, transcriptional coactivation, armadillo repeats, LXXLL motif, Wnt signaling, TCF4, E-cadherin, steroid hormone receptors
- MeSH terms
- Animals, Binding, Competitive, Cell Line, Cytoskeletal Proteins, Dose-Response Relationship, Drug, Glutathione Transferase, Kinetics, Ligands, Luciferases, Models, Molecular, Mutation, Peptides, Plasmids, Precipitin Tests, Protein Binding, Receptors, Androgen, Recombinant Fusion Proteins, Saccharomyces cerevisiae, Transcription Factors, Transcription, Genetic, Transfection, Protein Biosynthesis, Blotting, Western, Signal Transduction, Transcriptional Activation, Trans-Activators, Protein Structure, Tertiary, COS Cells, Two-Hybrid System Techniques, Amino Acid Motifs, beta Catenin, Nuclear Receptor Coactivator 2
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