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Structural basis of coactivation of liver receptor homolog-1 by ?-catenin.

ABSTRACT: We report the three-dimensional structure of a ?-catenin armadillo repeat in complex with the liver receptor homolog-1 (LRH-1) ligand binding domain at 2.8 ? resolution as the first structure of ?-catenin in complex with any nuclear receptor. The surface of ?-catenin that binds LRH-1 partly overlaps defined contact sites for peptide segments of ?-catenin partners, including T-cell factor-4. The surface of LRH-1 that engages ?-catenin is comprised of helices 1, 9, and 10 and is distinct from known interaction surfaces of LRH-1, including corepressor and coactivator binding sites. Targeted mutagenesis of amino acids forming both sides of the LRH-1/?-catenin interface reveals that they are essential for stable interactions between these proteins in solution. The LRH-1 binding site in ?-catenin is also required for association with androgen receptor, providing evidence that the observed LRH-1/?-catenin interaction may be prototypic.

SUBMITTER: Yumoto F

PROVIDER: S-EPMC3252924 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature

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Structural basis of coactivation of liver receptor homolog-1 by β-catenin.

Yumoto Fumiaki F Nguyen Phuong P Sablin Elena P EP Baxter John D JD Webb Paul P Fletterick Robert J RJ

Proceedings of the National Academy of Sciences of the United States of America 20111220 1

We report the three-dimensional structure of a β-catenin armadillo repeat in complex with the liver receptor homolog-1 (LRH-1) ligand binding domain at 2.8 Å resolution as the first structure of β-catenin in complex with any nuclear receptor. The surface of β-catenin that binds LRH-1 partly overlaps defined contact sites for peptide segments of β-catenin partners, including T-cell factor-4. The surface of LRH-1 that engages β-catenin is comprised of helices 1, 9, and 10 and is distinct from know ...[more]

PMID: 22187462

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Project description:Background and aimsHCC remains a major unmet clinical need. Although activating catenin beta-1 (CTNNB1) mutations are observed in prominent subsets of HCC cases, these by themselves are insufficient for hepatocarcinogenesis. Coexpression of mutant CTNNB1 with clinically relevant co-occurrence has yielded HCCs. Here, we identify cooperation between β-catenin and nuclear factor erythroid 2-related factor 2 (Nrf2) signaling in HCC.Approach and resultsPublic HCC data sets were assessed for concomitant presence of CTNNB1 mutations and either mutations in nuclear factor erythroid-2-related factor-2 (NFE2L2) or Kelch like-ECH-associated protein 1 (KEAP1), or Nrf2 activation by gene signature. HCC development in mice and similarity to human HCC subsets was assessed following coexpression of T41A-CTNNB1 with either wild-type (WT)-, G31A-, or T80K-NFE2L2. Based on mammalian target of rapamycin complex 1 activation in CTNNB1-mutated HCCs, response of preclinical HCC to mammalian target of rapamycin (mTOR) inhibitor was investigated. Overall, 9% of HCC cases showed concomitant CTNNB1 mutations and Nrf2 activation, subsets of which were attributable to mutations in NFE2L2/KEAP1. Coexpression of mutated CTNNB1 with mutant NFE2L2, but not WT-NFE2L2, led to HCC development and mortality by 12-14 weeks. These HCCs were positive for β-catenin targets, like glutamine synthetase and cyclin-D1, and Nrf2 targets, like NAD(P)H quinone dehydrogenase 1 and peroxiredoxin 1. RNA-sequencing and pathway analysis showed high concordance of preclinical HCC to human HCC subset showing activation of unique (iron homeostasis and glioblastoma multiforme signaling) and expected (glutamine metabolism) pathways. NFE2L2-CTNNB1 HCC mice were treated with mTOR inhibitor everolimus (5-mg/kg diet ad libitum), which led to >50% decrease in tumor burden.ConclusionsCoactivation of β-catenin and Nrf2 is evident in 9% of all human HCCs. Coexpression of mutant NFE2L2 and mutant CTNNB1 led to clinically relevant HCC development in mice, which responded to mTOR inhibitors. Thus, this model has both biological and therapeutic implications.

Project description:BACKGROUND & AIMS:Wnt/beta-catenin activation is observed in normal liver development, regeneration, and liver cancer. Our aim was to elucidate the regulation and mechanism of this pathway in liver. METHODS:We report the generation and characterization of liver-specific nonmutated beta-catenin-overexpressing transgenic mice. Transgenic livers were examined for their morphology and phenotype by histology, proliferation, apoptosis, and microarray analysis. RESULTS:Transgenic livers displayed a significant increase in cytoplasmic, membranous, and nuclear beta-catenin in hepatocytes as compared with their wild-type littermates, which display a predominant membranous localization only. A 15%-20% increase in the liver weight-body weight ratio was evident in transgenic mice secondary to increased hepatocyte proliferation. Microarray analysis showed differential expression of approximately 400 genes in the transgenic livers. Epidermal growth factor receptor RNA and protein and increased levels of activated epidermal growth factor receptor and Stat3 were observed in the transgenic livers. Epidermal growth factor receptor promoter analysis showed a T-cell factor-binding site, and subsequent reporter assay confirmed epidermal growth factor receptor activation in response to Wnt-3A treatment that was abrogated by frizzled related protein 1, a known Wnt antagonist. Epidermal growth factor receptor inhibition successfully decreased liver size in transgenic mice. Next, 7 of 10 hepatoblastomas displayed simultaneous beta-catenin and epidermal growth factor receptor up-regulation, thus suggesting a strong relationship between these 2 proteins in tumors. CONCLUSIONS:beta-Catenin transgenic mice show an in vivo hepatotrophic effect secondary to increased basal hepatocyte proliferation. Epidermal growth factor receptor seems to be a direct target of the pathway, and epidermal growth factor receptor activation might contribute toward some mitogenic effects of increased beta-catenin in liver: epidermal growth factor receptor inhibition might be useful in such states.

Dataset Information

Structural basis of coactivation of liver receptor homolog-1 by ?-catenin.

Publications

Structural basis of coactivation of liver receptor homolog-1 by β-catenin.

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