Direct Ubiquitination of β-Catenin by Siah-1 and Regulation by the Exchange Factor TBL1
Copyright policy )Direct Ubiquitination of β-Catenin by Siah-1 and Regulation by the Exchange Factor TBL1
Beta-catenin is a key component of the Wnt signaling pathway that functions as a transcriptional co-activator of Wnt target genes. Upon UV-induced DNA damage, beta-catenin is recruited for polyubiquitination and subsequent proteasomal degradation by a unique, p53-induced SCF-like complex (SCF(TBL1)), comprised of Siah-1, Siah-1-interacting protein (SIP), Skp1, transducin beta-like 1 (TBL1), and adenomatous polyposis coli (APC). Given the complexity of the various factors involved and the novelty of ubiquitination of the non-phosphorylated beta-catenin substrate, we have investigated Siah-1-mediated ubiquitination of beta-catenin in vitro and in cells. Overexpression and purification protocols were developed for each of the SCF(TBL1) proteins, enabling a systematic analysis of beta-catenin ubiquitination using an in vitro ubiquitination assay. This study revealed that Siah-1 alone was able to polyubiquitinate beta-catenin. In addition, TBL1 was shown to play a role in protecting beta-catenin from Siah-1 ubiquitination in vitro and from Siah-1-targeted proteasomal degradation in cells. Siah-1 and TBL1 were found to bind to the same armadillo repeat domain of beta-catenin, suggesting that polyubiquitination of beta-catenin is regulated by competition between Siah-1 and TBL1 during Wnt signaling.
- Stanford University United States
- Vanderbilt University United States
- University of California, Los Angeles United States
Proteasome Endopeptidase Complex, Cell-Free System, Ubiquitin-Protein Ligases, Adenomatous Polyposis Coli Protein, Calcium-Binding Proteins, Ubiquitination, Nuclear Proteins, Phosphoproteins, Cell Line, Wnt Proteins, Mice, Animals, Humans, Transducin, Tumor Suppressor Protein p53, S-Phase Kinase-Associated Proteins, Seven in Absentia Proteins, beta Catenin, Adaptor Proteins, Signal Transducing, Signal Transduction
Proteasome Endopeptidase Complex, Cell-Free System, Ubiquitin-Protein Ligases, Adenomatous Polyposis Coli Protein, Calcium-Binding Proteins, Ubiquitination, Nuclear Proteins, Phosphoproteins, Cell Line, Wnt Proteins, Mice, Animals, Humans, Transducin, Tumor Suppressor Protein p53, S-Phase Kinase-Associated Proteins, Seven in Absentia Proteins, beta Catenin, Adaptor Proteins, Signal Transducing, Signal Transduction
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