Beta-catenin (β-catenin) (Armadillo in Drosophila) is a multifunctional protein involved in two essential cellular events: cell–cell adhesion and the canonical Wnt signaling pathway (Takemaru 2006). β-Catenin/armadillo (Arm) was initially identified as a segment polarity protein in Drosophila in the early 1980s, and later recognized as a key downstream effector of the Wnt pathway. Meanwhile, β-catenin was shown to be an integral component of cadherin-mediated cell adhesion complexes. Over the past two decades, interdisciplinary research has tremendously advanced our knowledge of β-catenin function and its involvement in human disorders (Takemaru et al. 2008; Cadigan and Peifer 2009; MacDonald et al. 2009). At cell–cell adhesion junctions, β-catenin interacts with type-I cadherins and α-catenin, which in turn associates with the actin cytoskeleton. In canonical Wnt signaling, β-catenin acts as a transcriptional coactivator through its interaction with transcription factors and cofactors to stimulate expression of target genes. In recent years, aberrant activity of β-catenin signaling has been linked to various diseases, especially cancer.
Structural Features of β-Catenin
Human or mouse β-catenin consists of 781 amino acid residues, harboring a central structural core of 12 Arm repeats, flanked by unique N- and C-termini (Takemaru et al. 2008; Mosimann et al. 2009). The Arm repeat domain is highly conserved between vertebrates and other species but the terminal portions are diverged. The three-dimensional structure of the Arm repeat region has been determined, forming a twisted superhelical structure with a positively charged groove. Many β-catenin-binding partners bind to the Arm repeat domain. The precise structures of the N- and C-terminal tails remain unknown and may not form a rigid structure on their own. β-Catenin is subjected to posttranslational modifications such as ubiquitination, phosphorylation, and acetylation that control its protein stability, subcellular localization, and protein–protein interactions (Verheyen and Gottardi 2010). Plakoglobin (γ-catenin) is a close homologue of β-catenin in vertebrates and can fulfill some of the same functions (Zhurinsky et al. 2000).
β-Catenin as a Key Transcriptional Coactivator in the Canonical Wnt Pathway
β-Catenin is best known for its function as a transcriptional coactivator downstream of canonical Wnt signaling. Wnts are secreted extracellular proteins that play diverse roles in embryonic development and tissue homeostasis, including cell proliferation, cell fate decisions, and stem cell maintenance, as well as cell movement and polarity (Angers and Moon 2009; Cadigan and Peifer 2009; MacDonald et al. 2009). Core components of the Wnt/β-pathway are highly conserved in evolution from primitive cnidarians to humans.
It is noteworthy that several negative regulators of β-catenin signaling, including APC, Axin, and Chibby (Cby), have been shown to contain both nuclear localization and nuclear export signals that enable them to shuttle between the nucleus and cytoplasm, and facilitate nuclear export of β-catenin (Willert and Jones 2006; Cadigan and Peifer 2009; MacDonald et al. 2009). In contrast, nuclear β-catenin interactors, such as TCF and BCL9/Pygopus (Pygo), appear to retain β-catenin in the nucleus. Detailed information on Wnt signaling can be found on the Wnt Homepage (http://www.stanford.edu/∼rnusse/wntwindow.html).
Mechanisms of Target Gene Activation by β-Catenin
β-Catenin exerts its activation potential through assembly of coactivator and chromatin-remodeling complexes (Willert and Jones 2006; Takemaru et al. 2008; Mosimann et al. 2009). The C-terminal activation domain of β-catenin interacts with various positive cofactors such as the histone acetyltransferases CBP/p300, SWI/SNF ATPase subunit BRG1, and Parafibromin (Hyrax; a component of the RNA polymerase II-associated PAF1 complex). On the other hand, the N-terminal portion of β-catenin directly binds to the bridging molecule BCL9 (Legless), which in turn recruits the PHD-finger protein Pygo. Other β-catenin coactivators include TIP49 (Pontin), MED12, TRRAP, MLL1/2, and TBL1/TBLR1. The signaling activity of β-catenin is negatively regulated by its antagonists such as ICAT and Cby. There is also evidence that the TCF/β-catenin complex can function as a transcriptional repressor (Cadigan and Peifer 2009; MacDonald et al. 2009).
A considerable number of direct target genes of the TCF/β-catenin complex have been identified in various model systems including c-Myc, cyclinD1, Axin2, and TCF/LEF (for a comprehensive list of Wnt target genes, see the Wnt homepage). In general, cellular responses to Wnt signals vary significantly among different cell types, and many Wnt/β-catenin target genes are regulated in a cell-type specific manner. There are a number of reagents/tools available to monitor β-catenin signaling activity including cell-based reporters, transgenic reporter animals, and direct β-catenin target genes (Moon et al. 2004; Barker and Clevers 2006; Chien et al. 2009).
β-Catenin at the Crosstalk with Other Signaling Pathways
Besides the canonical Wnt pathway, β-catenin signaling activity is positively or negatively regulated by a variety of other signaling pathways including Akt (protein kinase B), Src, PTEN, p53, NF-κB, epidermal growth factor (EGF), integrin-linked kinase (ILK), insulin-like growth factor (IGF), and prostaglandin E2 (PGE2) (Moon et al. 2004; MacDonald et al. 2009).
In addition to TCF/LEF factors, β-catenin has been shown to serve as a coactivator or, in some cases, a corepressor for many DNA-binding transcription factors including members of the nuclear hormone receptor family and HMG-box-containing Sox proteins (Takemaru et al. 2008; MacDonald et al. 2009). For instance, the vitamin A, vitamin D, and androgen receptors physically interact with β-catenin in a ligand-dependent fashion to potentiate activation of their target genes, while suppressing expression of TCF/β-catenin-dependent genes. Thus, it is apparent that β-catenin, via these transcription factors, could impact a broader range of gene expression programs.
β-Catenin in Development and Disease
The Wnt/β-catenin pathway has been studied extensively in a wide spectrum of model organisms including C. elegans, Drosophila, zebrafish, Xenopus, and mouse, and proven to be essential for numerous aspects of embryonic development such as segmentation, axis formation, and brain patterning (Cadigan and Nusse 1997; Chien et al. 2009). In mice, β-catenin deficiency results in embryonic lethality at the gastrulation stage (Grigoryan et al. 2008). Over the last decade, through the use of conditional mouse models, β-catenin has been activated and inactivated in various tissues in a temporal and tissue-specific manner (Grigoryan et al. 2008). These studies revealed important roles of Wnt/β-catenin signaling in development and homeostatic maintenance of many organs. In adults, Wnt/β-catenin signaling is crucial for maintaining self-renewal of pluripotent stem cells in skin, blood, intestine, and brain, and for tissue regeneration and repair following injury (Reya and Clevers 2005; Clevers 2006; Stoick-Cooper et al. 2007). Remarkably, recent studies identified the Wnt/β-catenin target and orphan receptor Lgr5 (GPR49) as a marker for stem cells in the adult intestinal epithelium and hair follicle (Barker and Clevers 2010).
More recently, dysregulation of Wnt/β-catenin signaling activity has been linked to the pathogenesis of a wide range of human diseases such as bone density defects and cancer (Logan and Nusse 2004; Clevers 2006; MacDonald et al. 2009).
Loss-of-function mutations in the Wnt coreceptor LRP5 are associated with osteoporosis-pseudoglioma syndrome (OPPG) characterized by low bone mass and loss of vision. Conversely, activating mutations in LRP5 cause increased bone density. These findings clearly demonstrate that Wnt/β-catenin signaling positively regulates bone formation.
Constitutively activated β-catenin signaling, due to loss-of-function mutations in APC or Axin or gain-of-function mutations in β-catenin itself, is associated with a variety of human malignancies including melanoma and colon and hepatocellular carcinomas (Polakis 2000; Takemaru et al. 2008). Remarkably, greater than 70% of colon cancers show aberrant Wnt/β-catenin signaling activity. Mutations in APC or Axin compromise their function within the β-catenin destruction complex, while oncogenic mutations in the N-terminal regulatory domain of β-catenin block its degradation via the ubiquitin-proteasome pathway. In addition, some tumor types show loss of expression of the secreted Wnt antagonists sFRPs and WIF1 due to epigenetic silencing by hypermethylation (Barker and Clevers 2006; Takemaru et al. 2008). All of these alterations ultimately lead to stabilization and nuclear translocation of β-catenin, followed by activation of target gene expression. Hence, β-catenin is an attractive molecular target for cancer therapeutics as well as other Wnt-related diseases. To date, small molecules that disrupt TCF/β-catenin or CBP/β-catenin interaction or stabilize Axin protein and therefore inhibit β-catenin-dependent transcription have been reported (Moon et al. 2004; Barker and Clevers 2006; Takemaru et al. 2008).
β-Catenin plays crucial roles in diverse biological processes as a pivotal component of cell–cell adhesion and Wnt signaling. It serves as a protein network hub by mediating numerous protein–protein interactions to ensure proper development and homeostasis of multiple tissues. Recent advances in genome-wide RNAi screens and proteomics approaches greatly facilitate the identification of novel β-catenin regulators (Angers and Moon 2009). The realization that β-catenin signaling is perturbed in various human diseases continues to fuel worldwide research efforts in the future. Certainly, a better understanding of β-catenin functions has broad impact on human diseases, stem cell biology, and regenerative medicine.
- Takemaru K-I. Catenin beta. UCSD-nature molecule pages. 2006. doi: 10.1038/mp.a000506.01.