The many faces and functions of β-catenin

Abstract

β-Catenin (Armadillo in Drosophila) is a multitasking and evolutionary conserved molecule that in metazoans exerts a crucial role in a multitude of developmental and homeostatic processes. More specifically, β-catenin is an integral structural component of cadherin-based adherens junctions, and the key nuclear effector of canonical Wnt signalling in the nucleus. Imbalance in the structural and signalling properties of β-catenin often results in disease and deregulated growth connected to cancer and metastasis. Intense research into the life of β-catenin has revealed a complex picture. Here, we try to capture the state of the art: we try to summarize and make some sense of the processes that regulate β-catenin, as well as the plethora of β-catenin binding partners. One focus will be the interaction of β-catenin with different transcription factors and the potential implications of these interactions for direct cross-talk between β-catenin and non-Wnt signalling pathways.

Figure 1

The life of β-catenin within the cell. Newly synthesized β-catenin is immobilized by E-cadherin at adherens junctions, where it can interact also with α-catenin, thereby indirectly modulating the actin cytoskeleton. β-catenin can be released from the adherens junctions by the activity of protein kinases or by downregulation of E-cadherin. Free excess β-catenin is immediately phosphorylated by the destruction complex and thus marked for subsequent degradation. A portion of β-catenin can be kept in the cytoplasm protected by APC. Wnt signalling blocks the activity of the destruction complex resulting in increased levels of cytolasmic β-catenin, which is translocated to the nucleus. In the nucleus, β-catenin associates with transcription factors from the TCF/Lef family and drives transcription of Wnt/β-catenin target genes. Other factors can also provide β-catenin with a DNA binding platform, often counteracting canonical Wnt signalling. Signalling activity of β-catenin in the nucleus can be regulated by modulating its nuclear import/export. Besides its structural role in the adherens junctions and signalling activity in the nucleus, β-catenin may also play an important function in the centrosome. CTTA, C-Terminal Transcriptional Activators, NTTA, N-Terminal Transcriptional Activators.

Figure 2

β-Catenin serves as a binding platform for a multitude of interaction partners in adherens junctions, in the cytoplasm and in the nucleus. (A) The β-catenin protein consists of a central region composed of 12 Armadillo repeats (numbered boxes), flanked by an amino-terminal domain (NTD) and a carboxy-terminal domain (CTD). Between the last Armadillo repeat and the flexible part of the CTD is the conserved helix-C (C). Coloured bars show experimentally validated binding sites for β-catenin interaction partners. Colour code: purple, components of adherens junctions; blue, members of the β-catenin destruction complex; red, transcriptional co-activators; green, transcription factors providing DNA binding; gray, transcriptional inhibitors. C-Terminal Transcriptional Activators (CTTA), the critical domain for their binding is marked by brackets. Little circles indicate phosphorylation sites on either E-cadherin or APC that enhance the interactions. APC, Adenoma Polyposis Coli; TCF/Lef, T-cell factor/Lymphoid enhancer factor; AR, Androgen Receptor; LRH-1, Liver Receptor Homologue-1; ICAT, Inhibitor of β-catenin and TCF; BCL9, B-cell lymphoma-9. (B) The C-terminus of β-catenin serves as a binding factor for a multitude of complexes promoting β-catenin-mediated transcription. Experimentally validated binding motifs for particular proteins are indicated. In the grey boxes, the function is indicated of the particular β-catenin interactor or of a complex, where this binding partner is a member. Brg-1 is also known as SMARCA4, CBP as CREBBP. HAT, histone acetyl-transferase; HMT, histone methyl-transferase; MLL, mixed lineage leukaemia; PAF-1, Polymerase-associated factor-1; PIC, Pre-Initiation Complex; TBP, TATA-box Binding Protein; TRRAP, Transformation/transcription domain-associated protein.

Figure 3

β-Catenin is an evolutionarily ancient molecule that provided its function before Wnt signalling and classical cadherin-based adhesion appeared. Schematic evolutionary tree showing the relationships among Amoebozoa (represented by Dictyostelium discoideum) and metazoa, as well as the diversity of signalling components. In Dictyostelium discoideum, β-catenin acts as a functional molecule in polarized epithelia. In animals (metazoa), β-catenin plays a dual role as a signalling component of canonical Wnt signalling or as a structural component of cadherin-based cell–cell junctions. The presence of β-catenin and key components of adherens junctions (classical cadherins—containing an intracellular domain binding to β-catenin) and of canonical Wnt signalling (Wnt ligands, TCF/Lef transcription factors) is indicated to the right. In the case of Wnt ligands, the first number indicates how many different Wnt ligands were determined, the second number in brackets indicates how many Wnt subfamilies were determined in a particular group. The number in the case of TCF/Lef refers to how many different TCF/Lef proteins were found. Yes means presence, no absence. The following animal species were compared: Porifera (Sponges): Amphimedon queenslandica, Cnidaria: Nematostella vectans, Insects: Drosophila melanogaster; Vertebrates: Mus musculus.

Figure 4

The functional output of β-catenin is affected by post-translational modifications. (A) A representative scheme showing the sites where β-catenin is phosphorylated: those in blue promote its degradation, those in red and purple enhance the signalling activity. The Y654 site (purple) was experimentally validated in a mouse model in vivo. The protein kinases are denoted that promote each phosphorylation. (B) Table summarizing possible post-translational modifications of β-catenin with their functional consequences.

Figure 5

The TCF/β-catenin transcriptional switch. (A) In an unstimulated (Wnt OFF) situation, TCF/Lef transcription factors associated with Groucho and/or CtBP co-repressors act as transcriptional repressors. (B) As described so far only for TCF3 (Wray et al, 2011; Yi et al, 2011) the binding of β-catenin displaces co-repressors, thereby promoting transcriptional derepression. This mechanism is less well studied than the more classical activation by co-activator recruitment. The question mark indicates that the role of any β-catenin binding partners in this process is not yet clear. (C) β-Catenin converts TCF/Lef into transcriptional activators providing an interacting platform for the multitude of dynamically cycling transcriptional co-activators. (D) TCF/β-catenin-mediated transcription may also be deactivated by transcriptional co-repressors, such as Mtgr-1, COOP, or Groucho/TLE kicking off β-catenin. Some of these co-repressors may act by recruiting HDAC activity. (E) TCF/β-catenin-mediated transcription may also be deactivated by direct interaction with transcriptional co-repressors (Reptin or NCoR/SMRT) recruiting histone deacetylases. (F) Chibby with 14-3-3 protein or APC with CtBP can sequester β-catenin away from target promoters and export it out of the nucleus. Binding of ICAT or Chibby blocks the interaction between TCFs and β-catenin.

Figure 6

β-catenin in hypoxia and under oxidative stress. (A) Under hypoxic conditions in stem cells activated HIF1α stimulates transcription mediated by β-catenin and Lef1 (and/or TCF1) and by promoting nuclear translocation of β-catenin. (B) In differentiated or cancer cells, HIF1α usurps β-catenin at the expense of TCF/Lef transcription factors, thereby inhibiting Tcf/β-catenin-mediated transcription. β-Catenin potentiates transcription of HIF1α target genes. Among the others targets are the forkhead transcription factors FOXO, which are also upregulated under stress conditions caused by ROS. FOXO transcription factors even sequester β-catenin from TCF/Lef, counteracting TCF/β-catenin-mediated transcription. Growth stimuli (such as Insulin) can activate the protein kinase Akt/PKB, which blocks FOXO activity and may promote phosphorylation of β-catenin, restoring active TCF/β-catenin transcription.