Walking the tight wire between cell adhesion and WNT signalling: a balancing act for β-catenin

Abstract

CTNNB1 (catenin β-1, also known as β-catenin) plays a dual role in the cell. It is the key effector of WNT/CTNNB1 signalling, acting as a transcriptional co-activator of TCF/LEF target genes. It is also crucial for cell adhesion and a critical component of cadherin-based adherens junctions. Two functional pools of CTNNB1, a transcriptionally active and an adhesive pool, can therefore be distinguished. Whether cells merely balance the distribution of available CTNNB1 between these functional pools or whether interplay occurs between them has long been studied and debated. While interplay has been indicated upon artificial modulation of cadherin expression levels and during epithelial-mesenchymal transition, it is unclear to what extent CTNNB1 exchange occurs under physiological conditions and in response to WNT stimulation. Here, we review the available evidence for both of these models, discuss how CTNNB1 binding to its many interaction partners is controlled and propose avenues for future studies.

Keywords: WNT signal transduction; cell adhesion; e-cadherin; epithelial–mesenchymal transition; interplay; β-catenin.

Figure 1.

Schematic of CTNNB1 in cell adhesion and WNT/CTNNB1 signalling. Most schematic depictions of WNT/CTNNB1 signalling do not display the large CTNNB1 fraction at cell–cell junctions, and vice versa. This figure visualizes both the structural role of CTNNB1 in cell adhesion and the transcriptional role of CTNNB1 in WNT/CTNNB1 signalling. AJs can have different conformations, including a stable and remodelling state. AJs are formed by cadherins that bind their counterparts on adjacent cells via their extracellular domains and are attached to the cytoskeleton through their intracellular tails via CTNNB1 and CTNNA1. In remodelling AJs, the actin/myosin bundles run perpendicular to the membrane, and VCL is present. In stable AJs, actin/myosin bundles run parallel to the membrane. CTNNB1 is also a critical component of the WNT/CTNNB1 pathway. In the presence of WNT signals, it activates the transcription of WNT target genes in the nucleus together with TCF as part of the enhanceosome. In the absence of WNT, CTNNB1 is sequestered in the cytoplasm by the destruction complex, consisting of APC, AXIN, CK1 and GSK3, where it gets phosphorylated and subsequently degraded by the proteasome.

Figure 2.

Schematic visualization of the localization of CTNNB1 functional pools. CTNNB1 (yellow) functional pools cannot be distinguished based on their localization. The adhesion pool of CTNNB1 (blue) is present at the membrane, but also undergoes anterograde and retrograde trafficking. Furthermore, CTNNA1/CTNNB1 dimers have been shown to be present in the nucleus, but they are not transcriptionally active. The transcriptional pool of CTNNB1 (pink) is present in the nucleus to activate transcription. It is also present in the cytoplasm as free CTNNB1, and as bound CTNNB1 sequestered by the destruction complex. Finally, the transcriptional pool of CTNNB1 may be present at the membrane, possibly via interaction with the WNT signalosome.

Figure 3.

Schematic visualization of CTNNB1 and its key binding sites for interaction partners. CTNNB1 contains 12 armadillo repeats, which among others contain binding sites for cadherins, TCF, AXIN, APC and BCL9 L. These binding sites overlap, creating competition for binding. CTNNA1- and BCL9 L-binding sites at the NH2 terminus also overlap. The flexible C-terminal domain has been proposed to be able to change conformation, thus blocking the cadherin-binding site.