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.

USP2-Related Cellular Signaling and Consequent Pathophysiological Outcomes

“…Wnt/β-catenin signaling also plays a pivotal role in the EMT [53][54][55][56]. Although β-catenin functions as a component of adherens junctions, nuclear β-catenin augments the transcription of EMT-related genes by interacting with several transcription factors, such as DNA-bound T cell factor/lymphoid enhancer factor [56].…”

“…Wnt/β-catenin signaling also plays a pivotal role in the EMT [53][54][55][56]. Although β-catenin functions as a component of adherens junctions, nuclear β-catenin augments the transcription of EMT-related genes by interacting with several transcription factors, such as DNA-bound T cell factor/lymphoid enhancer factor [56]. In normal epithelial cells, β-catenin is continuously digested by a proteasome-dependent mechanism because the glycogen synthase kinase (GSK)3β /Axin/adenomatous polyposis coli (APC) complex promotes the polyubiquitination of β-catenin [57].…”

Wnt/β‐catenin signaling: Structure, assembly and endocytosis of the signalosome

“…Binding to the receptors promotes the recruitment of several downstream effectors such as the adaptor Dishevelled (Dvl in mammals, Dsh in Drosophila), CK1γ, Axin1, and GSK3β (Davidson et al, 2005;Del Valle-Perez et al, 2011), ultimately inhibiting the activity of the destruction complex. This allows the stabilization of β-catenin protein, which then shuttles into the nucleus and activates the transcription of Wnt-target genes upon binding to members of the DNA-associated T-cell factor/lymphoid enhancer-binding factor (TCF/LEF) family of transcription factors (Figure 1) (Behrens et al, 1996;Huber et al, 1996;Molenaar et al, 1996;van de Wetering et al, 1991). Over the years, many additional players and regulatory mechanisms have been identified at all levels of Wnt signal activation.…”

Parallel and Sequential Pathways of Molecular Recognition of a Tandem-Repeat Protein and Its Intrinsically Disordered Binding Partner

“…β-catenin fulfils two important functions in vivo, the first of which is as the signal transducer in the canonical Wnt signalling pathway [1]. Upon Wnt stimulation, β-catenin translocates to the nucleus, where it binds the T-cell factor/lymphoid enhancer-binding factor (TCF/LEF) family of transcription factors [2] and associates with a number of other proteins to form the Wnt enhanceosome [3], thus leading to transcription initiation and elongation, as well as histone and chromatin modification [4,5], resulting in the transcription of genes that are of developmental importance and those involved in tissue homeostasis.…”

“…In the BDC, β-catenin is hyperphosphorylated at its N-terminal disordered region by the combined action of GSK3β and CK1α [7], thus allowing it to be recognised and ubiquitinated by the E3 ubiquitin ligase β-TrCP [8] and subsequently degraded by the proteasome. The second function of β-catenin is as an adaptor that mediates cell-cell adhesion at adherens junctions, where β-catenin binds to the intracellular domain of the cadherin family of proteins [1,[9][10][11]. The deregulation of Wnt signalling has been implicated in numerous types of cancer [12], including colorectal and hepatocellular cancers.…”