Interplay of cadherin-mediated cell adhesion and canonical Wnt signaling

Abstract

The epithelial-mesenchymal transition is essential in both embryonic development and the progression of carcinomas. Wnt signaling and cadherin-mediated adhesion have been implicated in both processes; clarifying their role will depend on linking them to rearrangements of cellular structure and behavior. beta-Catenin is an essential molecule both in cadherin-mediated cell adhesion and in canonical Wnt signaling. Numerous experiments have shown that the loss of cadherin-mediated cell adhesion can promote beta-catenin release and signaling; this is accomplished by proteases, protein kinases and other molecules. Cadherin loss can also signal to several other regulatory pathways. Additionally, many target genes of Wnt signaling influence cadherin adhesion. The most conspicuous of these Wnt target genes encode the transcription factors Twist and Slug, which directly inhibit the E-cadherin gene promoter. Other Wnt/beta-catenin target genes encode metalloproteases or the cell adhesion molecule L1, which favor the degradation of E-cadherin. These factors provide a mechanism whereby cadherin loss and increased Wnt signaling induce epithelial-mesenchymal transition in both carcinomas and development.

Figure 1.

Epithelial–mesenchymal transition. EMT can be induced by the loss of E-cadherin and/or by the activation of canonical Wnt signaling. Epithelial cells become more motile and receive a mesenchymal character. The mesenchymal-like cells can pass the basement membrane and become invasive.

Figure 2.

Canonical Wnt pathway. (A) In the absence of a Wnt ligand, β-catenin is sequentially phosphorylated in the destruction complex of axin and APC by the kinases CK1α and GSK3β, which results in ubiquitination by β-TRCP and, finally, in the degradation of β-catenin in the proteasom. (B) In the presence of a Wnt ligand, a Fzd/LRP5/6 complex is formed and is bound by Dishevelled, leading to the phosphorylation of the LRP5/6 receptor by GSK3β, CK1γ and other kinases. Phosphorylated LRP5/6 recruits axin to the plasma membrane, which leads to decay of the destruction complex, inhibited phosphorylation, and degradation of β-catenin. Stabilized β-catenin is then translocated to the nucleus, a process that can involve BCl9-2. β-Catenin interacts with TCF/LEF, and the recruitment of cofactors like BCL9, Pygopus, or CBP as well as the replacement of Groucho leads to the activation of target genes.

Figure 3.

Proteolytic cleavage of cadherin can release β-catenin and induce canonical Wnt signaling. Under certain cellular conditions, cadherins can be cleaved by proteases like ADAM10 and Presenilin-1. This cleavage leads to loosening of cell adhesion, but also to the release of β-catenin, which is translocated into the nucleus and as a result, activates Wnt/β-catenin target genes. Another protease, calpain, is interfering with the adhesion complex by the amino-terminal cleavage of β-catenin. β-Catenin cleaved by calpain is stabilized and can enter the nucleus and activate target genes.

Figure 4.

Phosphorylation sites of β-catenin. β-Catenin can be sequentially phosphorylated by different kinases, either promoting the degradation or the signaling activity of β-catenin. Phosphorylation at the amino terminus favors degradation, whereas phosphorylation in the armadillo domain changes the adhesiveness to cadherins and promotes nuclear localization.

Figure 5.

Canonical Wnt signaling modulates cell adhesions. Activated Wnt signaling leads to stabilization and nuclear localization of β-catenin, which induces the expression of Wnt target genes: I) The transcription factors Slug and Twist both repress the expression of E-cadherin, and Twist activates the expression of N-cadherin. II) The cell adhesion molecule L1 interferes with E-cadherin-mediated cell adhesion. III) The proteases MMP3 and MMP7 modulate the extracellular matrix, and MMP3, MMP7, and ADAM10 cleave E-cadherin. IV) The cell matrix molecules fibronectin and laminin favor cell-substrate adhesion. V) Wnt signaling inactivates GSK3β, leading to stabilization of Snail, which also inhibits the expression of E-cadherin. VI) p120 relieves the repressor Kaiso from Wnt target genes.