Regulation of cell-cell adhesion by the cadherin-catenin complex

Abstract

Ca(2+)-dependent cell-cell adhesion is regulated by the cadherin family of cell adhesion proteins. Cadherins form trans-interactions on opposing cell surfaces which result in weak cell-cell adhesion. Stronger cell-cell adhesion occurs by clustering of cadherins and through changes in the organization of the actin cytoskeleton. Although cadherins were thought to bind directly to the actin cytoskeleton through cytoplasmic proteins, termed alpha- and beta-catenin, recent studies with purified proteins indicate that the interaction is not direct, and instead an allosteric switch in alpha-catenin may mediate actin cytoskeleton reorganization. Organization and function of the cadherin-catenin complex are additionally regulated by phosphorylation and endocytosis. Direct studies of cell-cell adhesion has revealed that the cadherin-catenin complex and the underlying actin cytoskeleton undergo a series of reorganizations that are controlled by the Rho GTPases, Rac1 and RhoA, that result in the expansion and completion of cell-cell adhesion. In the present article, in vitro protein assembly studies and live-cell studies of de novo cell-cell adhesion are discussed in the context of how the cadherin-catenin complex and the actin cytoskeleton regulate cell-cell adhesion.

Figure 1. Protein-protein interactions between cadherins, catenins and the actin cytoskeleton

Protein interactions formed between cadherin, β-catenin (β-cat), α-catenin monomers (α-cat^M), α-catenin dimers (α-cat^D) and actin. Differences in the thickness of the arrows represent strengths of protein-protein interactions (i.e. increased thickness shows increased binding). The interaction between cadherin and β-catenin is regulated by kinases that increase (green box: CK2 and GSK3β) or decrease (red box: Src, Fer, Abl and EGFR) the binding affinity.

Figure 2. A model for regulation of cytoskeleton and membrane dynamics by the cadherin–catenin complex

See the text for details.

Figure 3. A model for propagation of cell–cell adhesion in which two zones of Rho family GTPase activity are restricted to the edges of the cell–cell contact as it expands laterally

Left: cell–cell adhesion between pairs of MDCK cells involves initial E-cadherin engagement, followed by propagation and finally compaction of the contact. Upper-right: the initial zone comprises a zone of cadherin engagement (orange); a zone of active Rac1 and its downstream effectors, the Arp2/3 complex and lamellipodia, localized to de novo contacts between cells at the edges of the zone of cadherin engagement (blue); and the zone of RhoA and its downstream effector actomyosin contractility, restricted to the edges of the contact and is required to drive expansion and completion of cell–cell adhesion (green). The activity zone of Rac1 is transient and rapidly diminishes as cadherin accumulates, but a new round of activation occurs at the periphery of the contacting membranes that would push the membranes together to initiate new E-cadherin adhesion. These sequential signalling zones comprising E-cadherin accumulation, Rac1-induced lamellipodia and RhoA-induced actomyosin contraction co-ordinate the induction, propagation and expansion of the cell–cell contact. Lower-right: a model representing regulatory interactions between cadherin, p120-catenin, Rho GTPases and integrins (-, negative regulation; +, positive regulation) (see the text for details).