Bench to bedside and back again: molecular mechanisms of alpha-catenin function and roles in tumorigenesis

Abstract

The cadherin/catenin complex, comprised of E-cadherin, beta-catenin and alpha-catenin, is essential for initiating cell-cell adhesion, establishing cellular polarity and maintaining tissue organization. Disruption or loss of the cadherin/catenin complex is common in cancer. As the primary cell-cell adhesion protein in epithelial cells, E-cadherin has long been studied in cancer progression. Similarly, additional roles for beta-catenin in the Wnt signaling pathway has led to many studies of the role of beta-catenin in cancer. Alpha-catenin, in contrast, has received less attention. However, recent data demonstrate novel functions for alpha-catenin in regulating the actin cytoskeleton and cell-cell adhesion, which when perturbed could contribute to cancer progression. In this review, we use cancer data to evaluate molecular models of alpha-catenin function, from the canonical role of alpha-catenin in cell-cell adhesion to non-canonical roles identified following conditional alpha-catenin deletion. This analysis identifies alpha-catenin as a prognostic factor in cancer progression.

Figure 1. Schematic representations of protein-protein interactions at sites of cadherin-mediated cell-cell adhesion

Left: the textbook model assumes a quaternary complex of cadherin/β-catenin/α-catenin/actin that is involved in cadherin clustering and stablization of cell-cell adhesion. Center/Right: the new model of how the cadherin/catenin complex and actin organization are regulated based on data [54, 55]. In the absence of cell-cell adhesion (center), a ternary complex of cadherin/β-catenin/α-catenin is formed, but the local concentration of α-catenin that may dissociate from the complex is too low to affect actin assembly (by the Arp2/3 complex); under these conditions, cell-cell adhesion is low and cell migration/membrane dynamics are high. Right: Upon cell-cell interactions through cadherin extracellular domains, ternary complexes of cadherin/β-catenin/α-catenin cluster. Dissociation of α-catenin from the cadherin/catenin complex leads to an increase in the local cytoplasmic concentration of α-catenin above the critical concentration for dimerization. These resulting juxta-membrane α-catenin dimers bundle actin filaments and suppress actin assembly by inhibiting the Arp2/3 complex; under these conditions, cell-cell adhesion is high and cell migration/membrane dynamics are low.