Bench to bedside and back again: Molecular mechanisms of α-catenin function and roles in tumorigenesis

Abstract

The cadherin/catenin complex, comprised of E-cadherin, β-catenin and α-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 β-catenin in the Wnt signaling pathway has led to many studies of the role of β-catenin in cancer. Alpha-catenin, in contrast, has received less attention. However, recent data demonstrate novel functions for α-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 α-catenin function, from the canonical role of α-catenin in cell-cell adhesion to non-canonical roles identified following conditional α-catenin deletion. This analysis identifies α-catenin as a prognostic factor in cancer progression.

The epithelial polarity program: machineries involved and their hijacking by cancer

“…The EPP: machineries involved and their hijacking by cancer B Tanos and E Rodriguez-Boulan and E-cadherin inactivating mutations are found in a variety of breast and gastric carcinoma, supporting its denomination as a tumor suppressor (Benjamin and Nelson, 2008). Tumors may downregulate E-cadherin by promoter hypermethylation or by oncogenic activation of the E-cadherin repressors Snail, Slug, Twist, SIP1 and ZEB (see reviews by Massague, 2004 andPeinado et al, 2007) or, alternatively, through phosphorylation, ubiquitination and degradation of E-cadherin.…”

“…Recent work by Nelson's laboratory has developed a new model to account for the activity of this complex in organizing the actin cytoskeleton at the lateral membrane Yamada et al, 2005). According to this new model, a-catenin acts independently of E-cadherin to organize the lateral actin cytoskeleton, which has important consequences for the role of these molecules in cancer (Benjamin and Nelson, 2008), discussed below.…”

5q– myelodysplastic syndromes: chromosome 5q genes direct a tumor-suppression network sensing actin dynamics

“…Through an association with its well-known counterparts b-catenin and E-cadherin, the canonical roles for a-catenin were to promote the assembly of cell-cell junctions and to stabilize the actin cytoskeleton by directly binding actin (reviewed extensively in Benjamin and Nelson, (2008)). The quaternary complex then stabilized cell-cell linkages to promote cell adhesion.…”

“…Diminished (or complete loss of) a-catenin expression is observed in a host of primary cancers (for example, breast, colorectal, prostate), as well as in cancer cell lines derived from primary tumors (for example, leukemia, leukocyte, colon, prostate) (Benjamin and Nelson, 2008). Furthermore, human samples from MDS patients revealed a loss of a-catenin protein expression within myeloid progenitor cells (Desmond et al, 2007;Liu et al, 2007), and, in some cancers, diminished a-catenin is a strong predictor of invasive and metastatic behaviors, increased survival and proliferation.…”

Plakoglobin interacts with and increases the protein levels of metastasis suppressor Nm23-H2 and regulates the expression of Nm23-H1

“…Although the extracellular domain of cadherins interacts with cadherin molecules on adjacent cells, the intracellular domain interacts in a mutually exclusive manner, with either b-catenin or plakoglobin (g-catenin), which then interacts with a-catenin. a-Catenin, which binds actin, tethers the cadherin-catenin complex to the actin cytoskeleton (Perez-Moreno and Fuchs, 2006;Benjamin and Nelson, 2008;Nelson, 2008;Stemmler, 2008;van Roy and Berx, 2008).…”