The cadherin-catenin adhesion system in signaling and cancer

Abstract

The adhesion of cells to their neighbors determines cellular and tissue morphogenesis and regulates major cellular processes including motility, growth, differentiation, and survival. Cell-cell adherens junctions (AJs), the most common (indeed, essentially ubiquitous) type of intercellular adhesions, are important for maintaining tissue architecture and cell polarity and can limit cell movement and proliferation. AJs assemble via homophilic interactions between the extracellular domains of calcium-dependent cadherin receptors on the surface of neighboring cells. The cytoplasmic domains of cadherins bind to the submembranal plaque proteins β-catenin or plakoglobin (γ-catenin), which are linked to the actin cytoskeleton via α-catenin (Figure 1; refs. 1, 2). The transmembrane assembly of cadherin receptors with the cytoskeleton is necessary for the stabilization of cell-cell adhesions and normal cell physiology.Malignant transformation is often characterized by major changes in the organization of the cytoskeleton, decreased adhesion, and aberrant adhesion-mediated signaling. Disruption of normal cell-cell adhesion in transformed cells may contribute to tumor cells' enhanced migration and proliferation, leading to invasion and metastasis. This disruption can be achieved by downregulating the expression of cadherin or catenin family members or by activation of signaling pathways that prevent the assembly of AJs. The importance of the major epithelial cell cadherin, E-cadherin (E-cad, the product of the CDH1 gene), in the maintenance of normal cell architecture and behavior is underscored by the observation that hereditary predisposition to gastric cancer results from germline mutations in CDH1.Loss of E-cad expression eliminates AJ formation and is associated with the transition from adenoma to carcinoma and acquisition of metastatic capacity (3). Reestablishment of AJs in cancer cells by restoration of cadherin expression (4) exerts tumor-suppressive effects, including decreased proliferation and motility. In this Perspective, we discuss the molecular mechanisms underlying the role of the cadherin-catenin system in the regulation of cell proliferation, invasion, and intracellular signaling during cancer progression. Downregulation of AJ assembly by mutations, hypermethylation, and transcriptional repression of E-cad expressionMutations in CDH1 that compromise the adhesive function of E-cad have been observed in human gastric carcinoma cell lines, lobular breast cancer, and familial gastric cancer (5). Certain tumors, for example invasive lobular carcinoma of the breast, and tumor cell lines that display mutations in one allele of CDH1 also acquire a deletion in the other allele, consistent with a two-hit mechanism for the loss of E-cad and suggesting that CDH1 behaves as a classical tumor suppressor gene. While acquisition of loss-of-function mutations and the subsequent loss of heterozygosity are important mechanisms for silencing E-cad expression in tumor cells, progression to the metastatic phenotype can also in...

Cell surface glycoprotein profiling of cancer cells based on bioorthogonal chemistry

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Altered expression of desmocollin 3, desmoglein 3, and β-catenin in oral squamous cell carcinoma: correlation with lymph node metastasis and cell proliferation

“…Malignant transformation is often characterized by major changes in the organization of the cytoskeleton, decreased adhesive strength, and aberrant adhesion-mediated signaling [5,6]. Disruption of normal cell-cell adhesion in transformed cells may contribute to enhancement of tumor cell migration and proliferation, leading to invasion and metastasis [6].…”

Switch of cadherin expression from E- to N-type during the activation of rat hepatic stellate cells

“…Multiple mechanisms may inactivate the E-cadherin mediated cell adhesion system (Boyer et al 2000;Cavallaro et al 2002;Conacci-Sorrell et al 2002). Several recent studies have reported that the progressive loss or delocalization of E-cadherin from cell junctions occurs in association with an elevation of N-cadherin expression, suggesting that N-cadherin plays a role in the EMT (Islam et al 1996;Hazan et al 2000;Cavallaro et al 2002).…”