Plakoglobin: role in tumorigenesis and metastasis

Abstract

Plakoglobin (γ-catenin) is a member of the Armadillo family of proteins and a homolog of β-catenin. As a component of both the adherens junctions and desmosomes, plakoglobin plays a pivotal role in the regulation of cell-cell adhesion. Furthermore, similar to β-catenin, plakoglobin is capable of participating in cell signaling. However, unlike β-catenin that has well-documented oncogenic potential through its involvement in the Wnt signaling pathway, plakoglobin generally acts as a tumor/metastasis suppressor. The exact roles that plakoglobin plays during tumorigenesis and metastasis are not clear; however, recent evidence suggests that it may regulate gene expression, cell proliferation, apoptosis, invasion, and migration. In this paper, we describe plakoglobin, its discovery and characterization, its role in regulating cell-cell adhesion, and its signaling capabilities in regulation of tumorigenesis and metastasis.

Figure 1

Cell adhesion complexes in epithelial cells. Cell-cell adhesion is maintained in epithelial tissues by the adherens junction and desmosomes. At the adherens junctions, E-cadherin forms extracellular interactions with E-cadherin molecules on neighboring cells. Intracellularly, E-cadherin interacts with either β-catenin or plakoglobin, which then interact with α-catenin, an actin-binding protein. A fourth catenin, p120-catenin, also interacts with E-cadherin and regulates its stability at the membrane. At the desmosome, the desmosomal cadherins (desmoglein and desmocollin) interact with plakoglobin and plakophilin, which interact with desmoplakin, which in turn associates with the intermediate filament cytoskeleton. The basic, core protein composition of the desmosomes is represented here: the exact protein constituents of the desmosomes and their interactions vary between different types of cells and tissues.

Figure 2

Schematic structure of β-catenin and plakoglobin. Both β-catenin and plakoglobin contain 13 Armadillo repeats that are flanked by N- and C-terminal domains, respectively. The degree of homology between β-catenin and plakoglobin for each Armadillo domain is indicated. Protein partners that interact with plakoglobin and the domains involved in these interactions are indicated. The corresponding references are listed in brackets (see [–76]).

Figure 3

A potential model for regulation of gene expression by plakoglobin. Three concurrent mechanisms by which plakoglobin may regulate gene expression are proposed. (A) Cytoplasmic sequestration: plakoglobin sequesters a factor in the cytoplasm which, in the nucleus, suppresses the expression of a tumor suppressor gene or activates the expression of an oncogene. (B) Cytoplasmic cofactor independent: plakoglobin-transcription factor complexes promote the expression of tumor suppressor genes and repress the expression of oncogenes. (C) Cytoplasmic cofactor dependent: plakoglobin interacts with a cytoplasmic cofactor and this complex moves into the nucleus where it activates tumor suppressor gene expression or represses oncogenic gene expression. PG: plakoglobin; TF: transcription factor.