Protein Phosphatase 2A: More Than a Passenger in the Regulation of Epithelial Cell-Cell Junctions

Abstract

Cell-cell adhesion plays a key role in the maintenance of the epithelial barrier and apicobasal cell polarity, which is crucial for homeostasis. Disruption of cell-cell adhesion is a hallmark of numerous pathological conditions, including invasive carcinomas. Adhesion between apposing cells is primarily regulated by three types of junctional structures: desmosomes, adherens junctions, and tight junctions. Cell junctional structures are highly regulated multiprotein complexes that also serve as signaling platforms to control epithelial cell function. The biogenesis, integrity, and stability of cell junctions is controlled by complex regulatory interactions with cytoskeletal and polarity proteins, as well as modulation of key component proteins by phosphorylation/dephosphorylation processes. Not surprisingly, many essential signaling molecules, including protein Ser/Thr phosphatase 2A (PP2A) are associated with intercellular junctions. Here, we examine how major PP2A enzymes regulate epithelial cell-cell junctions, either directly by associating with and dephosphorylating component proteins, or indirectly by affecting signaling pathways that control junctional integrity and cytoskeletal dynamics. PP2A deregulation has severe consequences on the stability and functionality of these structures, and disruption of cell-cell adhesion and cell polarity likely contribute to the link between PP2A dysfunction and human carcinomas.

Keywords: PP2A; adherens junction; dephosphorylation; desmosome; polarity; signaling; tight junction.

FIGURE 1

Schematic structure of a classical PP2A holoenzyme. Catalytic (C or PPP2C), structural (A or PPP2R1), and regulatory (B or PPP2R) subunits make up the typical mammalian heterotrimeric PP2A holoenzyme. There are several families of B subunits, and multiple subunit isoforms (denoted A, B,…or α, β,…), resulting in a diversity of PP2A holoenzymes with distinct enzymatic activity and substrate specificity. Other atypical subunits and regulatory proteins not shown here can also associate with PP2A C (Sents et al., 2013). The PP2A/B structure (Xu et al., 2008) was adapted from https://www.ncbi.nlm.nih.gov/Structure/pdb/3DW8.

FIGURE 2

Schematic organization of the epithelial desmosome targeted by PP2A. There is emerging evidence that inhibition of PP2A promotes desmosomal disassembly by directly affecting the phosphorylation state of desmoplakin and plakoglobin, and indirectly, by inducing the reorganization of the IF cytoskeleton. PKG, plakoglobin; PKP, plakophilin.

FIGURE 3

PP2A associates with the E-cadherin/β-catenin complex at the epithelial AJ. The functional integrity of PP2A is required for the stabilization of the E-cadherin/β-catenin complex at areas of cell–cell contact. PP2A activity is also involved in dephosphorylation of β-catenin and modulation of the actin cytoskeleton that is essential for AJ formation.

FIGURE 4

PP2A interacts with apical TJ and polarity complexes in epithelial cells. PP2A enzymes are associated with the multifunctional apical TJ structure, a complex assembly of transmembrane, scaffolding, cytoskeletal and signaling proteins. PP2A also interacts with proteins of apical polarity complexes, which are essential for the establishment of epithelial cell polarity. PP2A activity is implicated in dephosphorylation of several TJ proteins (red P circles) that regulate TJ assembly and maintenance. PP2A enzymes also influence the formation and stability of TJs by modulating actin dynamics via their action on actin-regulatory proteins, as well as binding to and regulating microtubule stability.