Plakophilins: multifunctional scaffolds for adhesion and signaling

Abstract

Armadillo family proteins known as plakophilins have been characterized as structural components of desmosomes that stabilize and strengthen adhesion by enhancing attachments with the intermediate filament cytoskeleton. However, plakophilins and their close relatives are emerging as versatile scaffolds for multiple signaling and metabolic processes that not only facilitate junction dynamics but also more globally regulate diverse cellular activities. While perturbation of plakophilin functions contribute to inherited diseases and cancer pathogenesis, the functional significance of the multiple PKP isoforms and the mechanisms by which their behaviors are regulated remain to be elucidated.

Figure 1

Comparison of armadillo-family protein structures. (A) Classical Armadillo family proteins β-catenin and plakoglobin (also known as γ-catenin). (B) p120^ctn family armadillo proteins p120^ctn, ARVCF, δ-catenin (NPRAP), and p0071 (plakophilin 4). (C) Plakophilin family armadillo proteins plakophilin 1, 2, and 3. Armadillo-family proteins consist of an amino-terminal head domain, a central armadillo repeat domain with variable number of repeats, and a carboxy-terminal tail. Numbers indicate amino acid residues.

Figure 2

Comparison of epithelial cell desmosome and adherens junctions (A) with cardiac myocyte mixed junction structures (B). In the desmosome, the cadherin family proteins (desmogleins [DSGs] and desmocollins [DSCs]) are single-pass transmembrane glycoproteins that bind through homo and heterodimeric interactions to cadherins on neighboring cells via their extracellular domains in a calcium-dependent manner. The cytoplasmic plaque consists of the armadillo-family proteins (plakoglobin [PG] and plakophilins [PKPs]), and the intermediate filament (IF)-binding plakins (desmoplakin [DP]). PG and the PKPs bind to the cytoplasmic tail of either DSG or DSC where they serve as linker proteins to DP and also participate in lateral expansion and clustering of the plaque. In the adherens junction E-cadherin forms intercellular attachments through hemophilic interactions with cadherins on neighboring cells and interacts with the armadillo protein β-catenin through its cytoplasmic domain. β-catenin, which is essential for adherens junction adhesion, binds α-catenin, which may anchor actin to the junctional plaque either directly or through other catenin binding proteins such as Z0-1 or afadin. In vertebrate cardiac myocytes hybrid junctions, or area compositae, occupy a majority of the intercalated disc membrane (B). These specialized junctions contain components common to adherens junctions and desmosomes, possibly facilitated in part by interactions between proteins such as PKP2 and αT-catenin. Connexin 43 associates with PKP2, raising the possibility that gap junctions may be intimately associated with the area composita or co-localize in intercalated disc precursors.

Figure 3

Schematic of PKP family protein roles as multifunctional scaffolds. (a) PKP2 recruits PKCα to DP-containing desmosome precursors thereby modulating the DP-IF interaction, and potentially regulating actin reorganization. Direct or indirect interactions of PKP2 with actin may participate in precursor dynamics and promote their incorporation into junctions. PKP1, 2, and 3 all are found at the cytoplasmic face of the desmosome and link DP to cadherin tails. (b) PKP2 interacts with β-catenin and potentiates TCF/Lef-mediated transcriptional activity. (c) PKP2 interacts with extra-junctional β-catenin and is found in complexes with E-cadherin, possibly mediated via plakoglobin (PG). (d) Nuclear PKP2 interacts with the RNA polymerase III holoenzyme and may serve a role in rRNA and tRNA synthesis. (e) PKP2 is phosphorylated by c-TAK1, promoting 14-3-3 interaction with PKP2 and modulating PKP2-nuclear transport. (f) PKP3 colocalizes with large ribonucleoprotein complexes known as “stress granules”. (g) PKP3 interacts with DNM1L, a dynamin-related protein known to be found in endoplasmic reticulum (ER) tubules and secretory vesicles. (h) p0071 regulates recruitment and activity of Rho small GTPase via Ect2 at the midbody of a cell undergoing mitotic cell division. MT = microtubules; MTOC = microtubule organizing complex. Molecules depicted are not to scale.