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Review
. 2013 Jan;25(1):93-100.
doi: 10.1016/j.cellsig.2012.09.025. Epub 2012 Sep 27.

Beyond cell adhesion: the role of armadillo proteins in the heart

David Swope  1 , Jifen Li, Glenn L Radice
Affiliations
Review

Beyond cell adhesion: the role of armadillo proteins in the heart

David Swope et al. Cell Signal. 2013 Jan.

Abstract

Plakoglobin (PG, γ-Catenin, JUP), a member of the armadillo protein family and close homolog of β-catenin, functions to link cell surface cadherin molecules with the cytoskeleton. PG is the only junctional component found in both desmosomes and adherens junctions and thus plays a critical role in the regulation of cell-cell adhesion. Similar to β-catenin, PG is able to interact with components of the Wnt signaling pathway and directly affect gene expression by binding with LEF/TCF transcription factors. In addition, it has been proposed that PG functions primarily as a competitive inhibitor of β-catenin transcriptional activity by sequestering LEF/TCF. Compared to β-catenin, the contribution of PG as a transcriptional regulator in either physiological or pathological conditions is poorly understood. There is increasing clinical interest in PG as both a structural protein as well as a signaling molecule as mutations have been identified in the human PG gene that cause Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) and cutaneous syndromes. This review will discuss the connection between altered cell adhesion and gene expression and its contribution to disease pathogenesis.

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Figures

Figure 1
Figure 1. Plakoglobin and β-catenin have similar structure
Schematic representation of plakoglobin and β-catenin protein including the 13 armadillo repeats. PG and β-catenin share many of the same binding partners as shown above (boxes). Percent amino acid similarity between the central ‘armadillo’ domain and N- and C-terminus are shown below.
Figure 2
Figure 2. Structural and signaling functions of β-catenin and plakoglobin
(A) β-catenin (β-cat) is found in adherens junctions where it functions as a linker protein between N-cadherin, α-catenins, and the actin cytoskeleton. (B) In contrast, PG participates in both adherens junctions and desmosomes. PG binds to desmosomal cadherins, desmocollin2 (DSC2) and desmoglein2 (DSG2) and mediates their interaction, via desmoplakin (DP) and plakophilin (PKP2), with intermediate filaments (IF). In addition to their structural roles as part of the mechanical junctions, both β-cat and PG are regulated by Wnt signaling. Wnt ligands bind to the Frizzled (Frz) receptor and signal the inhibition of glycogen synthase kinase 3β (GSK3β) through disheveled (Dsh). If Wnt signaling is inactive, cytosolic β-cat and PG are degraded by the “destruction complex” composed of adenomatous polyposis coli (APC), axin and GSK3β. Phosphorylation of β-cat and PG by GSK3β target it for ubiquitination and subsequent degradation by the 26S proteasome. Following a Wnt signal, β-catenin and PG accumulate in the nucleus and bind members of the T-cell factor (TCF)/lymphoid enhancer-binding factor (LEF) family of transcription factors to activate target gene expression. (B) PG has been implicated as both a positive and negative regulator of gene expression. In the latter case, PG may interfere with gene expression by competing with β-catenin for binding to TCF/LEF thus suppressing β-catenin/TCF/LEF target gene transcription.
Figure 3
Figure 3. Identification of JUP mutations in human patients
The known JUP mutations (protein designation) and their associated phenotypes are shown. The one dominant heterozygous mutation is shown above PG whereas the recessive homozygous mutations are shown below the protein.
Figure 4
Figure 4. Model of the molecular pathogenesis of ARVC
Cascade of events leading from desmosomal gene mutation to disease pathogenesis (adapted from [99]). The mutant desmosomal protein weakens the mechanical junction causing a cell adhesion defect which has multiple consequences on heart physiology. Electron micrographs show normal (PG WT) and abnormal (PG CKO) desmosome structure in the heart [86]. The loss of membrane integrity leads to myocyte cell death. The lost myocytes are then replaced by fibro-fatty tissue, a unique pathology observed in ARVC. It has been proposed that destabilization of the desmosome allows release of PG from the sarcolemma and its translocation to the nucleus. The adipocytes are thought to originate from a cardiac progenitor cell that undergoes a myogenic to adipogenic gene expression switch due to the ability of PG to sequester TCF/LEF thus inhibiting pro-myogenic Wnt/β-cat signaling. Finally, altered mechanical junctions lead to diminished gap junction plaques at the ICD, a process called gap junction remodeling which is known to be pro-arrhythmic. Ventricular arrhythmia in an αMHC/Cre; PGflox/flox (Mut) mouse is shown [88].
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