Mice with Hepatic Loss of the Desmosomal Protein γ-Catenin Are Prone to Cholestatic Injury and Chemical Carcinogenesis

Abstract

.g-Catenin, an important component of desmosomes, may also participate in Wnt signaling. Herein, we dissect the role of g-catenin in liver by generating conditional g-catenin knockout (KO) mice and assessing their phenotype after bile duct ligation (BDL) and diethylnitrosamine-induced chemical carcinogenesis. At baseline, KO and wild-type littermates showed comparable serum biochemistry, liver histology, and global gene expression. b-Catenin protein was modestly increased without any change in Wnt signaling. Desmosomes were maintained in KO, and despite no noticeable changes in gene expression, differential detergent fractionation revealed quantitative and qualitative changes in desmosomal cadherins, plaque proteins, and b-catenin. Enhanced association of b-catenin to desmoglein-2 and plakophilin-3 was observed in KO. When subjected to BDL, wild-type littermates showed specific changes in desmosomal protein expression. In KO, BDL deteriorated baseline compensatory changes, which manifested as enhanced injury and fibrosis. KO also showed enhanced tumorigenesis to diethylnitrosamine treatment because of Wnt activation, as also verified in vitro. g-Catenin overexpression in hepatoma cells increased its binding to T-cell factor 4 at the expense of b-catenineT-cell factor 4 association, induced unique target genes, affected Wnt targets, and reduced cell proliferation and viability. Thus, g-catenin loss in liver is basally well tolerated. However, after insults like BDL, these compensations at desmosomes fail, and KO show enhanced injury. Also, g-catenin negatively regulates tumor growth by affecting Wnt signaling. Plakoglobin or g-catenin belongs to the catenin family of proteins and is a component of desmosomes. Desmosomes are submembranous plaques that provide resistance to mechanical and shear stresses within a tissue and contribute to intercellular adhesion.1 Analogous to b-catenin at adherens junctions (AJs), g-catenin, like other desmosomal plaque proteins, such as desmoplakin (DP) and plakophilin (Pkp), adheres to neighboring cells by linking intracytoplasmic domains of transmembrane desmosomal cadherins like desmoglein (Dsg) and desmocollin (Dsc) to intermediate filaments.1 g-Catenin can also be a structural component of AJ, where it may be exchangeable with its close homolog, b-catenin. Both catenins also contain an armadillo domain and can bind the T-cell factor (TCF) family of transcription factors to participate in Wnt signaling. 2 We have previously identified an increase in g-catenin in the liver-specific b-catenin knockout (KO) mice, 3,4 where it was able to compensate for b-catenin loss at AJs without compromising desmosomes. However, g-catenin did not compensate for b-catenin loss in Wnt signaling, and b-catenin KO continued to lack liver-specific Wnt targets, such as glutamine synthetase (GS) and P450 2e1 and 1a2. 5The primary role of g-catenin in liver pathobiology remains unknown. We addressed the function of g-catenin in liver Supported by NIH grants 1R01DK62277 and 1R01DK100287 and Endowed Chair...

Beyond cell-cell adhesion: Plakoglobin and the regulation of tumorigenesis and metastasis

“…We further showed that breast, squamous cell, ovarian and non-small cell lung carcinomas that expressed plakoglobin were less proliferative, migratory and invasive compared to those that did not express plakoglobin [ 29 , 58 , 146 , 149 ]. These results are in agreement with other studies that have demonstrated that plakoglobin expressing cells are considerably less proliferative and migratory than their non-plakoglobin expressing counterparts [ 30 , 44 – 52 , 54 , 55 , 155 – 157 ]. More importantly, our data also suggests that the plakoglobin-p53 complexes are both activating (in the case of the SFN and NME1 genes) and repressive ( SATB1 gene).…”

Wnt/β‐Catenin Signaling Plays a Protective Role in the Mdr2 Knockout Murine Model of Cholestatic Liver Disease

“…β‐catenin is an important component of AJ, and although its loss in normal liver is adequately compensated by γ‐catenin, recent reports suggest that loss of β‐catenin, γ‐catenin, or both catenins predisposes livers to intrahepatic cholestasis secondary to junctional defects . Additionally, the pore‐forming TJ protein claudin‐2, a downstream target of β‐catenin, is important for proper bile flow, although loss of claudin‐2 from hepatocytes did not cause a defect in TJ .…”

Dual catenin loss in murine liver causes tight junctional deregulation and progressive intrahepatic cholestasis

“…Previously reported homozygous β‐catenin–floxed mice and γ‐catenin–floxed mice were interbred to generate double‐floxed mice . Conditional deletion of both β‐ and γ‐catenin is described in the http://onlinelibrary.wiley.com/doi/10.1002/hep.29585/suppinfo.…”

“…However, there was maintenance of AJ due to compensatory increase in γ-catenin, a normal component of desmosomes, which associated with E-cadherin instead (7,8). Liver-specific γ-catenin knockout also showed increased β-catenin levels, suggesting a mutually compensatory role of the two catenins at hepatocyte junctions (9).…”