Plakophilins: multifunctional scaffolds for adhesion and signaling

Bass-Zubek, Amanda E.; Godsel, Lisa M.; Delmar, Mario; Green, Kathleen J.

doi:10.1016/j.ceb.2009.07.002

Cited by 139 publications

(145 citation statements)

References 68 publications

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“…22 b-CatenineE-cadherin association remained intact in the g-catenin KO livers. Dsg2 is reported to maintain tight junction integrity and the epithelial barrier in the intestine.…”

Section: G-catenin In Liver Pathophysiologymentioning

confidence: 85%

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

Zhou

Pradhan‐Sundd

Poddar

et al. 2015

The American Journal of Pathology

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.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...

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“…22 b-CatenineE-cadherin association remained intact in the g-catenin KO livers. Dsg2 is reported to maintain tight junction integrity and the epithelial barrier in the intestine.…”

Section: G-catenin In Liver Pathophysiologymentioning

confidence: 85%

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

Zhou

Pradhan‐Sundd

Poddar

et al. 2015

The American Journal of Pathology

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“…Previous studies indicate that the N-terminal region of PKP2 is sufficient for its localization to the membrane near areas of cell-to-cell attachment (12,13). This may suggest that PKP2 is involved in EGFR signal activation at regions of cell attachment.…”

Section: Discussionmentioning

confidence: 96%

“…They are composed of a basic N-terminal head domain, followed by a series of 42-amino-acid armadillo repeats (armrepeat) and a short C-terminal tail (12,13). Although the N-terminal head domains of PKPs are quite diversified, a consensus sequence termed the HR2 motif is shared by all the PKP head domains (12,13). PKP2 was originally isolated as a desmosomal protein, but additional studies have shown that it is also found in the cytoplasm and nucleus (14).…”

mentioning

confidence: 99%

Plakophilin-2 Promotes Tumor Development by Enhancing Ligand-Dependent and -Independent Epidermal Growth Factor Receptor Dimerization and Activation

Arimoto

Burkart

Yan

et al. 2014

Molecular and Cellular Biology

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Epidermal growth factor (EGF) receptor (EGFR) has been implicated in tumor development and invasion. Dimerization and autophosphorylation of EGFR are the critical events for EGFR activation. However, the regulation of EGF-dependent and EGFindependent dimerization and phosphorylation of EGFR has not been fully understood. Here, we report that cytoplasmic protein plakophilin-2 (PKP2) is a novel positive regulator of EGFR signaling. PKP2 specifically interacts with EGFR via its N-terminal head domain. Increased PKP2 expression enhances EGF-dependent and EGF-independent EGFR dimerization and phosphorylation. Moreover, PKP2 knockdown reduces EGFR phosphorylation and attenuates EGFR-mediated signal activation, resulting in a significant decrease in proliferation and migration of cancer cells and tumor development. Our results indicate that PKP2 is a novel activator of the EGFR signaling pathway and a potential new drug target for inhibiting tumor growth.

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“…Recently, the biological function of some classical arm repeat proteins have been well clarified. Such as β-catenin , a classical member of ARM family plays important roles both at cells adherence junctions and in Wnt signaling through interaction with E-cadherin and T cell factor/lymphoid enhancer factor (TCF/LEF) family transcription factors (Xu et al, 2007;Bass-Zubek et al, 2009). Tumor suppressor adenomatous polyposis coli (APC) is also an ARM family member and acts with casein kinase Ι, glycogen synthase kinase-3β and AXIN to regulate Wnt signaling through β-catenin degradation (Munemitsu et al, 1995; Rubinfeld et al, 1996; Goss et al, 2000), APC promoter methylation was found to be significantly associated with a higher risk of developing CRC and the findings indicate that APC promoter methylation may be a potential biomarker for the carcinogenesis of CRC (Ding et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

ALEX1 Regulates Proliferation and Apoptosis in Breast Cancer Cells

Gao

Wu²,

Zeng³

et al. 2015

Asian Pacific Journal of Cancer Prevention

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Background: Arm protein lost in epithelial cancers, on chromosome X (ALEX) is a novel subgroup within the armadillo (ARM) family, which has one or two ARM repeat domains as opposed to more than six-thirteen repeats in the classical Armadillo family members. Materials and Methods: In the study, we explore the biological functions of ALEX1 in breast cancer cells. Overexpression of ALEX1 and silencing of ALEX1 were performed with SK-BR3 and MCF-7 cell lines. Cell proliferation and colony formation assays, along with flow cytometry, were carried out to evaluate the roles of ALEX1. Results: ALEX1 overexpression in SK-BR3 breast cancer cells inhibited proliferation and induced apoptosis. Furthermore, depletion of ALEX1 in MCF-7 breast cancer cells increased proliferation and inhibited apoptosis. Additional analyses demonstrated that the overexpression of ALEX1 activated the intrinsic apoptosis cascades through up-regulating the expression of Bax, cytosol cytochrome c, active caspase-9 and active caspase-3 and down-regulating the levels of Bcl-2 and mitochondria cytochrome c. Simultaneouly, silencing of ALEX1 inhibited intrinsic apoptosis cascades through down-regulating the expression of Bax, cytosol cytochrome c, active caspase-9, and active caspase-3 and up-regulating the level of Bcl-2 and mitochondria cytochrome c. Conclusions: Our data suggest that ALEX1 as a crucial tumor suppressor gene has been involved in cell proliferation and apoptosis in breast cancer, which may serve as a novel candidate therapeutic target.

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Plakophilins: multifunctional scaffolds for adhesion and signaling

Cited by 139 publications

References 68 publications

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

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

Plakophilin-2 Promotes Tumor Development by Enhancing Ligand-Dependent and -Independent Epidermal Growth Factor Receptor Dimerization and Activation

ALEX1 Regulates Proliferation and Apoptosis in Breast Cancer Cells

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