Desmosomes: new perpetrators in tumour suppression

Dusek, Rachel L.; Attardi, Laura D.

doi:10.1038/nrc3051

Cited by 159 publications

(153 citation statements)

References 133 publications

Supporting

Mentioning

143

Contrasting

Order By: Relevance

“…Many descriptive studies have been published addressing the expression of desmosomal proteins including PKPs in cancer and trying to correlate the expression pattern with tumor progression (Dusek & Attardi, 2011). However, the results of these studies are contradictory with up-regulation, down-regulation, or maintenance of desmosome components being reported.…”

Section: Pkp Function In Cancer: Loss or Gain Of Function?mentioning

confidence: 85%

Plakophilins in Desmosomal Adhesion and Signaling

Hatzfeld

Wolf

Keil

2014

Cell Communication & Adhesion

View full text Add to dashboard Cite

The regulation of adhesion and growth is important for epithelial function and dysfunction. β -catenin ( armadillo in Drosophila ) is the prototype of a multifunctional molecule that regulates cell adhesion via adherens junctions and cell signaling via LEF/TCF transcription factors. Desmosomal armadillo proteins comprise plakoglobin and the plakophilins 1, 2, and 3. These proteins are essential for building up the desmosome and linking the desmosomal cadherins to keratin fi laments. High expression of plakophilins in desmosomes correlates with strong intercellular cohesion and is essential for tissue integrity under mechanical stress. However, like β -catenin, these proteins have diverse non-desmosomal functions, for example, in regulating actin organization, protein synthesis, and growth control. In line with these functions, their de-regulated expression with up-as well as down-regulation has been connected to cancer and metastasis. Now, recent evidence sheds light on the post-translational regulation and provides an explanation for how de-regulation of plakophilins can contribute to cancer.

show abstract

Section: Pkp Function In Cancer: Loss or Gain Of Function?mentioning

confidence: 85%

Plakophilins in Desmosomal Adhesion and Signaling

Hatzfeld

Wolf

Keil

2014

Cell Communication & Adhesion

View full text Add to dashboard Cite

show abstract

“…Lack of PKP2 dissociates desmoplakin from the cardiac adhering desmosomal junctions and results in disruption of heart morphogenesis (15)(16)(17), suggesting that PKP2 plays a major role in cell-to-cell junctions in cardiomyocytes. Desmosome proteins have been reported to both promote and inhibit cancer development (31). Interestingly, PKP2 was shown to interact with ␤-catenin and modestly enhance LEF/ TCF-mediated transactivation (13); however, the mechanism is not fully understood.…”

Section: Discussionmentioning

confidence: 97%

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

View full text Add to dashboard Cite

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.

show abstract

“…This effect was detectable at 0.1 mM and maximal at 1 mM ATRA. Differentiation included accumulation of oil-red droplets (lactogenesis) (Supplementary Figure S2b) and appearance of adherens junctions containing b-catenin, p120 and VE-cadherin (Supplementary Figure S2c; Dusek and Attardi, 2011). This was accompanied by the induction of the three proteins (see also Figure 2d) and restructuring of the actin cytoskeleton.…”

Section: Resultsmentioning

confidence: 99%

Synergistic antitumor activity of lapatinib and retinoids on a novel subtype of breast cancer with coamplification of ERBB2 and RARA

et al. 2011

View full text Add to dashboard Cite

All-trans retinoic acid (ATRA), the only clinically available cyto-differentiating agent, has potential for the therapy/chemoprevention of breast carcinoma. Given the heterogeneous nature of this tumor, a rational use of ATRA and derivatives (retinoids) in the clinic requires the identification of patients that would benefit from retinoidbased protocols. Here, we demonstrate that 23-32% of the human ERBB2 þ breast cancers show coamplification of retinoic acid receptor alpha (RARA), encoding the retinoic acid receptor, RARa. This represents a novel subtype of breast cancer characterized by remarkable sensitivity to ATRA and RARa agonists, regardless of positivity to the estrogen receptor, a known modulator of retinoid sensitivity. In estrogen-receptor-negative cellular models showing coamplification of ERBB2 and RARA, simultaneous targeting of the corresponding gene products with combinations of lapatinib and ATRA causes synergistic growth inhibition, cyto-differentiation and apoptosis. This provides proof-of-principle that coamplification of ERBB2 and RARA can be exploited for the stratified and targeted therapy of a novel subtype of breast cancer patients, with an approach characterized by tumor cell selectivity and low predicted toxicity. The available cellular models were exploited to define the molecular mechanisms underlying the antitumor activity of combinations between lapatinib and ATRA. Global gene expression and functional approaches provide evidence for three components of the antiproliferative/apoptotic responses triggered by lapatinib þ ATRA. Induction of the retinoiddependent RARRES3 protein by ATRA stabilizes the effect of lapatinib inhibiting ERBB2 phosphorylation. Upregulation and activation of the transcription factor FOXO3A integrates ATRA-dependent transcriptional and lapatinib-dependent posttranscriptional signals, controlling the levels of effector proteins like the antiapoptotic factor, BIRC5. Stimulation of the TGFb pathway by ATRA mediates other components of the apoptotic process set in motion by simultaneous targeting of ERBB2 and RARa.

show abstract

Desmosomes: new perpetrators in tumour suppression

Cited by 159 publications

References 133 publications

Plakophilins in Desmosomal Adhesion and Signaling

Plakophilins in Desmosomal Adhesion and Signaling

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

Synergistic antitumor activity of lapatinib and retinoids on a novel subtype of breast cancer with coamplification of ERBB2 and RARA

Contact Info

Product

Resources

About