Desmosomes: a role in cancer?

Chidgey, Martyn; Dawson, Chris

doi:10.1038/sj.bjc.6603808

Cited by 157 publications

(155 citation statements)

References 41 publications

(39 reference statements)

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“…Both interact with E-cadherin, a-catenin, Axin and APC and both have been shown to be involved in Wnt signaling (Ben-Ze'ev and Geiger, 1998;Zhurinsky et al, 2000b;Chidgey and Dawson, 2007). In addition to its associations with classic cadherins, plakoglobin interacts with desmosomal cadherins and is essential for the formation of desmosomes (Parker et al, 1998;Holthofer et al, 2007;Garrod and Chidgey, 2008), whereas b-catenin typically does not.…”

Section: Introductionmentioning

confidence: 99%

Plakoglobin interacts with and increases the protein levels of metastasis suppressor Nm23-H2 and regulates the expression of Nm23-H1

et al. 2010

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Plakoglobin (c-catenin) is a homolog of b-catenin with similar dual adhesive and signaling functions. The adhesive function of these proteins is mediated by their interactions with cadherins, whereas their signaling activity is regulated by association with various intracellular partners. In this respect, b-catenin has a well-defined oncogenic activity through its role in the Wnt signaling pathway, whereas plakoglobin acts as a tumor/metastasis suppressor through mechanisms that remain unclear. We previously expressed plakoglobin in SCC9 squamous carcinoma cells (SCC9-P) and observed a mesenchymalto-epidermoid transition. Comparison of the protein and RNA profiles of parental SCC9 cells and SCC9-P transfectants identified various differentially expressed proteins and transcripts, including the nonmetastatic protein 23 (Nm23). In this study, we show that Nm23-H1 mRNA and Nm23-H2 protein are increased after plakoglobin expression. Coimmunoprecipitation and confocal microscopy studies using SCC9-P and various epithelial cell lines with endogenous plakoglobin expression revealed that Nm23 interacts with plakoglobin, cadherins and a-catenin. Furthermore, Nm23-H2 is the primary isoform involved in these interactions, which occur prominently in the cytoskeleton-associated pool of cellular proteins. In addition, we show that plakoglobinNm23 interaction requires the N-terminal (a-catenin interacting) domain of plakoglobin. Our data suggest that by increasing the expression and stability of Nm23, plakoglobin has a role in regulating the metastasis suppressor activity of Nm23, which may further provide a potential mechanism for the tumor/metastasis suppressor function of plakoglobin itself.

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Section: Introductionmentioning

confidence: 99%

Plakoglobin interacts with and increases the protein levels of metastasis suppressor Nm23-H2 and regulates the expression of Nm23-H1

et al. 2010

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“…These cellular rivets are dynamic structures and participate in a number of pathologic processes, including tumor formation, invasion, and metastasis. 1,2 Inverted papilloma (IP) of the sinonasal cavity is a locally aggressive benign tumor characterized by a tendency for recurrence and the potential for malignant transformation. The microscopic feature of IP is the increase in thickness of the covering epithelium with extension into the connecting tissue stroma.…”

Section: Introductionmentioning

confidence: 99%

Desmoglein 3 is overexpressed in inverted papilloma and squamous cell carcinoma of sinonasal cavity

et al. 2009

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Objectives/Hypothesis: We sought to investigate the role of desmoglein 3 in pathogenesis of sinonasal inverted papilloma (IP) and its malignant transformation.Methods: Fifteen subjects with sinonasal IP and 15 subjects of normal sphenoid sinus mucosa were enrolled. Each specimen was divided into two portions: one for mRNA expression analysis by real-time polymerase chain reaction, and the other for detection of targeted proteins by immunohistochemistry analysis. In addition, another 10 cases of IP with squamous cell carcinoma (SCC) were added for immunohistochemistry analysis.Results: The mRNA expression level of desmoglein 3 was significantly higher in IP tissues than in the normal sinus mucosa (P < .001). In immunohistochemistry study, desmoglein 3 was detected in plasma membrane areas of IP and IP with SCC tissues, but no obvious expression was found in normal sinus mucosa (total score; both P < .001). Positive desmoglein 3 staining was strongly present in nearly all malignant transformation areas of IP with SCC cases (90%), but only in scattered areas of some cases of IP (53%) (total score; P < .001).Conclusions: Desmoglein 3 was overexpressed in IP and IP with SCC, and the overexpression was correlated with malignant transformation of IP. It may provide valuable insight into the pathobiology of this disease, and can potentially provide a venue to predict malignant transformation in sinonasal IP.

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Section: Introductionmentioning

confidence: 99%

“…Desmosomes provide mechanical integrity to epithelial and heart tissues by redistributing the forces of mechanical stress . In addition, desmosomal cadherins have more recently emerged as playing a role in tissue morphogenesis (Runswick et al, 2001;Chidgey and Dawson, 2007;Dusek et al, 2007).In spite of desmosomes' importance in tissue function, most studies have focused on the contribution of classic cadherins to epithelial remodeling. Classic cadherins engage in bidirectional signaling with receptor tyrosine kinases (RTKs), whereby they are both responsive to, and can trigger, signals that regulate cell behavior (Wheelock and Johnson, 2003;McLachlan and Yap, 2007).…”

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confidence: 99%

EGFR and ADAMs Cooperate to Regulate Shedding and Endocytic Trafficking of the Desmosomal Cadherin Desmoglein 2

Klessner

Desai

Amargo³

et al. 2009

MBoC

104

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Regulation of classic cadherins plays a critical role in tissue remodeling during development and cancer; however, less attention has been paid to the importance of desmosomal cadherins. We previously showed that EGFR inhibition results in accumulation of the desmosomal cadherin, desmoglein 2 (Dsg2), at cell-cell interfaces accompanied by inhibition of matrix metalloprotease (MMP)-dependent shedding of the Dsg2 ectodomain and tyrosine phosphorylation of its cytoplasmic domain. Here, we show that EGFR inhibition stabilizes Dsg2 at intercellular junctions by interfering with its accumulation in an internalized cytoplasmic pool. Furthermore, MMP inhibition and ADAM17 RNAi, blocked shedding and depleted internalized Dsg2, but less so E-cadherin, in highly invasive SCC68 cells. ADAM9 and 15 silencing also impaired Dsg2 processing, supporting the idea that this desmosomal cadherin can be regulated by multiple ADAM family members. In contrast, ADAM10 siRNA enhanced accumulation of a 100-kDa Dsg2 cleavage product and internalized pool of Dsg2. Although both MMP and EGFR inhibition increased intercellular adhesive strength in control cells, the response to MMP-inhibition was Dsg2-dependent. These data support a role for endocytic trafficking in regulating desmosomal cadherin turnover and function and raise the possibility that internalization and regulation of desmosomal and classic cadherin function can be uncoupled mechanistically. INTRODUCTIONThe ability of cells to modulate their contacts with each other and the underlying matrix is essential for epithelial remodeling that occurs in development and cancer progression (Behrens, 1999;Thiery, 2003;Kramer et al., 2005). In particular, members of cadherin family of calcium-dependent intercellular adhesion molecules have been demonstrated to both suppress (Frixen et al., 1991) and promote (Islam et al., 1996) cell migration and invasion. Although classic cadherins assemble into intercellular adhesive structures known as adherens junctions that associate with the cortical actin cytoskeleton, desmosomal cadherins, including desmogleins and desmocollins, make up the adhesive core of desmosomes, which anchor intermediate filaments (IF) to sites of strong intercellular adhesion (Green and Simpson, 2007).Anchorage to the IF cytoskeleton is established with the cooperation of the desmosomal cadherin-associated proteins plakoglobin and plakophilins, which in turn link the IF-associated protein desmoplakin (DP) to the membrane complex. Desmosomes provide mechanical integrity to epithelial and heart tissues by redistributing the forces of mechanical stress . In addition, desmosomal cadherins have more recently emerged as playing a role in tissue morphogenesis (Runswick et al., 2001;Chidgey and Dawson, 2007;Dusek et al., 2007).In spite of desmosomes' importance in tissue function, most studies have focused on the contribution of classic cadherins to epithelial remodeling. Classic cadherins engage in bidirectional signaling with receptor tyrosine kinases (RTKs), whereby they are both ...

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Desmosomes: a role in cancer?

Cited by 157 publications

References 41 publications

Plakoglobin interacts with and increases the protein levels of metastasis suppressor Nm23-H2 and regulates the expression of Nm23-H1

Plakoglobin interacts with and increases the protein levels of metastasis suppressor Nm23-H2 and regulates the expression of Nm23-H1

Desmoglein 3 is overexpressed in inverted papilloma and squamous cell carcinoma of sinonasal cavity

EGFR and ADAMs Cooperate to Regulate Shedding and Endocytic Trafficking of the Desmosomal Cadherin Desmoglein 2

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