Desmoglein 3 promotes cancer cell migration and invasion by regulating activator protein 1 and protein kinase C-dependent-Ezrin activation

Brown, Louise; Waseem, Ahmad; Cruz, Isa N.; Szary, Jarosław; Gunić, Esmir; Mannan, T.; Unadkat, M; Yang, Ming; Valderrama, Ferran; O’Toole, Edel A.; Wan, Hong

doi:10.1038/onc.2013.186

Cited by 60 publications

(78 citation statements)

References 79 publications

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“…Overexpression of Dsg3 in the oral squamous cell carcinoma (OSCC) cell lines A431 and SqCC/Y1 caused a marked increase in phosphorylation of the conserved ezrin residue T567, which resulted in increased migration and invasion in 3D cell culture assays. It has been suggested that ezrin is phosphorylated by PKC after its colocalisation with Dsg3, an interaction that might be responsible for the metastatic potential of OSCC cell lines (Brown et al, 2013). Ezrin has previously been proposed to act as a downstream signalling molecule in PKCinduced cell migration; here, PKCa phosphorylates specifically the conserved T567 residue on ezrin (Ng et al, 2001), which results in CD44-dependent directional migration (Legg et al, 2002).…”

Section: Ezrinmentioning

confidence: 99%

“…A so far unknown interaction between ezrin and the desomosome protein desmoglein 3 (Dsg3) has recently been identified; and Dsg3 appears to colocalise with ezrin at the plasma membrane (Brown et al, 2013). Overexpression of Dsg3 in the oral squamous cell carcinoma (OSCC) cell lines A431 and SqCC/Y1 caused a marked increase in phosphorylation of the conserved ezrin residue T567, which resulted in increased migration and invasion in 3D cell culture assays.…”

Section: Ezrinmentioning

confidence: 99%

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ERM proteins in cancer progression

Clucas

Valderrama

2014

Journal of Cell Science

223

152

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Members of the ezrin–radixin–moesin (ERM) family of proteins are involved in multiple aspects of cell migration by acting both as crosslinkers between the membrane, receptors and the actin cytoskeleton, and as regulators of signalling molecules that are implicated in cell adhesion, cell polarity and migration. Increasing evidence suggests that the regulation of cell signalling and the cytoskeleton by ERM proteins is crucial during cancer progression. Thus, both their expression levels and subcellular localisation would affect tumour progression. High expression of ERM proteins has been shown in a variety of cancers. Mislocalisation of ERM proteins reduces the ability of cells to form cell–cell contacts and, therefore, promotes an invasive phenotype. Similarly, mislocalisation of ERM proteins impairs the formation of receptor complexes and alters the transmission of signals in response to growth factors, thereby facilitating tumour progression. In this Commentary, we address the structure, function and regulation of ERM proteins under normal physiological conditions as well as in cancer progression, with particular emphasis on cancers of epithelial origin, such as those from breast, lung and prostate. We also discuss any recent developments that have added to the understanding of the underlying molecular mechanisms and signalling pathways these proteins are involved in during cancer progression.

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Section: Ezrinmentioning

confidence: 99%

Section: Ezrinmentioning

confidence: 99%

ERM proteins in cancer progression

Clucas

Valderrama

2014

Journal of Cell Science

223

152

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“…This suggests that other proteins may also be involved. Other cadherins, such as Nand P-cadherin and other desmosomal adhesion proteins (such as DSG1, DSG3, DSG4, DSC1 and DSC3), might take part in this process as their activities are associated with cancer development (1,6,22,30,40). Their involvement requires further investigation.…”

Section: Discussionmentioning

confidence: 99%

Cell–Cell Adhesion and Cytoskeleton Tension Oppose Each Other in Regulating Tumor Cell Aggregation

et al. 2015

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Cell aggregation is frequently impaired during the growth of primary tumors and the formation of metastatic lesions. Cell aggregation depends on cell-cell adhesion; however, no rigorous approach exists to monitor and quantify it accurately in the absence of the confounding factors of cell-substrate adhesion and the resulting cell motility on the substrate. We report here a highly reproducible, automated, microscopy-based quantification of tumor-cell spheroid formation in the absence of cellsubstrate adhesion and use it to characterize cell aggregation dynamics in the early steps of this process. This method is based on fluorescence and bright-field microscopy and on a custom MATLAB program to quantify automatically the cells' aggregation kinetics. We demonstrate that the cell-cell adhesion protein E-cadherin and the desmosome proteins DSG2 and DSC2 are important for aggregation. Furthermore, we show that inhibition or silencing of myosin IIa enhances aggregation, suggesting that cytoskeleton tension inhibits tumor cell aggregation. This work opens new avenues to study the principles that govern multicellular aggregation, to characterize the aggregation properties of various tumor cell types, as well as to screen for drugs that inhibit or promote aggregation. Cancer Res; 75(12); 2426-33. Ó2015 AACR.

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“…The relationship between these two superimposed mechanisms does not need to be strictly causal. Podoplanin does not necessarily alter the effective cohesiveness at the beginning of the process (Brown et al, 2014;de Toledo et al, 2012;Ewald et al, 2012;Hartsock and Nelson, 2012;Priya et al, 2013;Ratheesh et al, 2013;Smith et al, 2012). Gotzmann et al (2004) have proposed a two-hit model for epithelial cell plasticity, so that a given cell line could be "pre-activated" and need only one signal or two signals to trigger EMT; for example, TGF-β and active Ras, or TGF-β and EGF.…”

Section: Role Of Podoplanin In Emtmentioning

confidence: 99%