Desmoglein 3 acts as a potential oncogene in promoting cancer cell migration and invasion through regulating AP-1 and PKC dependent-Ezrin activation
Number of pieces
65 - 66
Meeting Abstract EP-72
MetadataShow full item record
Desmoglein 3 (Dsg3) is a core adhesion protein in desmosomes that anchor intermediate filaments and confer strong cell-cell adhesion in epithelial cells. It is best known as the pemphigus vulgaris antigen (PVA) as circulating autoantibodies in pemphigus patients target Dsg3 on keratinocytes and cause disruption of cell cohesion and blistering in the skin and oral mucosa. Based on this finding, it was thought that Dsg3 might potentially act as a tumour suppressor through its cell-cell adhesive function like E-cadherin. Paradoxically, recent studies have discovered that Dsg3 is upregulated in squamous cell carcinoma (SCC) of various organs including the skin, head and neck, lung and esophagus. Furthermore, Dsg3 has been identified to serve as a tumor-specific marker for clinical staging and for detection of lymph node metastasis in head and neck SCC. However, the biological function of Dsg3 in cancers remains poorly understood. The actin-binding protein Ezrin belongs to the ERM family of proteins found enriched in microvilli, ruffles, filopodia and cell adhesion sites. Upon phosphorylation at Thr-567, activated Ezrin links the plasma membrane to the actin cytoskeleton and recruits multi-protein complex to the membrane. AP-1 is a dimeric transcription factor composed of proteins including c-Jun and c-Fos. AP-1 is known as a proto-oncogene and a critical regulator of complex gene expression programs that defines the invasive phenotype associated with cancer. Both Ezrin and AP-1 can be activated by Protein kinase C (PKC) and Rho kinase (ROCK) and participate in diverse cellular processes thus have been implicated in cancer invasion and metastasis. In this study we showed that a pool of Dsg3 functioning outside of desmosomes, acts as a regulator of Ezrin and AP-1 (Brown et al., 2014). We found that Dsg3 formed a protein complex with Ezrin at the plasma membrane that was required for its proper function of interacting with F-actin and CD44 since Dsg3 depletion impaired their associations. Furthermore, the ectopic expression of Dsg3 in cancer cell lines resulted in an enhanced phosphorylation of Ezrin-Thr567 and transcriptional activity of c-Jun/AP-1 with concomitant augmented membrane protrusions, cell spreading and invasive phenotype. A marked increase in c-Jun S63 phosphorylation was also found in Dsg3 overexpressing cells compared to control cells with low Dsg3 expression. We demonstrated that these activation processes induced by Dsg3 could be abrogated substantially by various pharmacological inhibitors, including PKC and ROCK, JNK, p38, Rac1 and Src as well as by Dsg3 depletion. Finally, our later study suggested that this MAPK-dependent mechanism appears to be universal as it can be demonstrated in various cell types, including Cos-1 fibroblastic-like cells. Taken together, our study identifies a novel Dsg3 mediated c-Jun/AP-1 regulatory mechanism and PKC-dependent Ezrin phosphorylation that could be responsible for Dsg3-associated cancer cell invasion and metastasis.