title: Desmoglein 3 promotes cancer cell migration and invasion by regulating activator protein 1 and protein kinase C-dependent-Ezrin activation.
abstract: Desmoglein 3 (Dsg3), the pemphigus vulgaris antigen, has recently been shown to be upregulated in squamous cell carcinoma (SCC) and has been identified as a good tumor-specific marker for clinical staging of cervical sentinel lymph nodes in head and neck SCC. However, little is known about its biological function in cancer. The actin-binding protein Ezrin and the activator protein 1 (AP-1) transcription factor are implicated in cancer progression and metastasis. Here, we report that Dsg3 regulates the activity of c-Jun/AP-1 as well as protein kinase C (PKC)-mediated phosphorylation of Ezrin-Thr567, which contributes to the accelerated motility of cancer cells. Ectopic expression of Dsg3 in cancer cell lines caused enhanced phosphorylation at Ezrin-Thr567 with concomitant augmented membrane protrusions, cell spreading and invasive phenotype. We showed that Dsg3 formed a complex with Ezrin at the plasma membrane that was required for its proper function of interacting with F-actin and CD44 as Dsg3 knockdown impaired these associations. The increased Ezrin phosphorylation in Dsg3-overexpressing cells could be abrogated substantially by various pharmacological inhibitors for Ser/Thr kinases, including PKC and Rho kinase that are known to activate Ezrin. Furthermore, a marked increase in c-Jun S63 phosphorylation, among others, was found in Dsg3-overexpressing cells and the activation of c-Jun/AP-1 was further supported by a luciferase reporter assay. 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 metastasis.
authors.affiliation: Queen Mary University of London, Barts and The London School of Medicine and Dentistry, Centre for Clinical and Diagnostic Oral Sciences, Institute of Dentistry, London, UK.
authors.forename: L
authors.initials: L
authors.lastname: Brown
authors.affiliation: Queen Mary University of London, Barts and The London School of Medicine and Dentistry, Centre for Clinical and Diagnostic Oral Sciences, Institute of Dentistry, London, UK.
authors.forename: A
authors.initials: A
authors.lastname: Waseem
authors.affiliation: Department of Pharmaceutical and Biological Chemistry, UCL School of Pharmacy, London, UK.
authors.forename: I N
authors.initials: IN
authors.lastname: Cruz
authors.affiliation: Queen Mary University of London, Barts and The London School of Medicine and Dentistry, Centre for Clinical and Diagnostic Oral Sciences, Institute of Dentistry, London, UK.
authors.forename: J
authors.initials: J
authors.lastname: Szary
authors.affiliation: Queen Mary University of London, Barts and The London School of Medicine and Dentistry, Centre for Clinical and Diagnostic Oral Sciences, Institute of Dentistry, London, UK.
authors.forename: E
authors.initials: E
authors.lastname: Gunic
authors.affiliation: Queen Mary University of London, Barts and The London School of Medicine and Dentistry, Centre for Clinical and Diagnostic Oral Sciences, Institute of Dentistry, London, UK.
authors.forename: T
authors.initials: T
authors.lastname: Mannan
authors.affiliation: Queen Mary University of London, Barts and The London School of Medicine and Dentistry, Centre for Clinical and Diagnostic Oral Sciences, Institute of Dentistry, London, UK.
authors.forename: M
authors.initials: M
authors.lastname: Unadkat
authors.affiliation: Department of Pharmaceutical and Biological Chemistry, UCL School of Pharmacy, London, UK.
authors.forename: M
authors.initials: M
authors.lastname: Yang
authors.affiliation: Division of Biomedical Sciences, St George's, University of London, Cranmer Terrace, London, UK.
authors.forename: F
authors.initials: F
authors.lastname: Valderrama
authors.affiliation: Queen Mary University of London, Barts and The London School of Medicine and Dentistry, Centre for Cutaneous Research, Blizard Institute, London, UK.
authors.forename: E A
authors.initials: EA
authors.lastname: O'Toole
authors.affiliation: Queen Mary University of London, Barts and The London School of Medicine and Dentistry, Centre for Clinical and Diagnostic Oral Sciences, Institute of Dentistry, London, UK.
authors.forename: H
authors.initials: H
authors.lastname: Wan
mesh_terms: D045744:Cell Line, Tumor; D002465:Cell Movement; D022081:Cell Surface Extensions / Q000378:metabolism / Q000473:pathology; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D051184:Desmoglein 3 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D009361:Neoplasm Invasiveness; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism*; D016755:Proto-Oncogene Proteins c-jun; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D000099149:Ezrin
chemical_list: D003598:Cytoskeletal Proteins; D051184:Desmoglein 3; D011493:Protein Kinase C; D016755:Proto-Oncogene Proteins c-jun; D018808:Transcription Factor AP-1; D000099149:Ezrin; C071894:DSG3 protein, human