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Human Desmoglein 3

Associated Centre/s: Clinical and Diagnostic Oral Sciences

Associated Research: Infection, Immunity and Inflammation

Research Programme Funder: British Skin Foundation and others

Intercellular junctions are crucial for cell adhesion and tissue integrity and are critically coordinated with various cellular processes such as polarisation, differentiation, morphogenesis, and cell motility. Desmosomes and adherence junctions are the predominant intercellular junctions in epithelial tissues, including the skin and oral mucosa that experience extensive mechanical stress, and function as the anchors that connect the cell surface adhesion proteins to the intermediate filament and actin cytoskeletons, respectively.

Defects in the genes encoding the desmosomal proteins, or disruption of desmosome adhesion by autoimmune antibodies or bacterial toxins, result in disruption of the tissue integrity and clinical manifestation with blistering in the skin and oral mucosa as well as the heart in some cases. Increasing evidence suggests that desmosomal proteins have broader functions than simply joining the epithelial cells together and play a role in the regulation of signalling pathways that are involved in diverse cellular responses. Understanding these additional functions will be of great value for clinical diagnosis and treatment of the associated diseases.

Dr Wan's interests focus on these intercellular junctions in health and associated diseases and currently, in particular, on the novel signalling role of the desmosomal cadherin, desmogelin 3 (Dsg3) in cancer progression and metastasis as well as in pemphigus vulgaris, a life-threatening autoimmune blistering disease. Recent work from her team has shown that non-junctional pool of Dsg3 is involved in the regulation of signal pathways of Src and Rho family GTPases that are crucial for actin based E-cadherin junction adhesion, cell motility and cell shape change.

Since Dsg3 (also called pemphigus vulgaris antigen, PVA) is best known to be the key player in pemphigus vulgaris, the finding from their study will have important implication for better understanding of the pathogenesis of this disease. Using a combination of gain- and loss-of-function study approaches, Dr Wan’s team are trying to elucidate how Dsg3 is engaged in cellular processes such as cell adhesion, motility, polarisation, morphogenesis in normal epithelia and the dysregulation in disease conditions.

Dr Wan’s research focuses on the following three aspects:

  1. Dissecting the signalling role of human desmoglein 3, the pemphigus vulgaris antigen (funded by British Skin Foundation)
  2. Regulation of E-cadherin function by desmoglein 3 (funded by the Libya government)
  3. Role of Dsg3 in cancer cell migration and metastasis

Key Publications

Siu Man Tsang, Louise Brown, Hanan Gadmor, Luke Gammon, Farida Fortune, Ann Wheeler and Hong Wan. Desmoglein 3 acting as an upstream regulator of Rho GTPases, Rac-1/Cdc42 in the regulation of actin organisation and dynamics. Exp Cell Res. 2012 Nov 1;318(18):2269-83. Epub 2012 Jul 13.

Tsang SMBrown LLin KLiu LPiper KO'Toole EAGrose RHart IRGarrod DRFortune FWan H. Non junctional human desmoglein 3 acts as an upstream regulator of Src in E-cadherin adhesion, a pathway possibly involved in the pathogenesis of pemphigus vulgaris. J Pathol. 2012 Jan 4. doi: 10.1002/path.3982. [Epub ahead of print]

Tanima Mannan, Sara Heidari Foroushania, Farida Fortune and Hong Wan  RNAi mediated inhibition of the desmosomal cadherin, desmoglein 3, impaired epithelial cell proliferation. Cell Prolif. 2011 Aug;44(4):301-10. doi: 10.1111/j.1365-2184.2011.00765.x

Teh MT, Parkinson EK, Thurlow JK, Liu F, Fortune F, Wan H. A molecular study of desmosomes identifies a desmoglein isoform switch in head and neck squamous cell carcinoma. J Oral Pathol Med. 2011 Jan;40(1):67-76. doi: 10.1111/j.1600-0714.2010.00951.x. Epub 2010 Oct 4.

Tsang SM, Liu L, Teh MT, Wheeler A, Grose R, Hart IR, Garrod DR, Fortune F, Wan H. Desmoglein 3, via an interaction with E-cadherin, is associated with activation of Src. PLoS One. 2010 Dec 3;5(12):e14211.

Hong Wan, Ming Yuan, Cathy Simpson, Kirsty Allen, Nuzhat Baksh, Edel A O’Toole and Ian R Hart. Stem/progenitor cell-like properties of Desmoglein 3-dim cells in primary and immortalized keratinocyte lines.  Stem Cells 2007 May;25(5):1286-97. Epub 2007 Jan 25.

Wan H, Stone MG, Simpson C, Reynolds LE, Marshall JF, Hart IR, Hodivala-Dilke KM, Eady RA. Desmosomal proteins, including desmoglein 3, serve as novel negative markers for epidermal stem cell-containing population of keratinocytes.  J Cell Sci 2003 Oct 15;116(Pt 20):4239-48. Epub 2003 Sep 2.

H Wan, HL Winton, C Soeller, ER Tovey, DC Gruenert, PJ Thompson, GA Stewart, GW Taylor, DR Garrod, MB Cannell, and C Robinson. The transmembrane protein occludin of epithelial tight junctions is a functional target for serine peptidases from fecal pellets of Dermatophagoides pteronyssinus. Clin Exp Allergy. 2001 Feb;31(2):279-94.

H Wan, HL Winton, C Soeller, ER Tovey, DC Gruenert, PJ Thompson, GA Stewart, GW Taylor, DR Garrod, MB Cannell and C Robinson. Disruption of epithelial tight junctions by house dust mite faecal pellet proteinase.  J Clinical Invest, 1999 Jul;104(1):123-33.

Contact

Dr Hong Wan
Senior Lecturer

h.wan@qmul.ac.uk
+44 20 7882 7139

Research Centre for Clinical and Diagnostic Oral Sciences
Blizard Building
Barts and the London
Queen Mary's School of Medicine and Dentistry
4 Newark Street
London E1 2AT

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