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First published online 5 August 2003
doi: 10.1242/jcs.00725

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Journal of Cell Science 116, 3783-3791 (2003)
doi: 10.1242/jcs.00725

Research Article

Suprabasal {alpha}6ß4 integrin expression in epidermis results in enhanced tumourigenesis and disruption of TGFß signalling

David M. Owens1, M. Rosario Romero1,*, Clare Gardner2 and Fiona M. Watt1,{ddagger}

1 Keratinocyte Laboratory, CR-UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3PX, UK
2 Pfizer Global Research and Development, Sandwich Data Centre, Sandwich CT13 9NJ, UK

{ddagger} Author for correspondence (e-mail: fiona.watt{at}cancer.org.uk)

Accepted 24 June 2003

Inappropriate {alpha}6ß4 integrin expression correlates with a high risk of tumour progression in stratified squamous epithelia. Targeted expression of {alpha}6ß4 in the suprabasal layers of transgenic mouse epidermis dramatically increased the frequency of papillomas, carcinomas and metastases induced by chemical carcinogenesis, independent of the ß4 cytoplasmic domain. Suprabasal {alpha}6ß4 also perturbed transforming growth factor ß (TGFß) signalling as demonstrated by decreased nuclear Smad2 in transgenic epidermis and tumours. In cultured keratinocytes, suprabasal {alpha}6ß4 relieved TGFß-mediated growth inhibition and blocked nuclear translocation of activated Smad2/3. Responsiveness to TGFß could be restored by inhibiting cadherin-mediated cell-cell adhesion or phosphoinositide 3-kinase (PI3-K) activity, but not by inhibiting mitogen-activated protein kinase (MAPK) activity. These data suggest that suprabasal {alpha}6ß4 promotes tumourigenesis by preventing TGFß from suppressing clonal expansion of initiated cells in the epidermal basal layer.

Key words: Keratinocyte, Differentiation, Carcinogenesis, Skin, Smad


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