Squamous cell carcinomas in the skin arise from stem cells in the basal layer of the epidermis. Surprisingly, the suprabasal cells above frequently determine the severity of the disease: poor prognosis is associated with dysregulation of integrin α6β4 in these cells rather than the basal stem cells below. Fiona Watt and co-workers have examined the basis for the correlation between α6β4 dysregulation and tumor formation by creating transgenic mice that express α6β4 in the suprabasal cells (see p. 3783). They demonstrate that these mice are highly susceptible to chemicals that induce tumors in the skin. Importantly, they also show that TGFβ-mediated growth inhibition is compromised in keratinocytes from the mice: nuclear translocation of TGFβ-responsive Smad signalling molecules is suppressed both in vivo and in an in vitro model. The authors find that the suppression of TGF-β signalling can be relieved by PI 3-kinase (PI3K) inhibitors or a dominant negative mutant of the cell-cell adhesion protein E-cadherin. They therefore conclude that expression of integrin α6β4 in the differentiated suprabasal cells unleashes the malignant potential of the undifferentiated basal cells by activating a PI3K- and cell-adhesion-dependent pathway that antagonizes the TGFβ signal that normally prevents the basal cells from proliferating.