Integrins and signaling in psoriasis

August 15, 2001

The development of keratinocytes in the skin provides one of the clearest examples of a regulated change in cellular adhesion. Basal stem cells and their immediate progeny, the pluripotent "transit" cells that provide a continuous supply of new skin cells, are more highly adhesive than are terminally differentiated suprabasal cells, and they express correspondingly higher levels of several integrins. This regulation is lost in psoriatic lesions, which maintain integrin expression even at the suprabasal level. Following up on earlier evidence that suprabasal expression of integrins in mice is sufficient to induce a hyperproliferation and histological abnormalities that resemble psoriasis, Haase et al. have now sought evidence of signaling abnormalities that might explain the effect of these receptors. The authors focus on the MAP kinase pathway, which mediates integrin effects on basal cell growth. They show here that they can bypass a requirement for high integrin levels by using a constitutively active version of the regulatory MAP kinase kinase MEK to maintain high MAP kinase activity in suprabasal cells, thus promoting keratinocyte growth. Analysis of these cells maintained in organ culture suggests that this transgene delays terminal differentiation by transit cells and generates a thickened basal layer much like that seen in psoriasis. Because an inhibitory form of MEK opposes keratinocyte proliferation in this system, the authors suggest that MAP kinase would be a suitable target for drug therapies for this common disorder.
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