We previously proposed that the keratinocyte hyperproliferative state in psoriatic skin results from a combination of T cell cytokine interaction with basal keratinocytes that exist in a primed state. We now provide evidence that basal keratinocytes from psoriatic uninvolved skin are in a preactivated state with regard to their interaction with fibronectin. Freshly isolated basal keratinocytes (K(1)/K(10)(-)) from non-lesional psoriatic skin demonstrated a significantly higher percentage of spreading cells 1 h after plating on fibronectin-coated plates than keratinocytes isolated from normal skin (p =0.0002). No differences were observed on collagen-laminin-coated plates, however. The keratinocyte spreading on fibronectin-coated plates involved alpha 5 beta 1 and alpha V beta 1 integrins. To address the potential signaling cascades that may respond to integrin changes in psoriatic keratinocytes, focal adhesion kinase changes were assessed. The percentage of keratinocytes from psoriatic uninvolved skin that exhibit positive focal adhesion kinase staining was significantly greater than the percentage from healthy volunteers after 1 h incubation on fibronectin (p =0.006). Additionally, focal adhesion kinase isolated from uninvolved psoriatic keratinocytes had a greater degree of tyrosine phosphorylation. Thus, the proliferative effect of fibronectin in combination with T cell lymphokines on psoriatic uninvolved basal keratinocyte progenitors may be due to abnormal in vivo integrin-driven focal adhesion kinase activity and downstream signaling.