Transforming growth factor-alpha (TGF-alpha) appears to be an important autocrine/paracrine regulator of keratinocyte function. Not only does TGF-alpha induce keratinocyte proliferation and migration in vitro, but it also has been detected in normal human epidermis and at elevated levels in hyperproliferative epidermis. In the present study we report that exogenous TGF-alpha increases urokinase-type plasminogen activator (uPA) in cultured human keratinocytes. Furthermore, in the absence of exogenous growth factors, the "basal" levels of uPA are decreased by an antagonist monoclonal antibody to the receptor shared by TGF-alpha and epidermal growth factor (EGF). These results suggest that an endogenous factor serves as an autocrine/paracrine regulator of keratinocyte uPA. We hypothesize that activation of the TGF-alpha/EGF receptor may coordinately regulate the keratinocyte response to cutaneous wounding, which includes enhanced uPA expression, migration, and proliferation.