Involvement of the Ras/MAPK signaling pathway in the modulation of urokinase production and cellular invasiveness by transforming growth factor-beta(1) in transformed keratinocytes

Transformed PDV keratinocytes respond to TGF-beta(1) by stimulating cell mo tility and invasiveness concomitantly to enhancement of the urokinase-type plasminogen activator (uPA) expression/secretion. Depletion of extracellula r signal-regulated kinase (ERK1, 2) proteins by treatment of PDV cells with antisense oligonucleotides reduced basal uPA production and abolished stim ulation of uPA secreted levels and cell motility by TGF-beta(1). PD098059, an inhibitor of mitogen-activated protein kinase (MAPK) kinase (MEK), decre ased TGF-beta(1)-induced uPA mRNA expression, secreted activity in a dose-d ependent manner, and abrogated TGF-beta(1)-stimulated cell motility and inv asiveness. PDV-derived dominant-negative RasN17 cell transfectants secreted similar amounts of uPA and exhibited similar invasive abilities as the par ental cells or control clones, but were unable to respond to TGF-beta(1) fo r stimulation of uPA-secreted levels and invasiveness. These results sugges t that a Ras/MAPK transduction pathway is involved in the invasive response of transformed keratinocytes to TGF-beta(1). (C) 2000 Academic Press.