Involvement of the Ras/MAPK Signalling Pathway in the Modulation of Urokinase Production and Cellular Invasiveness by Transforming Growth Factor TGF-β1 in Transformed Keratinocytes

Abstract

Transformed PDV keratonocytes respond to TGF-β1 by stimulating cell motility and invasiveness concomitantly to enhancement of the urokinae-type plasmiogen activator (uPA) expression/secretion. Depletion of extracellular signal-regulated kinase (EREK1,2) proteins by treatment of PDV cells with antinese oligonucleotides reduced basal uPA production and abolished stimulation of uPA secreted levels and cell motility by TGF-β1. PD098059, an inhibitor of mitogenactivated protein kinase (MAPK) kinase (MEK), decreased TGF-β1-induced uPA mRNA expression, secreted activity in a dose-dependent manner, and abrogated TGF-β1-stimulated cell motility and invasiveness. PDV-derived dominant-negative RasN17 cell transfectants secreted similar amounts of uPA and exhibited similar invasive abilities as the parental cells or control clones, but were unable to respond to TGF-β1 for stimulation of uPA-secreted levels and invasiveness. These results suggest that a Ras/MAPK transduction pathway is involved in the invasive response ot transformed keratinocytes to TGF-β1.