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Activation of the ß-Catenin/T-Cell–Specific Transcription Factor/Lymphoid Enhancer Factor-1 Pathway by Plasminogen Activators in ECV304 Carcinoma Cells

Institut National de la Santé et de la Recherche Médicale U466, IFR31, Centre Hospitalier Universitaire Rangueil, Toulouse, France

Requests for reprints: Anne Negre-Salvayre, Institut National de la Santé et de la Recherche Médicale U-466 and Biochemistry Department, IFR31, Centre Hospitalier Universitaire Rangueil, 1 Avenue Jean Poulhès, TSA-50032, 31059 Toulouse Cedex 9, France. Phone: 33-561-32-31-48/33-561-32-27-05; Fax: 33-561-32-20-84; E-mail: anesalv{at}toulouse.inserm.fr.

Besides its involvement in clot lysis, the plasminogen activator (PA) system elicits various cellular responses involved in cell migration, adhesion, and proliferation and plays a key role in the progression of cancers. ß-Catenin interacts with E-cadherins and functions as transcriptional coactivator of the Wnt-signaling pathway, which is implicated in tumor formation when aberrantly activated. We report that tissue-type plasminogen activator (tPA) elicited tyrosine phosphorylation and cytosolic accumulation of an active (non–serine-threonin phosphorylated, nonubiquitinated) form of ß-catenin in ECV304 carcinoma cells. tPA-dependent ß-catenin activation is mediated through epidermal growth factor receptor (EGFR) transactivation (via Src), suggested by the inhibitory effects of AG1478 and PP2 (specific inhibitors of EGFR and Src, respectively) and by the lack of ß-catenin activation in EGFR-negative B82 fibroblasts. EGFR phosphorylation and ß-catenin activation were inhibited by plasminogen activator inhibitor 1 and pertussis toxin, two inhibitors of the urokinase-type plasminogen activator (uPA)/uPA receptor system. ß-Catenin activation was correlated with the phosphorylation of glycogen synthase kinase-3ß through a phosphatidylinositol 3-kinase/Akt-dependent mechanism. Gel shift experiments revealed the activation of ß-catenin/T-cell–specific transcription factor (Tcf)/lymphoid enhancer factor-1 (Lef) transcriptional complex, evidenced by an increased binding of nuclear extracts to oligonucleotides containing the cyclin D1 Lef/Tcf site. ß-Catenin silencing through small interfering RNA and antisense oligonucleotides inhibited both the tPA-mediated cyclin D1 expression and cell proliferation. A similar activation of the ß-catenin pathway was triggered by amino-terminal fragment, the NH₂-terminal catalytically inactive fragment of tPA, thus suggesting that this effect was independent of the proteolytic activity of plasminogen activators. In conclusion, the ß-catenin/Lef/Tcf pathway is activated by tPA and is involved in cell cycle progression and proliferation.

Key Words: tPA • ß-catenin • Lef/Tcf transcription factor • cyclin D1

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