Activation of the {beta}-catenin/T-cell-specific transcription factor/lymphoid enhancer factor-1 pathway by plasminogen activators in ECV304 carcinoma cells

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. beta-Catenin interacts with E-cadherins and functions as transcriptional coactiv...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 2005-01, Vol.65 (2), p.526-532
Main Authors: Maupas-Schwalm, Françoise, Robinet, Catherine, Augé, Nathalie, Thiers, Jean-Claude, Garcia, Virginie, Cambus, Jean-Pierre, Salvayre, Robert, Nègre-Salvayre, Anne
Format: Article
Language:English
Subjects:
Active Transport, Cell Nucleus - physiology
beta Catenin
Carcinoma - metabolism
Cell Cycle - physiology
Cell Growth Processes - physiology
Cell Line, Tumor
Cyclin D1 - antagonists & inhibitors
Cyclin D1 - biosynthesis
Cytoskeletal Proteins - antagonists & inhibitors
Cytoskeletal Proteins - genetics
Cytoskeletal Proteins - metabolism
Cytosol - metabolism
DNA-Binding Proteins - metabolism
Enzyme Activation
Glycogen Synthase Kinase 3 - metabolism
Glycogen Synthase Kinase 3 beta
Humans
Lymphoid Enhancer-Binding Factor 1
Oligonucleotides, Antisense - genetics
Oligonucleotides, Antisense - pharmacology
Phosphorylation
Protein-Serine-Threonine Kinases - metabolism
Proto-Oncogene Proteins - metabolism
Proto-Oncogene Proteins c-akt
Receptor, Epidermal Growth Factor - antagonists & inhibitors
Receptor, Epidermal Growth Factor - physiology
RNA, Small Interfering
Tissue Plasminogen Activator - metabolism
Trans-Activators - antagonists & inhibitors
Trans-Activators - genetics
Trans-Activators - metabolism
Transcription Factors - metabolism
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Summary: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. beta-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 beta-catenin in ECV304 carcinoma cells. tPA-dependent beta-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 beta-catenin activation in EGFR-negative B82 fibroblasts. EGFR phosphorylation and beta-catenin activation were inhibited by plasminogen activator inhibitor 1 and pertussis toxin, two inhibitors of the urokinase-type plasminogen activator (uPA)/uPA receptor system. beta-Catenin activation was correlated with the phosphorylation of glycogen synthase kinase-3beta through a phosphatidylinositol 3-kinase/Akt-dependent mechanism. Gel shift experiments revealed the activation of beta-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. beta-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 beta-catenin pathway was triggered by amino-terminal fragment, the NH(2)-terminal catalytically inactive fragment of tPA, thus suggesting that this effect was independent of the proteolytic activity of plasminogen activators. In conclusion, the beta-catenin/Lef/Tcf pathway is activated by tPA and is involved in cell cycle progression and proliferation.
ISSN:0008-5472
1538-7445