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      Plasminogen activator inhibitor-1 regulates integrin alphavbeta3 expression and autocrine transforming growth factor beta signaling.

      The Journal of Biological Chemistry

      Animals, Autocrine Communication, Cell Line, Cell Membrane, metabolism, Cell Nucleus, Collagen, biosynthesis, DNA, Complementary, Endocytosis, Fibrinolysin, Fibroblasts, Focal Adhesions, Humans, Integrin alphaVbeta3, Mice, Mice, Knockout, Mink, Plasminogen Activator Inhibitor 1, Protein Transport, Protein-Serine-Threonine Kinases, Receptors, Transforming Growth Factor beta, Receptors, Urokinase Plasminogen Activator, Smad2 Protein, Smad3 Protein, Transforming Growth Factor beta

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          Fibrosis is characterized by elevated transforming growth factor beta (TGFbeta) signaling, resulting in extracellular matrix accumulation and increased PAI-1 (plasminogen activator inhibitor) expression. PAI-1 induces the internalization of urokinase plasminogen activator/receptor and integrin alphavbeta3 from the cell surface. Since increased alphavbeta3 expression correlates with increased TGFbeta signaling, we hypothesized that aberrant PAI-1-mediated alphavbeta3 endocytosis could initiate an autocrine loop of TGFbeta activity. We found that in PAI-1 knock-out (KO) mouse embryonic fibroblasts), alphavbeta3 endocytosis was reduced by approximately 75%, leaving alphavbeta3 in enlarged focal adhesions, similar to wild type cells transfected with PAI-1 small interfering RNA. TGFbeta signaling was significantly enhanced in PAI-1 KO cells, as demonstrated by a 3-fold increase in SMAD2/3-containing nuclei and a 2.9-fold increase in TGFbeta activity that correlated with an increase in alphavbeta3 and TGFbeta receptor II expression. As expected, PAI-1 KO cells had unregulated plasmin activity, which was only partially responsible for TGFbeta activation, as evidenced by a mere 25% reduction in TGFbeta activity when plasmin was inhibited. Treatment of cells with an alphavbeta3-specific cyclic RGD peptide (GpenGRGD) led to a more profound (59%) TGFbeta inhibition; a nonspecific RGD peptide (GRGDNP) inhibited TGFbeta by only 23%. Human primary fibroblasts were used to confirm that PAI-1 inhibition and beta3 overexpression led to an increase in TGFbeta activity. Consistent with a fibrotic phenotype, PAI-1 KO cells were constitutively myofibroblasts that had a 1.6-fold increase in collagen deposition over wild type cells. These data suggest that PAI-1-mediated regulation of alphavbeta3 integrin is critical for the control of TGFbeta signaling and the prevention of fibrotic disease.

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