MT1-MMP releases latent TGF-β1 from endothelial cell extracellular matrix via proteolytic processing of LTBP-1
Copyright policy )MT1-MMP releases latent TGF-β1 from endothelial cell extracellular matrix via proteolytic processing of LTBP-1
Targeting of transforming growth factor beta (TGF-beta) to the extracellular matrix (ECM) by latent TGF-beta binding proteins (LTBPs) regulates the availability of TGF-beta for interactions with endothelial cells during their quiescence and activation. However, the mechanisms which release TGF-beta complexes from the ECM need elucidation. We find here that morphological activation of endothelial cells by phorbol 12-myristate 13-acetate (PMA) resulted in membrane-type 1 matrix metalloproteinase (MT1-MMP) -mediated solubilization of latent TGF-beta complexes from the ECM by proteolytic processing of LTBP-1. These processes required the activities of PKC and ERK1/2 signaling pathways and were coupled with markedly increased MT1-MMP expression. The functional role of MT1-MMP in LTBP-1 release was demonstrated by gene silencing using lentiviral short-hairpin RNA as well as by the inhibition with tissue inhibitors of metalloproteinases, TIMP-2 and TIMP-3. Negligible effects of TIMP-1 and uPA/plasmin system inhibitors indicated that secreted MMPs or uPA/plasmin system did not contribute to the release of LTBP-1. Current results identify MT1-MMP-mediated proteolytic processing of ECM-bound LTBP-1 as a mechanism to release latent TGF-beta from the subendothelial matrix.
- University of Helsinki Finland
- Helsinki University Hospital Finland
Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Endothelial Cells, Matrix Metalloproteinase Inhibitors, Gene Expression Regulation, Enzymologic, Extracellular Matrix, Transforming Growth Factor beta1, Latent TGF-beta Binding Proteins, Matrix Metalloproteinase 14, Humans, RNA, Small Interfering, Cell Shape, Protein Processing, Post-Translational, Cells, Cultured, Protein Kinase C, Signal Transduction
Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Endothelial Cells, Matrix Metalloproteinase Inhibitors, Gene Expression Regulation, Enzymologic, Extracellular Matrix, Transforming Growth Factor beta1, Latent TGF-beta Binding Proteins, Matrix Metalloproteinase 14, Humans, RNA, Small Interfering, Cell Shape, Protein Processing, Post-Translational, Cells, Cultured, Protein Kinase C, Signal Transduction
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