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Extracellular proteolytic cleavage by urokinase is required for activation of hepatocyte growth factor/scatter factor

Item Type:Article
Title:Extracellular proteolytic cleavage by urokinase is required for activation of hepatocyte growth factor/scatter factor
Creators Name:Naldini, L., Tamagnone, L., Vigna, E., Sachs, M., Hartmann, G., Birchmeier, W., Daikuhara, Y., Tsubouchi, H., Blasi, F. and Comoglio, P.M.
Abstract:The extracellular protease urokinase is known to be crucially involved in morphogenesis, tissue repair and tumor invasion by mediating matrix degradation and cell migration. Hepatocyte growth factor/scatter factor (HGF/SF) is a secretory product of stromal fibroblasts, sharing structural motifs with enzymes of the blood clotting cascade, including a zymogen cleavage site. HGF/SF promotes motility, invasion and growth of epithelial and endothelial cells. Here we show that HGF/SF is secreted as a single-chain biologically inactive precursor (pro-HGF/SF), mostly found in a matrix-associated form. Maturation of the precursor into the active alpha beta heterodimer takes place in the extracellular environment and results from a serum-dependent proteolytic cleavage. In vitro, pro-HGF/SF was cleaved at a single site by nanomolar concentrations of pure urokinase, generating the active mature HGF/SF heterodimer. This cleavage was prevented by specific urokinase inhibitors, such as plasminogen activator inhibitor type-1 and protease nexin-1, and by antibodies directed against the urokinase catalytic domain. Addition of these inhibitors to HGF/SF responsive cells prevented activation of the HGF/SF precursor. These data show that urokinase acts as a pro-HGF/SF convertase, and suggest that some of the growth and invasive cellular responses mediated by this enzyme may involve activation of HGF/SF.
Keywords:Cultured Cells, Polyacrylamide Gel Electrophoresis, Extracellular Matrix, Hepatocyte Growth Factor, Hydrolysis, Post-Translational Protein Processing, Protein-Tyrosine Kinases, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-met, Cell Surface Receptors, Serine Proteinase Inhibitors, Cultured Tumor Cells, Urokinase-Type Plasminogen Activator, Animals
Source:EMBO Journal
Publisher:Oxford University Press
Page Range:4825-4833
Date:1 December 1992
Official Publication:http://www.ncbi.nlm.nih.gov/pmc/articles/PMC556958/?tool=pubmed
PubMed:View item in PubMed

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