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

Luigi Naldini, Luca Tamagnone, Elisa Vigna, Martin Sachs, Guido Hartmann, Walter Birchmeier, Yasushi Daikuhara, Hirohito Tsubouchi, Francesco Blasi, Paolo M. Comoglio

Research output: Contribution to journalArticle

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 (proHGF/SF), mostly found in a matrix-associated form. Maturation of the precursor into the active αβ 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.

Original languageEnglish
Pages (from-to)4825-4833
Number of pages9
JournalEMBO Journal
Volume11
Issue number13
Publication statusPublished - 1992

Keywords

  • Extracellular proteases
  • Hepatocyte growth factor
  • Matrix invasion scatter factor
  • Urokinase

ASJC Scopus subject areas

  • Genetics
  • Cell Biology

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    Naldini, L., Tamagnone, L., Vigna, E., Sachs, M., Hartmann, G., Birchmeier, W., Daikuhara, Y., Tsubouchi, H., Blasi, F., & Comoglio, P. M. (1992). Extracellular proteolytic cleavage by urokinase is required for activation of hepatocyte growth factor/scatter factor. EMBO Journal, 11(13), 4825-4833.