TY - JOUR
T1 - Extracellular proteolytic cleavage by urokinase is required for activation of hepatocyte growth factor/scatter factor
AU - Naldini, Luigi
AU - Tamagnone, Luca
AU - Vigna, Elisa
AU - Sachs, Martin
AU - Hartmann, Guido
AU - Birchmeier, Walter
AU - Daikuhara, Yasushi
AU - Tsubouchi, Hirohito
AU - Blasi, Francesco
AU - Comoglio, Paolo M.
PY - 1992
Y1 - 1992
N2 - 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.
AB - 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.
KW - Extracellular proteases
KW - Hepatocyte growth factor
KW - Matrix invasion scatter factor
KW - Urokinase
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M3 - Article
C2 - 1334458
AN - SCOPUS:0027077443
VL - 11
SP - 4825
EP - 4833
JO - EMBO Journal
JF - EMBO Journal
SN - 0261-4189
IS - 13
ER -