Characterization of factors regulating the activity of hepatocyte growth factor which is being developed for a medicine

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Hepatocyte growth factor (HGF) is a potent mitogen for hepatocytes, and is being developed for a medicine of liver disease. HGF is activated in the liver by a serine protease, HGF activator (HGFA), following liver injury, and then functions as a liver regeneration factor. In this study, we examined mechanisms for activation and inactivation of HGFA and obtained the following results.1. Analysis of HGFA and its mRNA after liver injury induced by CClィイD24ィエD2 treatment of rat revealed that amount of HGFA mRNA increased, and HGFA, that circulates in the blood as an inactive precursor at normal state, was activated by thrombin following liver injury. These results indicate that HGFA plays an crucial role in regulating the activity of HGF by increase of its amount and proteolytic activation linked to blood coagulation system following liver injury.2. Two types of HGFA inhibitor, HAI-1 and HAI-2, were identified as potent inhibitors of HGFA. Using a monoclonal antibody against HAI-1, we identified a transmembrane form of HA1-1 integrated in the plasma membrane of cultured cells. We also identified several soluble forms of HAI-1 in the conditioned medium of the cells, indicating that multiple sites are present in the transmembrane form of HAI-1 at which proteolytic cleavage releases the extracellular domain. At least two proteases, one of which is a metalloprotease, appear to be responsible for the release. Further, the soluble forms of HAI-1 have different inhibitory activity against HGFA. These findings suggest that proteolytic processing plays important roles in regulation of the inhibitory activity of Hal-1.