In vitro evidence that KLK14 regulates the components of the HGF/Met axis, pro-HGF and HGF-activator inhibitor 1A and 1B

Kallikrein-related peptidase (<i>KLK</i>) 14 is a serine protease linked to several pathologies including prostate cancer. We show that <i>KLK</i>14 has biphasic effects in vitro on activating and inhibiting components of the prostate cancer associated hepatocyte growth factor (<i>HGF</i>)/Met system. At 5-10 nM <i>KLK</i>14 converts pro-<i>HGF</i> to the two-chain heterodimer required for Met activation, while higher concentrations degrade the <i>HGF</i> alpha-chain. <i>HGF</i> activator-inhibitor (<i>HAI</i>)-1A and HAI-1B, which inhibit pro-<i>HGF</i> activators, are degraded by <i>KLK</i>14 when protease:inhibitor stoichiometry is 1:1 or the protease is in excess. When inhibitors are in excess, <i>KLK</i>14 generates <i>HAI</i>-1A and <i>HAI</i>-1B fragments known to inhibit pro-<i>HGF</i> activating serine proteases. These in vitro data suggest that increased <i>KLK</i>14 activity could contribute at multiple levels to <i>HGF</i>/Met-mediated processes in prostate and other cancers.