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