Prostatic human kallikrein 2 inactivates and complexes with plasminogen activator inhibitor-1

Human kallikrein 2 (hK2) is a serine protease expressed predominantly in th e prostate which has 80% homology to prostate-specific antigen (PSA), hK2 i s an active trypsin-like protease which has been shown by immuno-histochemi cal staining to be more highly expressed in prostate carcinoma than in beni gn prostate tissue. Unlike PSA, hK2 activates pro-PSA, pro-hK2 and the zymo gen form of urokinase-type plasminogen activator (uPA), an extracellular pr otease correlated with prostate cancer and metastasis, We show here that hK 2 rapidly forms a complex with plasminogen activator inhibitor-1 (PAI-1), t he primary inhibitor of uPA in tissues. In addition, hK2 inactivated 6 to 7 mol of PAI-1 by cleavage at Arg(346)-Met(347) for every mole of hK2-PAI-1 complex formed. In contrast with hK2, PSA neither complexed with nor inacti vated PAI-1. PAI-1 inhibited hK2 comparably with protein C inhibitor (PCI) and at least 20 times more rapidly than alpha-anti-chymotrypsin (ACT), N-Te rminal sequencing shows that hK2 forms a covalent complex with PAI-1, PCI a nd ACT after cleavage at Arg(346)-Met(347), Arg(354)-Ser(355) and Leu(358)- Ser(359), respectively. During complex formation, hK2 inactivated PAI-1 but did not inactivate ACT or PCI, Our current results suggest that the increa sed hK2 expression in prostate cancer tissues could influence cancer biolog y not only by activation of uPA but also by inactivation of its primary inh ibitor, PAI-1. (C) 1999 Wiley-Liss, Inc.