Prostatic human kallikrein 2 inactivates and complexes with plasminogen activator inhibitor-1.
Human kallikrein 2 (hK2) is a serine protease expressed predominantly in the prostate which has 80% homology to prostate-specific antigen (PSA). hK2 is an active trypsin-like protease which has been shown by immuno-histochemical staining to be more highly expressed in prostate carcinoma than in benign prostate tissue. Unlike PSA, hK2 activates pro-PSA , pro-hK2 and the zymogen form of urokinase-type plasminogen activator (uPA), an extracellular protease correlated with prostate cancer and metastasis. We show here that hK2 rapidly forms a complex with plasminogen activator inhibitor-1 (PAI-1), the primary inhibitor of uPA in tissues. In addition, hK2 inactivated 6 to 7 mol of PAI-1 by cleavage at Arg346-Met347 for every mole of hK2-PAI-1 complex formed. In contrast with hK2, PSA neither complexed with nor inactivated PAI-1. PAI-1 inhibited hK2 comparably with protein C inhibitor (PCI) and at least 20 times more rapidly than alpha1-anti-chymotrypsin (ACT). N-Terminal sequencing shows that hK2 forms a covalent complex with PAI-1, PCI and ACT after cleavage at Arg346-Met347, Arg354-Ser355 and Leu358-Ser359, respectively. During complex formation, hK2 inactivated PAI-1 but did not inactivate ACT or PCI. Our current results suggest that the increased hK2 expression in prostate cancer tissues could influence cancer biology not only by activation of uPA but also by inactivation of its primary inhibitor, PAI-1.
Mikolajczyk
S D
SD
Hybritech Incorporated, a subsidiary of Beckman Coulter Inc., San Diego, CA 92196-9006, USA. sdmikolajczyk@beckman.com
Millar
L S
LS
Kumar
A
A
Saedi
M S
MS
D006801:Humans; D007610:Kallikreins / Q000037:antagonists & inhibitors / Q000502:physiology*; D008297:Male; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism* / Q000494:pharmacology; D011467:Prostate / Q000201:enzymology*; D017430:Prostate-Specific Antigen / Q000037:antagonists & inhibitors; D011471:Prostatic Neoplasms / Q000201:enzymology; D011486:Protein C / Q000037:antagonists & inhibitors; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism; D000514:alpha 1-Antichymotrypsin / Q000494:pharmacology
D017395:Plasminogen Activator Inhibitor 1; D011486:Protein C; D000514:alpha 1-Antichymotrypsin; D007610:Kallikreins; D014568:Urokinase-Type Plasminogen Activator; D017430:Prostate-Specific Antigen