Activation of thrombin‐inactivated single‐chain urokinase‐type plasminogen activator by dipeptidyl peptidase I (cathepsin C)

Abstract

Single‐chain urokinase‐type plasminogen activator (scu‐PA) is inactivated by thrombin, which cleaves the peptide bond between Arg156 and Phe157. In a search for potential activators of thrombin‐cleaved two‐chain urokinase‐type plasminogen activator (tcu‐PA/T), we found that the lysosomal aminopeptidase dipeptidyl‐peptidase I or cathepsin C efficiently activates tcu‐PA/T. Cathepsin C was as active towards tcu‐PA/T as the bacterial proteinase thermolysin and about 300‐times more active than plasmin. The activation by cathepsin C proceeded in a concentration‐dependent and time‐dependent manner with a pH optimum between 5 and 7. Furthermore, the effect of cathepsin C was inhibited by cystatin and stimulated by cysteine, typical for the action of a thiol proteinase. As no degradation of the tcu‐PA/T molecule by cathepsin C was visible on SDS/PAGE, we suggest that activation of tcu‐PA/T occurs by cleavage between Lys158‐Ile159 and removal of the two N‐terminal amino acid residues (Phe157‐Lys158) of the B chain of tcu‐PA/T. We conclude that both thrombin and dipeptidyl‐peptidases like cathepsin C might play a regulatory role in the plasminogen‐plasmin system by inactivating scu‐PA and activating tcu‐PA/T, respectively. Copyright © 1994, Wiley Blackwell. All rights reserved