The reciprocal pro-enzyme activation system of plasmin, urokinase-type plasminogen activator (uPA) and their respective zymogens is a potent mechanism in the generation of extracellular proteolytic activity. Plasminogen activator inhibitor type 1 (PAI-1) acts as a negative regulator. This system is complicated by a poorly understood intrinsic reactivity of the uPA pro-enzyme (pro-uPA) before proteolytic activation, directed against both plasminogen and PAI-1. We have studied the integrated activation mechanism under the repression of PAI-1 in a purified system. A covalent reaction between pro-uPA and PAI-1 was positively demonstrated but the reaction of PAI-1 with two-chain uPA was found to be at least 1000-fold faster. However, in spite of this very fast inhibition, two-chain uPA still became the dominant plasminogen activator when plasminogen was incubated with pro-uPA and PAI-1. The activity pattern observed under these conditions revealed an initial lag phase, followed by a continuous generation of minute amounts of active two-chain uPA, this uPA having a short lifetime before inhibition but still succeeding to generate new plasmin activity, thus preventing a complete inactivation of the feedback system. This property of the activation system was retained even in the simultaneous presence of PAI-1 and α2-antiplasmin. Addition of soluble uPA receptor to the system did not change the role of pro-uPA and the same pattern was observed when pro-uPA was bound to the uPA receptor on U937 cells. The present mechanism maintains the system at standby level and may be triggered to increased activity without the need for an external initiating event.
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April 2003
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Research Article|
April 15 2003
The pro-urokinase plasminogen-activation system in the presence of serpin-type inhibitors and the urokinase receptor: rescue of activity through reciprocal pro-enzyme activation
Niels BEHRENDT;
Niels BEHRENDT
1
∗Finsen Laboratory, Rigshospitalet, Strandboulevarden 49, Bldg. 7.2, DK-2100 Copenhagen Ø, Denmark
1To whom correspondence should be addressed (e-mail niels.behrendt@finsenlab.dk).
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Karin LIST;
Karin LIST
∗Finsen Laboratory, Rigshospitalet, Strandboulevarden 49, Bldg. 7.2, DK-2100 Copenhagen Ø, Denmark
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Peter A. ANDREASEN;
Peter A. ANDREASEN
†Department of Molecular and Structural Biology, Århus University, Gustav Wieds Vej 10, Bldg. 1.3, DK-8000 Århus, Denmark
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Keld DANØ
Keld DANØ
∗Finsen Laboratory, Rigshospitalet, Strandboulevarden 49, Bldg. 7.2, DK-2100 Copenhagen Ø, Denmark
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Publisher: Portland Press Ltd
Received:
September 27 2002
Revision Received:
January 16 2003
Accepted:
January 20 2003
Accepted Manuscript online:
January 20 2003
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London ©2003
2003
Biochem J (2003) 371 (2): 277–287.
Article history
Received:
September 27 2002
Revision Received:
January 16 2003
Accepted:
January 20 2003
Accepted Manuscript online:
January 20 2003
Citation
Niels BEHRENDT, Karin LIST, Peter A. ANDREASEN, Keld DANØ; The pro-urokinase plasminogen-activation system in the presence of serpin-type inhibitors and the urokinase receptor: rescue of activity through reciprocal pro-enzyme activation. Biochem J 15 April 2003; 371 (2): 277–287. doi: https://doi.org/10.1042/bj20021508
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