The Plasminogen Activation System

Abstract

The plasminogen activation system is a vertebrate extracellular enzyme system consisting of serine proteases, protease inhibitors of the serpin family and various binding proteins. The plasminogen activation system generates extracellular proteolytic activity for physiological and pathophysiological fibrinolysis and tissue remodelling. The capacity of this system to remove the fibrin component of blood clots led to the pharmaceutical development of the plasminogen activators for thrombotic complications initially for myocardial infarction and later for ischaemic stroke. It also has a major role in the central nervous system, where it influences neuronal function in relation to learning and memory, and has a major influence on blood–brain barrier function. While these are physiological processes, overactivation of the plasminogen‐activating system can promote excessive bleeding and also initiate both protective and damaging effects in the brain.

Key Concepts

  • Plasminogen activation was initially described for its role in the removal of blood clots.
  • This system uses many receptors to permit protease activation on cell surfaces.
  • Bacteria harness this system to help in dissemination.
  • This system actively contributes to cancer progression.
  • Recent findings have established important roles for the plasminogen‐activating system in the brain.
  • Modulation of this system can be used for therapeutic benefit.

Keywords: plasminogen activators; t‐PA; u‐PA; fibrinolysis; tissue remodelling; central nervous system

Figure 1. The plasminogen activators u‐PA and t‐PA catalyse the proteolytic conversion of the zymogen plasminogen into the active protease plasmin, which can degrade fibrin and other extracellular matrix (ECM) proteins. u‐PA and t‐PA activity can be inhibited by either of two plasminogen activator inhibitors, PAI‐1 and PAI‐2, and plasmin activity can be inhibited by α2‐antiplasmin (α2AP).
Figure 2. Cartoon of the domain structure of proteins of the plasminogen activation system. Red arrows indicate the positions at which the two‐chain forms of the serine proteases were cleaved when generated from their single‐chain precursors. The dotted lines indicate intradomain disulfide bridges. SPD, serine protease domain; K, kringle domain; G, growth factor domain; F, fibronectin type II domain.
Figure 3. The various effects of the plasminogen‐activating system in biology.
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Further Reading

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Medcalf, Robert L(Apr 2017) The Plasminogen Activation System. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0001990.pub3]