The Plasminogen Activation System


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.


Almholt K, Nielsen BS, Frandsen TL, et al. (2003) Metastasis of transgenic breast cancer in plasminogen activator inhibitor‐1 gene‐deficient mice. Oncogene 22 (28): 4389–4397.

Bajou K, Noel A, Gerard RD, et al. (1998) Absence of host plasminogen activator inhibitor‐1 prevents cancer invasion and vascularization. Nature Medicine 4: 923–928.

Bhattacharya S, Ploplis VA and Castellino FJ (2012) Bacterial plasminogen receptors utilize host plasminogen system for effective invasion and dissemination. Journal of Biomedicine and Biotechnology 2012: 482096. DOI: 10.1155/2012/482096.

Bugge TH, Flick MJ, Daugherty CC and Degen JL (1995) Plasminogen deficiency causes severe thrombosis but is compatible with development and reproduction. Genes and Development 9: 794–807.

Bugge TH, Kombrinck KW, Flick MJ, et al. (1996) Loss of fibrinogen rescues mice from the pleiotropic effects of plasminogen deficiency. Cell 87: 709–719.

Bugge TH, Kombrinck KW, Xiao Q, et al. (1997) Growth and dissemination of Lewis lung carcinoma in plasminogen‐deficient mice. Blood 90: 4522–4531.

Bugge TH, Lund LR, Kombrinck KK, et al. (1998) Reduced metastasis of Polyoma virus middle T antigen‐induced mammary cancer in plasminogen‐deficient mice. Oncogene 16: 3097–3104.

Carmeliet P, Schoojans L, Kiekens L, et al. (1994) Physiological consequences of loss of plasminogen activator gene function in mice. Nature 368: 419–424.

Chen ZL and Strickland S (1997) Neuronal death in the hippocampus is promoted by plasmin‐catalysed degradation of laminin. Cell 91: 917–925.

Collen D (1998) Staphylokinase: a potent, uniquely fibrin‐selective thrombolytic agent. Nature Medicine 4: 279–284.

De Lorenzi V, Sarra Ferraris GM, Madsen JB, et al. (2016) Urokinase links plasminogen activation and cell adhesion by cleavage of the RGD motif in vitronectin. EMBO Reports 17: 982–998.

Donate LE, Gherardi E, Srinivasan N, et al. (1994) Molecular evolution and domain structure of plasminogen‐related growth factors (HGF/SF and HGF1/MSP). Protein Science 3: 2378–2394.

Draxler D and Medcalf RL (2015) The fibrinolytic system: more than fibrinolysis? Transfusion Medicine Reviews 29: 102–109.

Duffy MJ (1996) Proteases as prognostic markers in cancer. Clinical Cancer Research 2: 613–618.

Eren M, Boe AE, Klyachko EA and Vaughan DE (2014) Role of plasminogen activator inhibitor‐1 in senescence and aging. Seminars in Thrombosis and Hemostasis 40: 645–651.

Goguen JD, Bugge TH and Degen JL (2000) Role of the pleiotropic effects of plasminogen deficiency in infection experiments with plasminogen deficient mice. Methods 21: 179–183.

Ghosh AK, Rai R, Park KE, Eren M, et al. (2016) A small molecule inhibitor of PAI-1 protects against doxorubicin-induced cellular senescence. Oncotarget 7: 2443–72457.

Huntington JA, Read RJ and Carrell RW (2000) Structure of a serpin–protease complex shows inhibition by deformation. Nature 407: 923–926.

Kanse SM, Kost C, Wilhelm OG, Andreasen PA and Preissner KT (1996) The urokinase receptor is a major vitronectin‐binding protein on endothelial cells. Experimental Cell Research 224: 344–353.

Kjøller L, Kanse S, Kirkegaard T, et al. (1997) Plasminogen activator inhibitor‐1 represses integrin‐ and vitronectin‐mediated cell migration independently of its function as an inhibitor of plasminogen activation. Experimental Cell Research 232: 420–429.

Kristensen P, Eriksen J and Danø K (1991) Localization of urokinase‐type plasminogen activator messenger RNA in the normal mouse by in situ hybridization. Journal of Histochemistry and Cytochemistry 39: 341–349.

Liu D, Aguirre Ghiso J, Estrada Y and Ossowski L (2002) EGFR is a transducer of the urokinase receptor initiated signal that is required for in vivo growth of a human carcinoma. Cancer Cell 1: 445–457.

Lund LR, Bjørn SF, Sternlicht MD, et al. (2000) Lactational development and involution of the mouse mammary gland requires plasminogen. Development 127: 4481–4492.

Medcalf RL (2012) Desmoteplase: discovery, insights and opportunities for ischaemic stroke. British Journal of Pharmacology 165: 75–89.

Miles LA and Parmer RJ (2013) Plasminogen receptors: the first quarter century. Seminars in Thrombosis and Hemostasis 39: 329–337.

Nicole O, Docagne F, Ali C, et al. (2001) The proteolytic activity of tissue‐plasminogen activator enhances NMDA receptor‐mediated signaling. Nature Medicine 7: 59–64.

Ossowski L, Biegel D and Reich E (1979) Mammary plasminogen activator: correlation with involution, hormonal modulation and comparison between normal and neoplastic tissue. Cell 16: 929–940.

Parcq J, Bertrand T, Montagne A, et al. (2012) Unveiling an exceptional zymogen: the single-chain form of tPA is a selective activator of NMDA receptor-dependent signaling and neurotoxicity. Cell Death and Differentiation 19: 1983–1991.

Parry MA, Fernandez‐Catalan C, Bergner A, et al. (1998) The ternary complex microplasmin–staphylokinase–microplasmin complex is a proteinase–cofactor–substrate complex in action. Nature Structural Biology 5: 917–923.

Renatus M, Engh RA, Stubbs MT, et al. (1997) Lysine 156 promotes the anomalous proenzyme activity of t‐PA: X‐ray crystal structure of single‐chain human t‐PA. EMBO Journal 16: 4797–4805.

Rømer J, Bugge TH, Pyke C, et al. (1996) Impaired wound healing in mice with a disrupted plasminogen gene. Nature Medicine 2: 287–292.

Sabapathy KT, Pepper MS, Kiefer F, et al. (1997) Polyoma middle T‐induced vascular tumor formation: the role of the plasminogen activator/plasmin system. Journal of Cell Biology 137: 953–963.

Samson AL and Medcalf RL (2006) Tissue‐type plasminogen activator: a multifaceted modulator of neurotransmission and synaptic plasticity. Neuron 50: 673–678.

Samson AL, Nevin ST, Croucher D, et al. (2008) Tissue‐type plasminogen activator requires a co‐receptor to enhance N‐Methyl‐d‐Aspartate receptor function. Journal of Neurochemistry 107: 1091–1101.

Samson AL, Knaupp AS, Sashindranath M, et al. (2012) Nucleocytoplasmic coagulation: an injury‐induced aggregation event that crosslinks intracellular proteins and facilitates their clearance by plasmin. Cell Reports 2: 889–901.

Sashindranath M, Sales E, Freeman R, et al. (2012) The tissue‐type plasminogen activator‐plasminogen activator inhibitor‐1 complex promotes neurovascular injury in brain trauma: evidence from mice and humans. Brain 135: 3251–3264.

Shapiro RL, Duquette JG, Roses DF, et al. (1996) Induction of primary cutaneous melanocytic neoplasms in urokinase‐type plasminogen activator (u‐PA)‐deficient and wild‐type mice: cellular blue nevi invade but do not progress to malignant melanoma in u‐PA‐deficient animals. Cancer Research 56: 3597–3604.

Singh S, Houng AK and Reed GL (2016) Releasing the brakes on the fibrinolytic system in pulmonary emboli: unique effects of plasminogen activation and α2‐antiplasmin inactivation. Circulation. DOI: 10.1161/CIRCULATIONAHA.116.024421.

Sodeinde OA, Subrahmanyam YVBK, Stark K, et al. (1992) A surface protease and the invasive character of plague. Science 258: 1004–1007.

Stefansson S and Lawrence DA (1996) The serpin PAI‐1 inhibits cell migration by blocking integrin αvβ3 binding to vitronectin. Nature 383: 441–443.

Stratikos E and Gettins PG (1999) Formation of the covalent serpin–proteinase complex involves translocation of the protease by more than 70 Å and full insertion of the reactive center loop into β‐sheet A. Proceedings of the National Academy of Sciences of the United States of America 96: 4808–4813.

Sulniute R, Shen Y, Guo YZ, et al. (2016) Plasminogen is a critical regulator of cutaneous wound healing. Thrombosis and Haemostasis 115: 1001–1009.

Taniguchi Y, Inoue N, Morita S, et al. (2011) Localization of plasminogen in mouse hippocampus, cerebral cortex, and hypothalamus. Cell and Tissue Research 343: 303–317.

Tsirka SE, Gualandris A, Amaral DG and Strickland S (1995) Excitotoxin‐induced neuronal degeneration and seizure are mediated by tissue plasminogen activator. Nature 377: 340–344.

Vaughan DE (1998) Plasminogen activator inhibitor‐1: a common denominator in cardiovascular disease. Journal of Investigative Medicine 8: 370–376.

Wang X, Lin X, Loy JA, Tang J and Zhang XC (1998) Crystal structure of the catalytic domain of human plasmin complexed with streptokinase. Science 281: 1662–1665.

Wu F, Wu J, Nicholson A, Echeverry R, et al. (2012) Tissue‐type plasminogen activator regulates the neuronal uptake of glucose in the ischemic brain. Journal of Neuroscience 32: 9848–9858.

Ye S, Cech AL, Belmares R, et al. (2001) The structure of a Michaelis serpin–protease complex. Nature Structural Biology 8: 979–983.

Yepes M (2015) Tissue‐type plasminogen activator is a neuroprotectant in the central nervous system. Frontiers in Cellular Neuroscience 9: 304. DOI: 10.3389/fncel.2015.00304.

Zhang Y, Mayfield JA, Ploplis VA and Castellino FJ (2014) The β‐domain of cluster 2b streptokinase is a major determinant for the regulation of its plasminogen activation activity by cellular plasminogen receptors. Biochemical and Biophysical Research Communications 444: 595–598.

Zhou A, Huntington JA, Pannu NS, Carell RW and Read RJ (2003) How vitronectin binds PAI‐1 to modulate fibrinolysis and cell migration. Nature Structural Biology 10: 541–544.

Further Reading

Andreasen PA, Egelund R and Petersen HH (2000) The plasminogen activation system in tumor growth, invasion, and metastasis. Cellular and Molecular Life Sciences 57: 25–40.

Bode W and Renatus M (1997) Tissue‐type plasminogen activator: variants and crystal/solution structures demarcate structural determinants of function. Current Opinion in Structural Biology 7: 865–872.

Carrell RW and Stein PE (1996) The biostructural pathology of the serpins: critical functions of sheet opening mechanism. Biological Chemistry Hoppe – Seyler 377: 1–17.

Chapman HA (1997) Plasminogen activators, integrins, and the coordinated regulation of cell adhesion and migration. Current Opinion in Cell Biology 9: 714–724.

Irigoyen JP, Munoz‐Canoves P, Montero L, Koziczak M and Nagamine Y (1999) The plasminogen activator system: biology and regulation. Cellular and Molecular Life Sciences 56: 104–132.

Kjøller L (2000) The urokinase plasminogen activator receptor in the regulation of the actin cytoskeleton and cell motility. Biological Chemistry 383: 5–19.

Nykjaer A and Willnow TE (2002) The low‐density lipoprotein receptor gene family: a cellular Swiss army knife? Trends in Cell Biology 12: 273–280.

Wind T, Hansen M, Jensen JK and Andreasen PA (2000) The molecular basis for anti‐proteolytic and non‐proteolytic functions of plasminogen activator inhibitor type‐1: roles of the reactive centre loop, the shutter region, the flexible joint region and the small serpin fragment. Biological Chemistry 383: 21–36.

Ye S and Goldsmith E (2001) Serpins and other covalent protease inhibitors. Current Opinion in Structural Biology 11: 740–745.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Medcalf, Robert L(Apr 2017) The Plasminogen Activation System. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0001990.pub3]