Plasminogen Activation System

Peter A Andreasen, University of Århus, Århus, Denmark

Published online: January 2006

DOI: 10.1038/npg.els.0004013

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.

Keywords: plasminogen activators; tPA; uPA; fibrinolysis; tissue remodelling

Figure 1. The plasminogen activators uPA and tPA catalyse the proteolytic conversion of the zymogen plasminogen into the active protease plasmin, which can degrade fibrin and other extracellular matrix (ECM) proteins. uPA and tPA activity can be inhibited by either of two plasminogen activator inhibitors, PAI-1 and PAI-2, and plasmin activity can be inhibited by 2-antiplasmin (2AP).
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.
close
 References
    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.
    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.
    Deng G, Curriden SA, Wang S, Rosenberg S and Loskutoff DJ (1996) Is plasminogen activator inhibitor-1 the molecular switch that governs urokinase receptor-mediated cell adhesion and release?. Journal of Cell Biology 134: 1563–1571.
    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.
    Duffy MJ (1996) Proteases as prognostic markers in cancer. Clinical Cancer Research 2: 613–618.
    Egelund R, Rodenburg KW, Andreasen PA et al. (1998) An ester bond linking a fragment of a serine proteinase to its serpin inhibitor. Biochemistry 37: 6375–6379.
    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.
    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.
    Ke SH, Coombs GS, Tachias K, Corey DR and Madison EL (1997) Optimal subsite occupancy and design of a selective inhibitor of urokinase. Journal of Biological Chemistry 272: 20456–20462.
    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, Larsson LI, Nielsen LS et al. (1984) Human endothelial cells contain one type of plasminogen activator. FEBS Letters 168: 33–37.
    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.
    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.
    O'Reilly MS, Holmgren L, Shing Y et al. (1994) Angiostatin: a novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma. Cell 79: 315–328.
    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.
    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.
    Pawlak R, Magarinos AM, Melchot J, McEwen B and Strickland S (2003) Tissue plasminogen activator in the amygdala is critical for stress-induced anxiety-like behaviour. Nature Neuroscience 6: 168–174.
    Renatus M, Engh RA, Stubbs MT et al. (1997) Lysine 156 promotes the anomalous proenzyme activity of tPA: X-ray crystal structure of single-chain human tPA. 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.
    Shapiro RL, Duquette JG, Roses DF et al. (1996) Induction of primary cutaneous melanocytic neoplasms in urokinase-type plasminogen activator (uPA)-deficient and wild-type mice: cellular blue nevi invade but do not progress to malignant melanoma in uPA-deficient animals. Cancer Research 56: 3597–3604.
    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 v3 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 70Å and full insertion of the reactive center loop into -sheet A. Proceedings of the National Academy of Sciences of the USA 96: 4808–4813.
    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.
    Tsirka SE, Rogove AD, Bugge TH, Degen JL and Strickland S (1997a) An extracellular proteolytic cascade promotes neuronal degeneration in the mouse hippocampus. Journal of Neuroscience 17: 543–552.
    Tsirka SE, Bugge TH, Degen JL and Strickland S (1997b) Neuronal death in the central nervous system demonstrates a non-fibrin substrate for plasmin. Proceedings of the National Academy of Sciences of the USA 94: 9779–9781.
    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.
    Ye S, Cech AL, Belmares R et al. (2001) The structure of a Michaelis serpin–protease complex. Nature Structural Biology 8: 979–983.
    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.
    Zhuo M, Holtzman DM, Li Y et al. (2000) Role of tissue plasminogen activator receptor LRP in hippocampal long-term potentiation. Journal of Neuroscience 20: 542–549.
 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.
    Andreasen PA, Kjøller L, Christensen L and Duffy MJ (1997) The urokinase-type plasminogen activator system in cancer metastasis. A review. International Journal of Cancer 72: 1–22.
    Andreasen PA, Petersen LC and Danø K (1991) Diversity in catalytic properties of single-chain and two-chain tissue-type plasminogen activator. Fibrinolysis 5: 207–215.
    Andreasen PA, Sottrup-Jensen L, Kjøller L et al. (1994) Receptor-mediated endocytosis of plasminogen activators and activator/inhibitor complexes. FEBS Letters 338: 239–245.
    Behrendt N and Stephens RW (1998) The urokinase receptor. Fibrinolysis and Proteolysis 12: 191–204.
    Besser D, Verde P, Nagamine Y and Blasi F (1996) Signal transduction and the u-PA/u-PAR system. Fibrinolysis 10: 215–237.
    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.
    Danø K, Andreasen PA, Grøndahl-Hansen J et al. (1985) Plasminogen activators, tissue degradation and cancer. Advances in Cancer Research 44: 139–266.
    Huber R and Carrell RW (1989) Implications of the three-dimensional structure of 1-antitrypsin for structure and functions of serpins. Biochemistry 28: 8951–8966.
    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.
    Ossowski L and Aguirre-Ghiso JA (2000) Urokinase receptor and integrin partnership: coordination of signaling for cell adhesion, migration and growth. Current Opinion in Cell Biology 12: 613–620.
    Werb Z (1997) ECM and cell surface proteolysis: regulating cellular ecology. Cell 91: 439–442.
    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.

Related Sub-Topics:

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

* Required Field

Article Title: Plasminogen Activation System
 
How to Cite close
Andreasen, Peter A(Jan 2006) Plasminogen Activation System. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1038/npg.els.0004013]