Russian Journal of Bioorganic Chemistry

, Volume 40, Issue 6, pp 590–605 | Cite as

Structure and function of plasminogen/plasmin system

  • R. B. Aisina
  • L. I. Mukhametova
Review Article


The main physiological function of plasmin is blood clot fibrinolysis and restoration of normal blood flow. To date, however, it became apparent that in addition to thrombolysis, the plasminogen/plasmin system plays an important physiological and pathological role in a number of other essential processes: degradation of the extracellular matrix, embryogenesis, cell migration, tissue remodeling, wound healing, angiogenesis, inflammation, and tumor cell migration. This review focuses on structural features of plasminogen, regulation of its activation by physiological plasminogen activators, inhibitors of plasmin, and plasminogen activators, and the role of plasminogen binding to fibrin, cellular receptors, and extracellular ligands in various functions performed by plasmin thus formed.


plasminogen plasmin plasminogen activators inhibitors angiostatins fibrinolysis inflammation angiogenesis oncogenesis 



plasminogen activators


6-aminohexanoic acid


angiotensin-converting enzyme




extracellular endothelium matrix


urokinase-type plasminogen activator

PAI-1 and PAI-2

plasminogen activator inhibitors types 1 and 2


kringle domain


lysine-binding site




matrix metalloproteinases


single-chain urokinase-type plasminogen activator


finger-like domain





Glu-Pg and Lys-Pg

Glu- and Lys-forms of plasminogen




renin-angiotensin system


urokinase and pro-urokinase receptor


vascular endothelium growth factor


N-terminal peptide


tissue plasminogen activator


trans-(4-aminomethyl)cyclohexane carboxylic acid (or tranexamic acid)


platelet-derived growth factor


fibroblast growth factor


epidermal growth factor-like domain


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Raum, D., Marcus, D., Alper, C.A., Levey, R., Taylor, P.D., and Starzl, T.E., Science, 1980, vol. 208, pp. 1036–1037.PubMedCentralPubMedCrossRefGoogle Scholar
  2. 2.
    Zhang, L., Seiffert, D., Fowler, B.J., Jenkins, G.R., Thinnes, T.C., Loskutoff, D.J., Parmer, R.J., and Miles, L.A., Thromb. Haemost., 2002, vol. 87, pp. 493–501.PubMedGoogle Scholar
  3. 3.
    de Souza, L.R., M. Melo, P., Paschoalin, T., Carmona, A.K., Kondo, M., Hirata, I.Y., Blaber, M., Tersariol, I., Takatsuka, J., Juliano, M.A., Juliano, L., Gomes, R.A., and Puzer, L., Biochem. Biophys. Res. Commun., 2013, vol. 433, pp. 333–337.PubMedCrossRefGoogle Scholar
  4. 4.
    Miles, L.A., Castellino, F.J., and Gong, Y., Trends Cardiovasc. Med., 2003, vol. 13, pp. 21–30.PubMedCrossRefGoogle Scholar
  5. 5.
    Binder, B.R., Fibrinolysis, 1995, vol. 9(suppl.), pp. 3–8.CrossRefGoogle Scholar
  6. 6.
    Panchenko, E.P. and Dobrovol’skii, A.B., Trombozy v kardiologii. Mekhanizmy razvitiya i vozmozhnosti terapii (Thromboses in Cardiology: Mechanisms of Development and Possibilities of Therapy), Moscow: Izd. Sport i kul’tura, 1999.Google Scholar
  7. 7.
    Ponting, C.P., Marshall, J.M., and Cederholm-Williams, S.A., Blood Coagul. Fibrinolysis, 1992, vol. 3, pp. 605–614.PubMedCrossRefGoogle Scholar
  8. 8.
    Soff, G.A., Cancer Metastasis Rev., 2000, vol. 19, pp. 97–107.PubMedCrossRefGoogle Scholar
  9. 9.
    Miles, L.A., Dahlberg, C.M., Plescia, J., Felez, J., Kato, K., and Plow, E.F., Biochemistry, 1991, vol. 30, pp. 1682–1691.PubMedCrossRefGoogle Scholar
  10. 10.
    Wu, H.L., Wu, I.S., Fang, R.Y., Hau, J.S., Wu, D.H., Chang, B.I., Lin, T.M., and Shi, G.Y., Biochem. Biophys. Res. Commun., 1992, vol. 188, pp. 703–71.PubMedCrossRefGoogle Scholar
  11. 11.
    Thorsen, S., Clemmensen, I., Sottrup-Jensen, L., and Magnusson, S., Biochim. Biophys. Acta, 1981, vol. 668, pp. 377–387.PubMedCrossRefGoogle Scholar
  12. 12.
    Matsuka, Iu.V., Novokhatnii, V.V., and Kudinov, S.A., Ukr. Biokhim. Zh., 1990, vol. 62, pp. 83–86.PubMedGoogle Scholar
  13. 13.
    Wiman, B., Lijnen, H.R., and Collen, D., Biochim. Biophys. Acta, 1979, vol. 579, pp. 142–154.PubMedCrossRefGoogle Scholar
  14. 14.
    Lijnen, H.R., Hoylaerts, M., and Collen, D., J. Biol. Chem., 1980, vol. 255, pp. 10214–10222.PubMedGoogle Scholar
  15. 15.
    Rijken, D.C. and Sakharov, D.V., Thromb. Res., 2001, vol. 103, pp. 41–49.CrossRefGoogle Scholar
  16. 16.
    Castellino, F.J. and Ploplis, V.A., Thromb. Haemost., 2005, vol. 93, pp. 647–654.PubMedGoogle Scholar
  17. 17.
    Takada, A., Makino, Y., and Takada, Y., Thromb. Res., 1986, vol. 42, pp. 39–47.PubMedCrossRefGoogle Scholar
  18. 18.
    Levashov, M.Yu., Aisina, R.B., Gershkovich, K.B., and Varfolomeyev, S.D., Biochemistry (Moscow), 2007, vol. 72, pp. 707–715.CrossRefGoogle Scholar
  19. 19.
    Aisina, R.B., Gaisaryan, E.C., Snitko, Ya.E., and Varfolomeev, S.D., Bioorg. Khim., 1993, vol. 20, pp. 182–189.Google Scholar
  20. 20.
    Davidson, D.D. and Castellino, F.J., J. Clin. Invest., 1993, vol. 92, pp. 249–254.PubMedCentralPubMedCrossRefGoogle Scholar
  21. 21.
    Aisina, R., Moukhametova, L., Gershkovich, K., and Varfolomeyev, S., Biochim. Biophys. Acta, 2005, vol. 1725, pp. 370–376.PubMedCrossRefGoogle Scholar
  22. 22.
    Mogues, T., Etzerodt, M., Hal, C., Engelich, G., Graversen, J.H., and Hartshorn, K.L., J. Biomed. Biotechnol., 2004, vol. 2, pp. 73–78.CrossRefGoogle Scholar
  23. 23.
    Lijnen, H.R. and Collen, D., Baillieres Clin. Haematol., 1995, vol. 8, pp. 277–290.PubMedCrossRefGoogle Scholar
  24. 24.
    Rijken, D.C., Hoylaerts, M., and Collen, D., J. Biol. Chem., 1982, vol. 257, pp. 2920–2925.PubMedGoogle Scholar
  25. 25.
    Duffy, M.G., Fibrinolysis, 1993, vol. 7, pp. 295–302.CrossRefGoogle Scholar
  26. 26.
    Cesarman-Maus, G. and Hajjar, K.A., Br. J. Haematol., 2005, vol. 129, pp. 307–321.PubMedCrossRefGoogle Scholar
  27. 27.
    Otter, M., Kuiper, J., van Berkel, T.J., and Rijken, D.C., Ann. N. Y. Acad. Sci., 1992, vol. 667, pp. 431–442.PubMedCrossRefGoogle Scholar
  28. 28.
    Stack, M.S., Gately, S., Bafetti, L.M., Enghild, J.J., and Soff, G.A., Biochem. J., 1999, vol. 340, pp. 77–84.PubMedCentralPubMedCrossRefGoogle Scholar
  29. 29.
    Dano, K., Behrendt, N., Hoyer-Hansen, G., Johnsen, M., Lund, L.R., Ploug, M., and Romer, J., Thromb. Haemost., 2005, vol. 93, pp. 676–681.PubMedGoogle Scholar
  30. 30.
    Vassalli, J.D., Fibrinolysis, 1994, vol. 8, pp. 172–181.CrossRefGoogle Scholar
  31. 31.
    Stillfried, G.E., Saunders, D.N., and Ranson, M., Breast Cancer Res., 2007, vol. 9, p. R14.CrossRefGoogle Scholar
  32. 32.
    Ploug, M., Curr. Pharmaceut. Design, 2003, vol. 9, pp. 1499–1528.CrossRefGoogle Scholar
  33. 33.
    van Meijer, M. and Pannekoek, H., Fibrinolysis, 1995, vol. 9, pp. 263–276.CrossRefGoogle Scholar
  34. 34.
    Booth, N.A., Fibrinolysis Proteolysis, 2000, vol. 14, pp. 206–213.CrossRefGoogle Scholar
  35. 35.
    Ha, H., Oh, E.Y., and Lee, H.B., Nat. Rev. Nephrol., 2009, vol. 5, pp. 203–211.PubMedCrossRefGoogle Scholar
  36. 36.
    Francis, C.W., Arch. Pathol. Lab. Med., 2002, vol. 126, pp. 1401–1404.PubMedGoogle Scholar
  37. 37.
    Smolarczyk, K., Boncela, J., Szymanski, J., Gils, A., and Cierniewski, C.S., Arterioscler. Thromb. Vasc. Biol., 2005, vol. 25, pp. 2679–2684.PubMedCrossRefGoogle Scholar
  38. 38.
    Mutch, N.J., Thomas, L., Moore, N.R., Lisiak, K.M., and Booth, N.A., J. Thromb. Haemost., 2007, vol. 5, pp. 812–817.PubMedCrossRefGoogle Scholar
  39. 39.
    Kimura, S. and Aoki, N., J. Biol. Chem., 1986, vol. 261, pp. 15591–15595.PubMedGoogle Scholar
  40. 40.
    Gaffney, P.J., Fibrinolysis: Current Fundamental and Clinical Concepts, International Society of Hematology, European and African Division, Academic Press, 1978.Google Scholar
  41. 41.
    Ogiwara, K., Nogami, K., Nishiya, K., and Shima, M., Blood Coagul. Fibrinolysis, 2010, vol. 21, pp. 568–576.PubMedCrossRefGoogle Scholar
  42. 42.
    Pryzdial, E.L., Lavigne, N., Dupuis, N., and Kessler, G.E., J. Biol. Chem., 1999, vol. 274, pp. 8500–8505.PubMedCrossRefGoogle Scholar
  43. 43.
    Waisman, D.M., Plasminogen: Structure, Activation and Regulation, Springer, 2003.Google Scholar
  44. 44.
    Gavrilovic, J. and Murphy, G., Cell Biol. Int. Rep., 1989, vol. 13, pp. 367–375.PubMedCrossRefGoogle Scholar
  45. 45.
    Santala, A., Saarinen, J., Kovanen, P., and Kuusela, P., FEBS Lett., 1999, vol. 461, pp. 153–156.PubMedCrossRefGoogle Scholar
  46. 46.
    Miles, L. and Parmer, R., Semin. Thromb. Hemost., 2013, vol. 39, pp. 329–337.PubMedCentralPubMedCrossRefGoogle Scholar
  47. 47.
    Law, R.H.P., Abu-Ssaydeh, D., and Whisstock, C., Curr. Opin. Struct. Biol., 2013, vol. 23, pp. 836–841.PubMedCrossRefGoogle Scholar
  48. 48.
    Syrovets, T. and Simmet, T., Cell Mol. Life Sci., 2004, vol. 61, pp. 873–885.PubMedCrossRefGoogle Scholar
  49. 49.
    Medved, L. and Nieuwenhuizen, W., Thromb. Haemost., 2003, vol. 89, pp. 409–419.PubMedGoogle Scholar
  50. 50.
    Rijken, D.C. and Sakharov, D.V., Thromb. Res., 2001, vol. 103, pp. 41–49.CrossRefGoogle Scholar
  51. 51.
    Collen, D. and Lijnen, H.R., Thromb. Haemost., 2005, vol. 93, pp. 627–630.PubMedGoogle Scholar
  52. 52.
    Mogielnicki, A., Chabielska, E., Pawlak, R., Szemraj, J., and Buczko, W., Thromb. Haemost, 2005, vol. 93, pp. 1069–1076.PubMedGoogle Scholar
  53. 53.
    Pretorius, M., Rosenbaum, D.A., Vaughan, D.E., and Brown, N.J., Circulation, 2003, pp. 579–585.Google Scholar
  54. 54.
    Brown, N.J., Ryder, D., Gainer, J.V., Morrow, J.D., and Nadeau, J., J. Pharmacol. Exp. Ther., 1996, vol. 279, pp. 703–712.PubMedGoogle Scholar
  55. 55.
    Mukhametova, L.I., Gulin, D.A., Binevskii, P.V., Aisina, R.B., Kost, O.A., and Nikol’skaia, I.I., Russ. J. Bioorg. Chem., 2008, vol. 34, pp. 421–427.CrossRefGoogle Scholar
  56. 56.
    Entsiklopediya lekarstv (Encyclopedia of Drugs), Krylov, Yu.F., Ed., Moscow: RLS-2001, 2001.Google Scholar
  57. 57.
    Birkedal-Hansen, H., Moore, W.G., Bodden, M.K., Birkedal-Hansen, B., DeCarlo, A., and Engler, J.A., Crit. Rev. Oral. Biol. Med., 1993, vol. 4, pp. 197–250.PubMedGoogle Scholar
  58. 58.
    Kleiner, D.E. and Stetler-Stevenson, W.G., Curr. Opin. Cell. Biol., 1993, vol. 5, pp. 891–897.PubMedCrossRefGoogle Scholar
  59. 59.
    Ugwu, F., Van Hoef, B., Bini, A., Collen, D., and Lijnen, H.R., Biochemistry, 1998, vol. 37, pp. 7231–7236.PubMedCrossRefGoogle Scholar
  60. 60.
    Mulligan-Kehoe, M.J., Drinane, M.C., Mollmark, J., Casciola-Rosen, L., Hummers, L.K., Hall, A., Wigley, F.M., and Simons, M., Arthritis Rheum., 2007, vol. 56, pp. 3448–3458.PubMedCrossRefGoogle Scholar
  61. 61.
    Dvorak, H.F., J. Thromb. Haemost, 2005, vol. 3, pp. 1835–1842.PubMedCrossRefGoogle Scholar
  62. 62.
    Del Rosso, M., Fibbi, G., Pucci, M., Margheri, F., and Serrati, S., Front. Biosci., 2008, vol. 13, pp. 4667–4686.PubMedCrossRefGoogle Scholar
  63. 63.
    Li, W.Y., Chong, S.S., Huang, E.Y., and Tuan, T.L., Wound Repair Regen., 2003, vol. 11, pp. 239–247.PubMedCrossRefGoogle Scholar
  64. 64.
    Chesnokova, N.B., Nikol’skaya, I.I., Mukhametova, L.I., Kost, O.A., Aisina, R.B., Beznos, O.V., Stolyarova, E.P., Gulin, D.A., and Binevskii, P.V., Ross. Oftal’mol. Zh., 2008, vol. 1, pp. 46–50.Google Scholar
  65. 65.
    Gulin, D.A., Kinetic patterns and mechanism of regulation of fibrinolytic system activity with various effectors, Cand. Sci. (Chem.) Dissertation, Moscow: Mosk. Gos. Univ., 2009.Google Scholar
  66. 66.
    Melchor, J.P. and Strickland, S., Thromb. Haemost., 2005, vol. 93, pp. 655–660.PubMedCentralPubMedGoogle Scholar
  67. 67.
    Díaz, V.M., Hurtado, M., Thomson, T.M., Reventós, J., and Paciucci, R., Gut, 2004, vol. 53, pp. 993–1000.PubMedCentralPubMedCrossRefGoogle Scholar
  68. 68.
    Bugge, T.H., Flick, M.J., Danton, M.J., Daugherty, C.C., Romer, J., Dano, K., Carmeliet, P., Collen, D., and Degen, J.L., Proc. Nat. Acad. Sci. U.S.A., 1996, vol. 93, pp. 5899–5904.CrossRefGoogle Scholar
  69. 69.
    Burtin, P., Chavanel, G., and Andre, J., Int. J. Cancer, 1985, vol. 35, pp. 307–314.PubMedCrossRefGoogle Scholar
  70. 70.
    Clavel, C., Chavanel, G., and Birembaut, P., Cancer. Res., 1986, vol. 46, pp. 5743–5747.PubMedGoogle Scholar
  71. 71.
    Burtin, P., Chavanel, G., Andre-Bougaran, J., and Gentile, A., Int. J. Cancer, 1987, vol. 39, pp. 170–178.PubMedCrossRefGoogle Scholar
  72. 72.
    Wojtukiewicz, M.Z., Sierko, E., Klementyz, P., and Rakz, J., Neoplasia, 2001, vol. 3, pp. 371–384.PubMedCentralPubMedCrossRefGoogle Scholar
  73. 73.
    O’Reilly, M.S., Holmgren, L., Chen, C., and Folkman, J., Nat. Med., 1996, vol. 2, pp. 689–692.PubMedCrossRefGoogle Scholar
  74. 74.
    Gately, S., Twardowski, P., Stack, S., Cundiff, D., Grella, D., Castellino, F.J., Enghild, J., Kwaan, H.C., Lee, F., Kramer, R., Volpert, O., Bouck, N., and Soff, G., Proc. Natl. Acad. Sci. USA, 1997, vol. 94, pp. 10868–10872.PubMedCentralPubMedCrossRefGoogle Scholar
  75. 75.
    Kassam, G., Kwon, M., Yoon, C.-S., Graham, K.S., Young, M.K., Gluck, S., and Waisman, D.M., J. Biol. Chem., 2001, vol. 276, pp. 8924–8933.PubMedCrossRefGoogle Scholar
  76. 76.
    Kwon, M. and Waisman, D.M., in Plasminogen: Structure, Activation and Regulation, Waisman, D.M., Ed., New York: Kluwer Academic/Plenum Publishers, 2003, pp. 135–156.Google Scholar
  77. 77.
    Cao, R., Wu, H.L., Veitonmaki, N., Linden, P., Farnebo, J., Shi, G.Y., and Cao, Y., Proc. Natl. Acad. Sci. USA, 1999, vol. 96, pp. 5728–5733.PubMedCentralPubMedCrossRefGoogle Scholar
  78. 78.
    Wu, H.-L., Chang, B.-I., Wu, D.-H., Chang, L.-C., Gong, C.-C., Lou, K.-L., and Shi, G.-Y., J. Biol. Chem., 1990, vol. 265, pp. 19658–19664.PubMedGoogle Scholar
  79. 79.
    Cao, Y., Haematologica, 1999, vol. 84, pp. 643–650.PubMedGoogle Scholar
  80. 80.
    Chen, Y.-H., Wu, H.-L., Li, C., Huang, Y.-H., Chiangc. W., Wu, M.-P., and Wu, L.-W., Thromb. Haemost., 2006, vol. 95, pp. 668–677.PubMedGoogle Scholar
  81. 81.
    Moser, T.L., Stack, M.S., Asplin, I., Enghild, J.J., Jrup, P., Everitt, L., Hubchak, S., Schnaper, H.W., and Pizzo, S.V., Proc. Natl. Acad. Sci. USA, 1999, vol. 96, pp. 2811–2816.PubMedCentralPubMedCrossRefGoogle Scholar
  82. 82.
    Aisina, R.B., Mukhametova, L.I., Gulin, D.A., Levashov, M.Y., Prisyazhnaya, N.V., Gershkovich, K.B., and Varfolomeyev, S.D., Biochemistry (Moscow), 2009, vol. 10, pp. 1104–1113.Google Scholar
  83. 83.
    Aisina, R.B., Mukhametova, L.I., Prisiazhnaia, N., Gulin, D.A., Levashov, M.Y., and Gershkovich, K.B., Russ. J. Bioorg. Chem., 2011, vol. 3, pp. 319–326.Google Scholar

Copyright information

© Pleiades Publishing, Ltd. 2014

Authors and Affiliations

  1. 1.Department of ChemistryMoscow State UniversityMoscowRussia

Personalised recommendations