rmtОбщая реаниматологияGeneral Reanimatology1813-97792411-7110FSBI "SRIGR" RAMS10.15360/1813-9779-2018-6-61-79rmt-1726Research ArticleОБЗОРЫ И КРАТКИЕ СООБЩЕНИЯREVIEWS & SHORT COMMUNICATIONSСистема активатора плазминогена урокиназного типа в норме и при жизнеугрожающих процессах (обзор)Urokinase-Type Plasminogen Activator System in Norm and in Life-Threatening Processes (Review)КугаевскаяЕ. В.KugaevskayaElena V.

19121, г. Москва, ул. Погодинская, д. 10

10 Pogodinskaya Str., 19121 Moscow

ГурееваТ. А.GureevaTatiana A.

19121, г. Москва, ул. Погодинская, д. 10

10 Pogodinskaya Str., 19121 Moscow

ТимошенкоО. С.TimoshenkoOlga S.

19121, г. Москва, ул. Погодинская, д. 10

10 Pogodinskaya Str., 19121 Moscow

СоловьеваН. И.SolovyevaNina I.

19121, г. Москва, ул. Погодинская, д. 10

10 Pogodinskaya Str., 19121 Moscow

Nina.Solovyeva@ibmc.msk.ruНИИ биомедицинской химии им. В.Н. ОреховичаРоссияV. N. Orekhovich Research Institute of Biomedical ChemistryRussian Federation2018271220181466179Copyright © Кугаевская Е.В., Гуреева Т.А., Тимошенко О.С., Соловьева Н.И., 20182018Кугаевская Е.В., Гуреева Т.А., Тимошенко О.С., Соловьева Н.И.Kugaevskaya E.V., Gureeva T.A., Timoshenko O.S., Solovyeva N.I.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.reanimatology.com/rmt/article/view/1726

Многофункциональная система активатора плазминогена урокиназного типа (uPA-система) включает сериновую протеиназу — uPA или урокиназу, ее рецептор — uPAR и два ингибитора — PAI-1 и PAI-2. В обзоре рассмотрены структурные особенности и участие компонентов системы в развитии таких жизнеугрожающих процессов, как канцерогенез, воспаление, нейрогенез и фибринолиз, в регуляции которых решаюшую роль играют деструкция соединительнотканного матрикса (СТМ) и мобильность клеток, а также индукция сигнальных путей внутри и вне клетки. uPA запускает процессы, осуществляемые uPA-системой, путем активации плазминогена и превращения его в плазмин, который, помимо регуляции фибринолиза, вовлечен в акивацию матриксных металлопротеиназ (ММП). ММП могут гидролизовать все основные компоненты СТМ и тем самым выполнять ключевую роль в развитии процессов инвазии, метастазирования, мобильности клеток, а также активировать и освобождать из СТМ ряд биологически активных регуляторных молекул. uPAR, PAI-1 и PAI-2 отвечают за регуляцию активности uPA. Кроме того, uPAR, который является сигнальным рецептором, наряду с ММП приводят к стимуляции целый ряд сигнальных путей, которые связаны с регуляцией процессов пролиферации, апоптоза, адгезии, роста и миграции клеток, определяющих развитие таких процессов, как прогрессия опухолей, воспаление, хемотаксис, ангиогенез. Эффективное участие uPA-системы в деструкци СТМ и регуляции внутри- и внеклеточных сигнальных путей, свидетельствует о том, что эта система является важнейшим регулятором физиологических и патологических процессов.

The multifunctional urokinase-type plasminogen activator system (uPA-system) includes serine proteinase — uPA or urokinase, its receptor (uPAR) and two inhibitors (PAI-1 and PAI-2). The review discusses the structural features and involvement of the system components in the development of life-threatening processes including carcinogenesis, inflammation, neurogenesis and fibrinolysis, in regulation of which the destruction of extracellular matrix (ECM), cell mobility and signaling inside and outside the cell play a decisive role. uPA triggers the processes by activating the plasminogen and its convertion into plasmin involved in the activation of matrix metalloproteinases (MMPs) in addition to the regulation of fibrinolysis. MMPs can hydrolyze all the major ECM components and therefore play a key role in invasion, metastasis, and cell mobility. MMPs activates a cassette of biologically active regulatory molecules and release them from ECM. uPAR, PAI-1 and PAI-2 are responsible for regulation of the uPA activity. In addition, being a signaling receptor, uPAR along with MMPs lead to the stimulation of a number of signaling pathways that are associated with the regulation of proliferation, apoptosis, adhesion, growth and migration of cells contributing to tumor progression, inflammation, chemotaxis, and angiogenesis. Effective participation of the uPA system components in ECM destruction and regulation of intracellular and extracellular signaling pathways demonstrates that the system significantly contributes to the regulation of various physiological and pathological processes.

uPAuPARPAI-1PAI-2матриксные металлопротеиназыканцерогенезвоспалениенейрогенезфибринолизuPAuPARPAI-1PAI-2matrix metalloproteinasescarcinogenesisinflammationneurogenesisfibrinolysisReferencesJaiswal R.K., VarshneyA.K., Yadava P.K. Diversity and functional evolution of the plasminogen activator system. Biomed. Pharmacother. 2018; 98: 886–898. DOI: 10.1016/j.biopha.2018.01.029. PMID: 29571259Jaiswal R.K., VarshneyA.K., Yadava P.K. Diversity and functional evolution of the plasminogen activator system. Biomed. Pharmacother. 2018; 98: 886–898. DOI: 10.1016/j.biopha.2018.01.029. PMID: 29571259Mahmood N., Mihalcioiu C., Rabbani S.A. Multifaceted role of the urokinase-type plasminogen activator (uPA) and its receptor (uPAR): diagnostic, prognostic, and therapeutic applications. Front. Oncol. 2018; 8: 24. DOI: 10.3389/fonc.2018.00024. PMID: 29484286Mahmood N., Mihalcioiu C., Rabbani S.A. Multifaceted role of the urokinase-type plasminogen activator (uPA) and its receptor (uPAR): diagnostic, prognostic, and therapeutic applications. Front. Oncol. 2018; 8: 24. DOI: 10.3389/fonc.2018.00024. PMID: 29484286Айсина Р.Б., Мухаметова Л.И. Структура и функции системы плазминоген/плазмин. Биоорганич. химия. 2014; 40 (6): 642–657. DOI: 10.7868/S0132342314060025. PMID: 25895360Aisina R.B., Mukhametova L.I. Structure and functions of plasminogen/plasmin system. Bioorganicheskaya Khimiya. 2014; 40 (6): 642–657. DOI: 10.7868/S0132342314060025. PMID: 25895360. [In Russ.]Mekkawy A.H., Pourgholami M.H., Morris D.L. Involvement of urokinase-type plasminogen activator system in cancer: an overview. Med. Res. Rev. 2014; 34 (5): 918–956. DOI: 10.1002/med.21308. PMID: 24549574Mekkawy A.H., Pourgholami M.H., Morris D.L. Involvement of urokinase-type plasminogen activator system in cancer: an overview. Med. Res. Rev. 2014; 34 (5): 918–956. DOI: 10.1002/med.21308. PMID: 24549574Ткачук В.А., Плеханова О.С., Белоглазова И.Б., Парфенова Е.В. Роль мультидоменной структуры урокиназы в регуляции роста и ремоделирования сосудов. Укр. биохим. журнал. 2013; 85 (6): 18–45.Tkachuk V.A., Plekhanova O.S., Beloglazova I.B., Parfenova E.V. The role of the multi-domain structure of urokinase in the regulation of vascular growth and remodeling. Ukrainsky Biokhimichesky Zhurnal. 2013; 85 (6): 18–45. . [In Russ.]Law R.H., Abu-Ssaydeh D., Whisstock J.C. New insights into the structure and function of the plasminogen/plasmin system. Curr. Opin. Struct. Biol. 2013; 23 (6): 836–841. DOI: 10.1016/j.sbi.2013.10.006. PMID: 24252474Law R.H., Abu-Ssaydeh D., Whisstock J.C. New insights into the structure and function of the plasminogen/plasmin system. Curr. Opin. Struct. Biol. 2013; 23 (6): 836–841. DOI: 10.1016/j.sbi.2013.10.006. PMID: 24252474Cui N., Hu M., Khalil R.A. Biochemical and biological attributes of matrix metalloproteinases. Prog. Mol. Biol. Transl. Sci. 2017; 147: 1–73. DOI: 10.1016/bs.pmbts.2017.02.005. PMID: 28413025Cui N., Hu M., Khalil R.A. Biochemical and biological attributes of matrix metalloproteinases. Prog. Mol. Biol. Transl. Sci. 2017; 147: 1–73. DOI: 10.1016/bs.pmbts.2017.02.005. PMID: 28413025Duffy M.J. The urokinase plasminogen activator system: role in malignancy. Curr. Pharm. Des. 2004; 10 (1): 39–49. DOI: 10.2174/1381612043453559. PMID: 14754404Duffy M.J. The urokinase plasminogen activator system: role in malignancy. Curr. Pharm. Des. 2004; 10 (1): 39–49. DOI: 10.2174/1381612043453559. PMID: 14754404Duffy M.J., Duggan C. The urokinase plasminogen activator system: a rich source of tumour markers for the individualised management of patients with cancer. Clin. Biochem. 2004; 37 (7): 541–548. DOI: 10.1016/j.clinbiochem.2004.05.013. PMID: 15234235Duffy M.J., Duggan C. The urokinase plasminogen activator system: a rich source of tumour markers for the individualised management of patients with cancer. Clin. Biochem. 2004; 37 (7): 541–548. DOI: 10.1016/j.clinbiochem.2004.05.013. PMID: 15234235Mondino A., Blasi F. uPA and uPAR in fibrinolysis, immunity and pathology. Trends Immunol. 2004; 25 (8): 450–455. DOI: 10.1016/j.it.2004. 06.004. PMID: 15275645Mondino A., Blasi F. uPA and uPAR in fibrinolysis, immunity and pathology. Trends Immunol. 2004; 25 (8): 450–455. DOI: 10.1016/j.it.2004.06. 004. PMID: 15275645Visse R., Nagase H. Matrix metalloproteinases and tissue inhibitors of metalloproteinases: structure, function, and biochemistry. Circ. Res. 2003; 92 (8): 827–839. DOI: 10.1161/01.RES.0000070112.80711.3D. PMID: 12730128Visse R., Nagase H. Matrix metalloproteinases and tissue inhibitors of metalloproteinases: structure, function, and biochemistry. Circ. Res. 2003; 92 (8): 827–839. DOI: 10.1161/01.RES.0000070112.80711.3D. PMID: 12730128Smith H.W., Marshall C.J. Regulation of cell signalling by uPAR. Nat. Rev. Mol. Cell Biol. 2010; 11 (1): 23–36. DOI: 10.1038/nrm2821. PMID: 20027185Smith H.W., Marshall C.J. Regulation of cell signalling by uPAR. Nat. Rev. Mol. Cell Biol. 2010; 11 (1): 23–36. DOI: 10.1038/nrm2821. PMID: 20027185D’Alessio S., Gerasi L, Blasi F. uPAR-deficient mouse keratinocytes fail to produce EGFR-dependent laminin-5, affecting migration in vivo and in vitro. J. Cell Sci. 2008; 121 (Pt 23): 3922-3932. DOI: 10.1242/jcs. 037549. PMID: 19001498D’Alessio S., Gerasi L, Blasi F. uPAR-deficient mouse keratinocytes fail to produce EGFR-dependent laminin-5, affecting migration in vivo and in vitro. J. Cell Sci. 2008; 121 (Pt 23): 3922-3932. DOI: 10.1242/jcs. 037549. PMID: 19001498Madsen C.D., Sidenius N. The interaction between urokinase receptor and vitronectin in cell adhesion and signaling. Eur. J. Cell Biol. 2008; 87 (8-9): 617–629. DOI: 10.1016/j.ejcb.2008.02.003. PMID: 18353489Madsen C.D., Sidenius N. The interaction between urokinase receptor and vitronectin in cell adhesion and signaling. Eur. J. Cell Biol. 2008; 87 (8-9): 617–629. DOI: 10.1016/j.ejcb.2008.02.003. PMID: 18353489Mimuro J., Kaneko M., Murakami T., Matsuda M., Sakata Y. Reversible interactions between plasminogen activators and plasminogen activator inhibitor-1. Biochim. Biophys. Acta. 1992; 1160 (3): 325–334. DOI: 10.1016/0167-4838(92)90095-U. PMID: 1477106Mimuro J., Kaneko M., Murakami T., Matsuda M., Sakata Y. Reversible interactions between plasminogen activators and plasminogen activator inhibitor-1. Biochim. Biophys. Acta. 1992; 1160 (3): 325–334. DOI: 10.1016/0167-4838(92)90095-U. PMID: 1477106Lijnen H.R. Pleiotropic functions of the plasminogen activator inhibitor-1. J. Thromb. Haemost. 2005; 3 (1): 35–45. DOI: 10.1111/j.1538-7836.2004.00827.x. PMID: 15634264Lijnen H.R. Pleiotropic functions of the plasminogen activator inhibitor-1. J. Thromb. Haemost. 2005; 3 (1): 35–45. DOI: 10.1111/j.1538-7836.2004.00827.x. PMID: 15634264Kruithof E.K., Baker M.S., Bunn C.L. Biological and clinical aspects of plasminogen activator inhibitor type 2. Blood. 1995; 86 (11): 4007–4024. PMID: 7492756Kruithof E.K., Baker M.S., Bunn C.L. Biological and clinical aspects of plasminogen activator inhibitor type 2. Blood. 1995; 86 (11): 4007–4024. PMID: 7492756Crippa M.P. Urokinase-type plasminogen activator. Int. J. Biochem. Cell Biol. 2007; 39 (4): 690–694. DOI: 10.1016/j.biocel.2006.10.008. PMID: 17118695Crippa M.P. Urokinase-type plasminogen activator. Int. J. Biochem. Cell Biol. 2007; 39 (4): 690–694. DOI: 10.1016/j.biocel.2006.10.008. PMID: 17118695Schmitt M., Kanayama N., Jänicke F., Hafter R., Graeff H. Human tumor cell urokinase-type plasminogen activator (uPA): degradation of the proenzyme form (pro-uPA) by granulocyte elastase prevents subsequent activation by plasmin. Adv. Exp. Med. Biol. 1991; 297: 111–128. DOI: 10.1007/978-1-4899-3629-5_10. PMID: 1837419Schmitt M., Kanayama N., Jänicke F., Hafter R., Graeff H. Human tumor cell urokinase-type plasminogen activator (uPA): degradation of the pro-enzyme form (pro-uPA) by granulocyte elastase prevents subsequent activation by plasmin. Adv. Exp. Med. Biol. 1991; 297: 111–128. DOI: 10.1007/978-1-4899-3629-5_10. PMID: 1837419Behrens M.A., Botkjaer K.A., Goswami S., Oliveira C.L.P., Jensen J.K., Schar C.R., Declerck P.J., Peterson C.B., Andreasen P.A., Pedersen J.S. Activation of the zymogen to urokinase-type plasminogen activator is associated with increased interdomain flexibility. J. Mol. Biol. 2011; 411 (2): 417–429. DOI: 10.1016/j.jmb.2011.05.026. PMID: 21669207Behrens M.A., Botkjaer K.A., Goswami S., Oliveira C.L.P., Jensen J.K., Schar C. R., Declerck P.J., Peterson C.B., Andreasen P.A., Pedersen J. S. Activation of the zymogen to urokinase-type plasminogen activator is associated with increased interdomain flexibility. J. Mol. Biol. 2011; 411 (2): 417–429. DOI: 10.1016/j.jmb.2011.05.026. PMID: 21669207Appella E., Robinson E.A., Ullrich S.J., Stoppelli M.P., Corti A., Cassani G., Blasi F. The receptor-binding sequence of urokinase. A biological function for the growth-factor module of proteases. J. Biol. Chem. 1987; 262 (10): 4437–4440. PMID: 3031025Appella E., Robinson E.A., Ullrich S.J., Stoppelli M.P., Corti A., Cassani G., Blasi F. The receptor-binding sequence of urokinase. A biological function for the growth-factor module of proteases. J. Biol. Chem. 1987; 262 (10): 4437–4440. PMID: 3031025Kwak S.H., Mitra S., Bdeir K., Strassheim D., Park J.S., Kim J.Y., Idell S., Cines D., Abraham E. The kringle domain of urokinase-type plasminogen activator potentiates LPS-induced neutrophil activation through interaction with {alpha}V{beta}3 integrins. J. Leukoc. Biol. 2005; 78 (4): 937– 945. DOI: 10.1189/jlb.0305158. PMID: 16033814Kwak S.H., Mitra S., Bdeir K., Strassheim D., Park J.S., Kim J.Y., Idell S., Cines D., Abraham E. The kringle domain of urokinase-type plasminogen activator potentiates LPS-induced neutrophil activation through interaction with {alpha}V{beta}3 integrins. J. Leukoc. Biol. 2005; 78 (4): 937– 945. DOI: 10.1189/jlb.0305158. PMID: 16033814Pluskota E., Soloviev D.A., Bdeir K., Cines D.B., Plow E.F. Integrin alphaMbeta2 orchestrates and accelerates plasminogen activation and fibrinolysis by neutrophils. J. Biol. Chem. 2004; 279 (17): 18063–18072. DOI: 10.1074/jbc.M310462200. PMID: 14769799Pluskota E., Soloviev D.A., Bdeir K., Cines D.B., Plow E.F. Integrin alphaMbeta2 orchestrates and accelerates plasminogen activation and fibrinolysis by neutrophils. J. Biol. Chem. 2004; 279 (17): 18063–18072. DOI: 10.1074/jbc.M310462200. PMID: 14769799Mukhina S., Stepanova V., Traktouev D., Poliakov A., Beabealashvilly R., Gursky Ya., Minashkin M., Shevelev A., Tkachuk V. The chemotactic action of urokinase on smooth muscle cells is dependent on its kringle domain. Characterization of interactions and contribution to chemotaxis. J. Biol. Chem. 2000; 275 (22): 16450–16458. DOI: 10.1074/jbc.M909080199. PMID: 10749881Mukhina S., Stepanova V., Traktouev D., Poliakov A., Beabealashvilly R., Gursky Ya., Minashkin M., Shevelev A., Tkachuk V. The chemotactic action of urokinase on smooth muscle cells is dependent on its kringle domain. Characterization of interactions and contribution to chemotaxis. J. Biol. Chem. 2000; 275 (22): 16450–16458. DOI: 10.1074/jbc.M909080199. PMID: 10749881Poliakov A.A., Mukhina S.A., Traktouev D.O., Bibilashvily R.S., Gursky Y. G., Minashkin, M.M., Stepanova V.V., Tkachuk V.A. Chemotactic effect of urokinase plasminogen activator: a major role for mechanisms independent of its proteolytic or growth factor domains. J. Recept. Signal Transduct. Res. 1999; 19 (6): 939–951. DOI: 10.3109/10799899909038433. PMID: 10533982Poliakov A.A., Mukhina S.A., Traktouev D.O., Bibilashvily R.S., Gursky Y. G., Minashkin, M.M., Stepanova V.V., Tkachuk V.A. Chemotactic effect of urokinase plasminogen activator: a major role for mechanisms independent of its proteolytic or growth factor domains. J. Recept. Signal Transduct. Res. 1999; 19 (6): 939–951. DOI: 10.3109/10799899909038433. PMID: 10533982Bdeir K., Kuo A., Sachais B.S., Rux A.H., Bdeir Y., Mazar A., Higazi A.A., Cines D.B. The kringle stabilizes urokinase binding to the urokinase receptor. Blood. 2003; 15 (10): 3600–3608. DOI: 10.1182/blood-2003-03-0949. PMID: 12881310Bdeir K., Kuo A., Sachais B.S., Rux A.H., Bdeir Y., Mazar A., Higazi A.A., Cines D.B. The kringle stabilizes urokinase binding to the urokinase receptor. Blood. 2003; 15 (10): 3600–3608. DOI: 10.1182/blood-2003-03-0949. PMID: 12881310Petersen L.C., Lund L.R., Nielsen L.S., Danø K., Skriver L. One-chain urokinase-type plasminogen activator from human sarcoma cells is a proenzyme with little or no intrinsic activity. J. Biol. Chem. 1988; 263 (23): 11189–11195. PMID: 2969891Petersen L.C., Lund L.R., Nielsen L.S., Danø K., Skriver L. One-chain urokinase-type plasminogen activator from human sarcoma cells is a proenzyme with little or no intrinsic activity. J. Biol. Chem. 1988; 263 (23): 11189–11195. PMID: 2969891Spraggon G., Phillips C., Nowak U.K., Ponting C.P., Saunders D., Dobson C.M., Stuart D.I., Jones E.Y. The crystal structure of the catalytic domain of human urokinase-type plasminogen activator. Structure. 1995; 3 (7): 681–691. DOI: 10.1016/S0969-2126(01)00203-9. PMID: 8591045Spraggon G., Phillips C., Nowak U.K., Ponting C.P., Saunders D., Dobson C.M., Stuart D.I., Jones E.Y. The crystal structure of the catalytic domain of human urokinase-type plasminogen activator. Structure. 1995; 3 (7): 681–691. DOI: 10.1016/S0969-2126(01)00203-9. PMID: 8591045Blasi F., Carmeliet P. uPAR: a versatile signalling orchestrator. Nat. Rev. Mol. Cell Biol. 2002; 3 (12): 932–943. DOI: 10.1038/nrm977. PMID: 12461559Blasi F., Carmeliet P. uPAR: a versatile signalling orchestrator. Nat. Rev. Mol. Cell Biol. 2002; 3 (12): 932–943. DOI: 10.1038/nrm977. PMID: 12461559D’Alessio S., Blasi F. The urokinase recertor as an entertainer of signal transduction. Front. Biosci. (Landmark Ed.). 2009; 14: 4575-4587. DOI: 10.2741/3550. PMID: 19273372D’Alessio S., Blasi F. The urokinase recertor as an entertainer of signal transduction. Front. Biosci. (Landmark Ed.). 2009; 14: 4575-4587. DOI: 10.2741/3550. PMID: 19273372Ellis V., Scully M.F., Kakkar V.V. Plasminogen activation initiated by single-chain urokinase-type plasminogen activator. Potentiation by U937 monocytes. J. Biol. Chem. 1989; 264 (4): 2185–2188. PMID: 2521625Ellis V., Scully M.F., Kakkar V.V. Plasminogen activation initiated by single-chain urokinase-type plasminogen activator. Potentiation by U937 monocytes. J. Biol. Chem. 1989; 264 (4): 2185–2188. PMID: 2521625Carmeliet P., Moons L., Lijnen R., Baes M., Lemaitre V., Tipping P., Drew A., Eeckhout Y., Shapiro S., Lupu F., Collen D. Urokinase-generated plasmin activates matrix metalloproteinase during aneurysm formation. Nat. Gen. 1997; 17 (4): 439–444. DOI: 10.1038/ng1297-439. PMID: 9398846Carmeliet P., Moons L., Lijnen R., Baes M., Lemaitre V., Tipping P., Drew A., Eeckhout Y., Shapiro S., Lupu F., Collen D. Urokinase-generated plasmin activates matrix metalloproteinase during aneurysm formation. Nat. Gen. 1997; 17 (4): 439–444. DOI: 10.1038/ng1297-439. PMID: 9398846Lijnen H.R. Plasmin and matrix metalloproteinases in vascular remodeling. Thromb. Haemost. 2001; 86 (1): 324–333. DOI: 10.1055/s-0037-1616230. PMID: 11487021Lijnen H.R. Plasmin and matrix metalloproteinases in vascular remodeling. Thromb. Haemost. 2001; 86 (1): 324–333. DOI: 10.1055/s-0037-1616230. PMID: 11487021Choong P.F., Nadesapillai A.P. Urokinase plasminogen activator system: a multifunctional role in tumor progression and metastasis. Clin. Orthop. Relat. Res. 2003; 415 Suppl: S46–S58. DOI: 10.1097/01.blo.0000093845. 72468.bd. PMID: 14600592Choong P.F., Nadesapillai A.P. Urokinase plasminogen activator system: a multifunctional role in tumor progression and metastasis. Clin. Orthop. Relat. Res. 2003; 415 Suppl: S46–S58. DOI: 10.1097/01.blo.0000093845. 72468.bd. PMID: 14600592Соловьева Н.И., Тимошенко О.С., Гуреева Т.А., Кугаевская Е.В. Матриксные металлопротеиназы и их эндогенные регуляторы при плоскоклеточной карциноме шейки матки: (обзор собственных данных). Биомед. химия. 2015; 61 (6): 694–704. DOI: 10.18097/PBMC20156106694. PMID: 26716740Solovуeva N.I., Timoshenko O.S., Gureeva T.A., Kugaevskaya E.V. Matrix metalloproteinases and their endogenous regulators in squamous cervical carcinoma (review of the own data). Biomeditsinskaya Khimiya. 2015; 61 (6): 694–704. DOI: 10.18097/PBMC20156106694. PMID: 26716740. [In Russ.]Тимошенко О.С., Кугаевская Е.В., Гуреева Т.А., Завалишина Л.Э., Андреева Ю.Ю., Соловьева Н.И. Матриксные металлопротеиназы -2 и -9, их эндогенные регуляторы и ангиотензинпревращающий фермент при плоскоклеточной карциноме щейки матки. Архив патологии. 2015; 77 (5): 31-35. DOI: 10.17116/patol201577531-35. PMID: 26978018Timoshenko O.S., Kugaevskaya E.V., Gureeva T.A., Zavalishina L.E., Andreeva Y.Y., Solovуeva N.I. Matrix metalloproteinases 2 and 9, their endogenous regulators, and angiotensin-converting enzyme in cervical squamous cell carcinoma. Arkhiv Patologii. 2015; 77 (5): 31-35. DOI: 10.17116/patol201577531-35. PMID: 26978018. [In Russ.]Тимошенко О.С., Гуреева Т.А., Кугаевская Е.В., Завалишина Л.Э., Соловьева Н.И. Интерстициальная коллагеназа ММП-1 и ее эндогенные регуляторы в теле матки при поскоклеточной карциноме шейки матки. Биомед. химия. 2017; 63 (6): 513-519. DOI: 10.18097/PBMC20176306513. PMID: 29251612Timoshenko O.S., Gureeva T.A., Kugaevskaya E.V., Zavalishina L.E., Solovyeva N.I. Interstitial collagenase and their endogenous regulators in squamous cell cervical carcinoma. Biomeditsinskaya Khimiya. 2017; 63 (6): 513-519. DOI: 10.18097/PBMC20176306513. PMID: 29251612. [In Russ.]Duffy M.J., McGowan P.M., Gallagher W.M. Cancer invasion and metastasis: changing views. J. Pathol. 2008; 214 (3): 283–293. DOI: 10.1002/path.2282. PMID: 18095256Duffy M.J., McGowan P.M., Gallagher W.M. Cancer invasion and metastasis: changing views. J. Pathol. 2008; 214 (3): 283–293. DOI: 10.1002/path.2282. PMID: 18095256Ulisse S., Baldini E., Sorrenti S., D’Armiento M. The urokinase plasminogen activator system: a target for anti-cancer therapy. Curr. Cancer Drug Targets. 2009; 9 (1): 32–71. DOI: 10.2174/156800909787314002. PMID: 19200050Ulisse S., Baldini E., Sorrenti S., D’Armiento M. The urokinase plasminogen activator system: a target for anti-cancer therapy. Curr. Cancer Drug Targets. 2009; 9 (1): 32–71. DOI: 10.2174/156800909787314002. PMID: 19200050Vassilli J.D., Baccino D., Belin D. A cellular binding site for the Mr 55,000 form of the human plasminogen activator, urokinase. J. Cell Biol. 1985; 100 (1): 86–92. DOI: 10.1083/jcb.100.1.86. PMID: 3880760Vassilli J.D., Baccino D., Belin D. A cellular binding site for the Mr 55,000 form of the human plasminogen activator, urokinase. J. Cell Biol. 1985; 100 (1): 86–92. DOI: 10.1083/jcb.100.1.86. PMID: 3880760Cubellis M.V., Nolli M.L., Cassani G., Blasi F. Binding of single-chain pro-urokinase to the urokinase receptor of human U937 cells. J. Biol. Chem. 1986; 261 (34): 15819–15822. PMID: 3023326Cubellis M.V., Nolli M.L., Cassani G., Blasi F. Binding of single-chain prourokinase to the urokinase receptor of human U937 cells. J. Biol. Chem. 1986; 261 (34): 15819–15822. PMID: 3023326Stephens R.W., Pöllänen J., Tapiovaara H., Leung K.C., Sim P.S., Salonen E.M., Rønne E., Behrendt N., Danø K., Vaheri A. Activation of pro-urokinase and plasminogen on human sarcoma cells: a proteolytic system with surface-bound reactants. J. Cell Biol. 1989; 108 (5): 1987–1995. DOI: 10.1083/jcb.108.5.1987. PMID: 2523891Stephens R.W., Pöllänen J., Tapiovaara H., Leung K.C., Sim P.S., Salonen E.M., Rønne E., Behrendt N., Danø K., Vaheri A. Activation of pro-urokinase and plasminogen on human sarcoma cells: a proteolytic system with surface-bound reactants. J. Cell Biol. 1989; 108 (5): 1987–1995. DOI: 10.1083/jcb.108.5.1987. PMID: 2523891Félez J. Plasminogen binding to cell surfaces. Fibrinol. Proteol. 1998; 12 (4): 183–189. DOI: 10.1016/S0268-9499(98)80012-XFélez J. Plasminogen binding to cell surfaces. Fibrinol. Proteol. 1998; 12 (4): 183–189. DOI: 10.1016/S0268-9499(98)80012-XHu Z., Xu R., Liu J., Zhang Y., Du J., Li W., Zhang W., Li Y., Zhu Y., Gu L. GEP100 regulates epidermal growth factor-induced MDA-MB-231 breast cancer cell invasion through the activation of Arf6/ERK/uPAR signaling pathway. Exp. Cell Res. 2013; 319 (13): 1932–1941. DOI: 10.1016/j.yexcr.2013.05.028. PMID: 23747719Hu Z., Xu R., Liu J., Zhang Y., Du J., Li W., Zhang W., Li Y., Zhu Y., Gu L. GEP100 regulates epidermal growth factor-induced MDA-MB-231 breast cancer cell invasion through the activation of Arf6/ERK/uPAR signaling pathway. Exp. Cell Res. 2013; 319 (13): 1932–1941. DOI: 10.1016/j.yexcr.2013.05.028. PMID: 23747719Yan Q., Bach D.Q., Gatla N., Sun P., Liu J.W., Lu J.Y., Paller A.S., Wang X.Q. Deacetylated GM3 promotes uPAR-associated membrane molecular complex to activate p38 MAPK in metastatic melanoma. Mol. Cancer Res. 2013; 11 (6): 665–675. DOI: 10.1158/1541-7786.MCR-12-0270-T. PMID: 23525268Yan Q., Bach D.Q., Gatla N., Sun P., Liu J.W., Lu J.Y., Paller A.S., Wang X.Q. Deacetylated GM3 promotes uPAR-associated membrane molecular complex to activate p38 MAPK in metastatic melanoma. Mol. Cancer Res. 2013; 11 (6): 665–675. DOI: 10.1158/1541-7786.MCR-12-0270-T. PMID: 23525268Keasey M.P., Jia C., Pimentel L.F., Sante R.R., Lovins C., Hagg T. Blood vitronectin is a major activator of LIF and IL-6 in the brain through integrin-FAK and uPAR signaling. J. Cell Sci. 2018; 131 (3): pii:jcs202580. DOI: 10.1242/jcs.202580. PMID: 29222114Keasey M.P., Jia C., Pimentel L.F., Sante R.R., Lovins C., Hagg T. Blood vitronectin is a major activator of LIF and IL-6 in the brain through integrin-FAK and uPAR signaling. J. Cell Sci. 2018; 131 (3): pii:jcs202580. DOI: 10.1242/jcs.202580. PMID: 29222114Plesner T., Behrendt N., Ploug M. Structure, function and expression on blood and bone marrow cells of the urokinase-type plasminogen activator receptor, uPAR. Stem Cells. 1997; 15 (6): 398–408. DOI: 10.1002/stem.150398. PMID: 9402652Plesner T., Behrendt N., Ploug M. Structure, function and expression on blood and bone marrow cells of the urokinase-type plasminogen activator receptor, uPAR. Stem Cells. 1997; 15 (6): 398–408. DOI: 10.1002/stem.150398. PMID: 9402652Gårdsvoll H., Danø K., Ploug M. Mapping part of the functional epitope for ligand binding on the receptor for urokinase-type plasminogen activator by site-directed mutagenesis. J. Biol. Chem. 1999; 274 (53): 37995– 8003. DOI: 10.1074/jbc.274.53.37995. PMID: 10608868Gårdsvoll H., Danø K., Ploug M. Mapping part of the functional epitope for ligand binding on the receptor for urokinase-type plasminogen activator by site-directed mutagenesis. J. Biol. Chem. 1999; 274 (53): 37995– 8003. DOI: 10.1074/jbc.274.53.37995. PMID: 10608868Xu X., Gårdsvoll H., Yuan C., Lin L., Ploug M., Huang M. Crystal structure of the urokinase receptor in a ligand-free form. J. Mol. Biol. 2012; 416 (5): 629–641. DOI: 10.1016/j.jmb.2011.12.058. PMID: 22285761Xu X., Gårdsvoll H., Yuan C., Lin L., Ploug M., Huang M. Crystal structure of the urokinase receptor in a ligand-free form. J. Mol. Biol. 2012; 416 (5): 629–641. DOI: 10.1016/j.jmb.2011.12.058. PMID: 22285761Kjaergaard M., Hansen L.V., Jacobsen B., Gardsvoll H., Ploug M. Structure and ligand iinteractions of the urokinase(uPAR). Front. Biosci. 2008; 13: 5441-5461. DOI: 10.2741/3092. PMID: 18508598Kjaergaard M., Hansen L.V., Jacobsen B., Gardsvoll H., Ploug M. Structure and ligand iinteractions of the urokinase(uPAR). Front. Biosci. 2008; 13: 5441-5461. DOI: 10.2741/3092. PMID: 18508598Annis M.G., Ouellet V., Rennhack J.P., L’Esperance S., Rancourt C., Mes-Masson A.M., Andrechek E.R., Siegel P.M. Integrin-uPAR signaling leads to FRA-1 phosphorylation and enhanced breast cancer invasion. Breast Cancer Res. 2018; 20 (1): 9. DOI: 10.1186/s13058-018-0936-8. PMID: 29382358Annis M.G., Ouellet V., Rennhack J.P., L’Esperance S., Rancourt C., Mes-Masson A.M., Andrechek E.R., Siegel P.M. Integrin-uPAR signaling leads to FRA-1 phosphorylation and enhanced breast cancer invasion. Breast Cancer Res. 2018; 20 (1): 9. DOI: 10.1186/s13058-018-0936-8. PMID: 29382358Degryse B., Restani M., Czekay R.P., Loskutoff D.J., Blasi F. Domain 2 of the urokinase receptor contains an integrin-interacting epitope with intrinsic signaling activity: generation of a new integrin inhibitor. J. Biol. Chem. 2005; 280 (26): 24792–24803. DOI: 10.1074/jbc.M413954200. PMID: 15863511Degryse B., Restani M., Czekay R.P., Loskutoff D.J., Blasi F. Domain 2 of the urokinase receptor contains an integrin-interacting epitope with intrinsic signaling activity: generation of a new integrin inhibitor. J. Biol. Chem. 2005; 280 (26): 24792–24803. DOI: 10.1074/jbc.M413954200. PMID: 15863511Elen G., Archinti M., Arnaudova R., Andreotti G., Motta A., Furlan F., Citro V., Cubellis M.V., Degryse B. D2A sequence of the urokinase receptor induces cell growth through v 3 integrin and EGFR. Cell Mol. Life Sci. 2018; 75 (10): 1889–1907. DOI: 10.1007/s00018-017-2718-3. PMID: 29184982Elen G., Archinti M., Arnaudova R., Andreotti G., Motta A., Furlan F., Citro V., Cubellis M.V., Degryse B. D2A sequence of the urokinase receptor induces cell growth through v 3 integrin and EGFR. Cell Mol. Life Sci. 2018; 75 (10): 1889–1907. DOI: 10.1007/s00018-017-2718-3. PMID: 29184982Hu J., Muller K.A., Furnari F.B., Cavenee W.K., VandenBerg S.R., Gonias S.L. Neutralizing the EGF receptor in glioblastoma cells stimulates cell migration by activating uPAR-initiated cell signaling. Oncogene. 2015; 34 (31): 4078–4088. DOI: 10.1038/onc.2014.336. PMID: 25347738Hu J., Muller K.A., Furnari F.B., Cavenee W.K., VandenBerg S.R., Gonias S.L. Neutralizing the EGF receptor in glioblastoma cells stimulates cell migration by activating uPAR-initiated cell signaling. Oncogene. 2015; 34 (31): 4078–4088. DOI: 10.1038/onc.2014.336. PMID: 25347738Tarighi P., Montazeri H., Khorramizadeh M.R., Sobhani A.M., Ostad S.N., Ghahremani M.H. uPAR peptide antagonist alters regulation of MAP kinases and Bcl-2 family members in favoof apoptosis in MDA-MB-231 cell line. Res. Pharm. Sci. 2015; 10 (3): 200–205. PMID: 26600846Tarighi P., Montazeri H., Khorramizadeh M.R., Sobhani A.M., Ostad S.N., Ghahremani M.H. uPAR peptide antagonist alters regulation of MAP kinases and Bcl-2 family members in favoof apoptosis in MDA-MB-231 cell line. Res. Pharm. Sci. 2015; 10 (3): 200–205. PMID: 26600846Liu X., Qiu F., Liu Z., Lan Y., Wang K., Zhou P.K., Wang Y., Hua Z.C. Urokinase-type plasminogen activator receptor regulates apoptotic sensitivity of colon cancer HCT116 cell line to TRAIL via JNK-p53 pathway. Apoptosis. 2014; 19 (10): 1532–1544. DOI: 10.1007/s10495-014-10259. PMID: 25113506Liu X., Qiu F., Liu Z., Lan Y., Wang K., Zhou P.K., Wang Y., Hua Z.C. Urokinase-type plasminogen activator receptor regulates apoptotic sensitivity of colon cancer HCT116 cell line to TRAIL via JNK-p53 pathway. Apoptosis. 2014; 19 (10): 1532–1544. DOI: 10.1007/s10495-014-1025-9. PMID: 25113506Larusch G.A., Merkulova A., Mahdi F., Shariat-Madar Z., Sitrin R.G., Cines D.B., Schmaier A.H. Domain 2 of uPAR regulates single-chain urokinase-mediated angiogenesis through 1-integrin and VEGFR2. Am. J. Physiol. Heart Circ. Physiol. 2013; 305 (3): H305-H320. DOI: 10.1152/ajpheart.00110.2013. PMID: 23709605Larusch G.A., Merkulova A., Mahdi F., Shariat-Madar Z., Sitrin R.G., Cines D.B., Schmaier A.H. Domain 2 of uPAR regulates single-chain urokinase-mediated angiogenesis through 1-integrin and VEGFR2. Am. J. Physiol. Heart Circ. Physiol. 2013; 305 (3): H305-H320. DOI: 10.1152/ajpheart.00110.2013. PMID: 23709605Hekenne S., Paques C., Nivelles O., Lion M., Bajou K., Pollenus T., Fontaine M., Carmeliet P., Martia J.A., Nguyen N.Q., Struman I. The interaction of uPAR with VEGFR2 promotes VEGF-induced angiog angiogenesis. Sci. Signal. 2015; 8 (403): ra117. DOI: 10.1126/scisignal.aaa2403. PMID: 26577922Hekenne S., Paques C., Nivelles O., Lion M., Bajou K., Pollenus T., Fontaine M., Carmeliet P., Martia J.A., Nguyen N.Q., Struman I. The interaction of uPAR with VEGFR2 promotes VEGF-induced angiog angiogenesis. Sci. Signal. 2015; 8 (403): ra117. DOI: 10.1126/scisignal.aaa2403. PMID: 26577922Montuori N., Pesapane A., Rossi F.W., Giudice V., De Paulis A., Selleri C., Ragno P. Urokinase type plasminogen activator receptor (uPAR) as a new therapeutic target in cancer. Transl. Med. UniSa. 2016; 15: 15–21. PMID: 27896223Montuori N., Pesapane A., Rossi F.W., Giudice V., De Paulis A., Selleri C., Ragno P. Urokinase type plasminogen activator receptor (uPAR) as a new therapeutic target in cancer. Transl. Med. UniSa. 2016; 15: 15–21. PMID: 27896223Montuori N., Visconte V., Rossi G., Ragno P. Soluble and cleaved forms of the urokinase-receptor: degradation products or active molecules? Thromb. Haemost. 2005; 93 (2): 192–198. DOI: 10.1160/TH04-09-0580. PMID: 15711732Montuori N., Visconte V., Rossi G., Ragno P. Soluble and cleaved forms of the urokinasereceptor: degradation products or active molecules? Thromb. Haemost. 2005; 93 (2): 192–198. DOI: 10.1160/TH04-09-0580. PMID: 15711732Høyer-Hansen G., Ploug M., Behrendt N., Rønne E., Danø K. Cell surface acceleration of urokinase-catalyzed receptor cleavage. Eur. J. Biochem. 1997; 243 (1-2): 21–26. DOI: 10.1111/j.1432-1033.1997.0021a.x. PMID: 9030717Høyer-Hansen G., Ploug M., Behrendt N., Rønne E., Danø K. Cell surface acceleration of urokinase-catalyzed receptor cleavage. Eur. J. Biochem. 1997; 243 (1-2): 21–26. DOI: 10.1111/j.1432-1033.1997.0021a.x. PMID: 9030717Mazar A.P. Urokinase plasminogen activator receptor choreographs multiple ligand interactions: implications for tumor progression and therapy. Clin. Cancer Res. 2008; 14 (18): 5649–5655. DOI: 10.1158/1078-0432.CCR-07-4863. PMID: 18794071Mazar A.P. Urokinase plasminogen activator receptor choreographs multiple ligand interactions: implications for tumor progression and therapy. Clin. Cancer Res. 2008; 14 (18): 5649–5655. DOI: 10.1158/1078-0432.CCR-07-4863. PMID: 18794071Stillfried G.E., Saunders D.N., Ranson M. Plasminogen binding and activation at the breast cancer cell surface: the integral role of urokinase activity. Breast Cancer Res. 2007; 9 (1): R14. DOI: 10.1186/bcr1647. PMID: 17257442Stillfried G.E., Saunders D.N., Ranson M. Plasminogen binding and activation at the breast cancer cell surface: the integral role of urokinase activity. Breast Cancer Res. 2007; 9 (1): R14. DOI: 10.1186/bcr1647. PMID: 17257442Ploug M. Structure-function relationships in the interaction between the urokinase-type plasminogen activator and its receptor. Curr. Pharm. Des. 2003; 9 (19): 1499–1528. DOI: 10.2174/1381612033454630. PMID: 12871065Ploug M. Structure-function relationships in the interaction between the urokinase-type plasminogen activator and its receptor. Curr. Pharm. Des. 2003; 9 (19): 1499–1528. DOI: 10.2174/1381612033454630. PMID: 12871065Bao Y.N., Cao X., Luo D.H., Sun R., Peng L.X., Wang L., Yan Y.P., Zheng L.S., Xie P., Cao Y., Liang Y.Y., Zheng F.J., Huang B.J., Xiang Y.Q., Lv X., Chen Q.Y., Chen M.Y., Huang P.Y., Guo L., Mai H.Q., Guo X., Zeng Y.X., Qian C.N. Urokinase-type plasminogen activator receptor signaling is critical in nasopharyngeal carcinoma cell growth and metastasis. Cell Cycle. 2014; 13 (12): 1958–1969. DOI: 10.4161/cc.28921. PMID: 24763226Bao Y.N., Cao X., Luo D.H., Sun R., Peng L.X., Wang L., Yan Y.P., Zheng L.S., Xie P., Cao Y., Liang Y.Y., Zheng F.J., Huang B.J., Xiang Y.Q., Lv X., Chen Q.Y., Chen M.Y., Huang P.Y., Guo L., Mai H.Q., Guo X., Zeng Y.X., Qian C.N. Urokinase-type plasminogen activator receptor signaling is critical in nasopharyngeal carcinoma cell growth and metastasis. Cell Cycle. 2014; 13 (12): 1958–1969. DOI: 10.4161/cc.28921. PMID: 24763226Fleetwood A.J., Achuthan A., Schultz H., Nansen A., Almholt K., Usher P., Hamilton J.A. Urokinase plasminogen activator is a central regulator of macrophage three-dimensional invasion, matrix degradation, and adhesion. J. Immunol. 2014; 192 (8): 3540–3547. DOI: 10.4049/jimmunol. 1302864. PMID: 24616477Fleetwood A.J., Achuthan A., Schultz H., Nansen A., Almholt K., Usher P., Hamilton J.A. Urokinase plasminogen activator is a central regulator of macrophage three-dimensional invasion, matrix degradation, and adhesion. J. Immunol. 2014; 192 (8): 3540–3547. DOI: 10.4049/jimmunol. 1302864. PMID: 24616477Crriero M.V., Stopelli M.P. The urokinase-type plasminogen activator and the generation of inhibitors activity and signaling. Curr. Pharm. Des. 2011; 17 (19): 1944-1961. DOI: 10.2174/138161211796718143. PMID: 21711236Crriero M.V., Stopelli M.P. The urokinase-type plasminogen activator and the generation of inhibitors activity and signaling. Curr. Pharm. Des. 2011; 17 (19): 1944-1961. DOI: 10.2174/138161211796718143. PMID: 21711236Ellis V., Wun T.C., Behrendt N., Rønne E., Danø K. Inhibition of receptor-bound urokinase by plasminogen-activator inhibitors. J. Biol. Chem. 1990; 265 (17): 9904–9908. PMID: 2161846Ellis V., Wun T.C., Behrendt N., Rønne E., Danø K. Inhibition of receptor-bound urokinase by plasminogen-activator inhibitors. J. Biol. Chem. 1990; 265 (17): 9904–9908. PMID: 2161846Stefansson S., McMahon G.A., Petitclerc E., Lawrence D.A. Plasminogen activator inhibitor-1 in tumor growth, angiogenesis and vascular remodeling. Curr. Pharm. Des. 2003; 9 (19): 1545–1564. DOI: 10.2174/ 1381612033454621. PMID: 12871067Stefansson S., McMahon G.A., Petitclerc E., Lawrence D.A. Plasminogen activator inhibitor-1 in tumor growth, angiogenesis and vascular remodeling. Curr. Pharm. Des. 2003; 9 (19): 1545–1564. DOI: 10.2174/ 1381612033454621. PMID: 12871067Dellas C., Loskutoff D. J. Historical analysis of PAI-1 from its discovery to its potential role in cell motility and disease. Thromb. Haemost. 2005; 93 (4): 631–640. DOI: 10.1160/TH05-01-0033. PMID: 15841306Dellas C., Loskutoff D. J. Historical analysis of PAI-1 from its discovery to its potential role in cell motility and disease. Thromb. Haemost. 2005; 93 (4): 631–640. DOI: 10.1160/TH05-01-0033. PMID: 15841306Placencio V.R., DeClerck Y.A. Plasminogen activator inhibitor-1 in cancer: rationale and insight for future therapeutic testing. Cancer Res. 2015; 75 (15): 2969–2974. DOI: 10.1158/0008-5472.CAN-15-0876. PMID: 26180080Placencio V.R., DeClerck Y.A. Plasminogen activator inhibitor-1 in cancer: rationale and insight for future therapeutic testing. Cancer Res. 2015; 75 (15): 2969–2974. DOI: 10.1158/0008-5472.CAN-15-0876. PMID: 26180080Nagamine Y., Medcaf R.L., Muñoz-Cánoves P. Transcriptional and posttranscriptional regulation of the plasminogen activator system. Thromb. Haemost. 2005; 93 (4): 661–675. DOI: 10.1160/TH04-12-0814. PMID: 15841310Nagamine Y., Medcaf R.L., Muñoz-Cánoves P. Transcriptional and posttranscriptional regulation of the plasminogen activator system. Thromb. Haemost. 2005; 93 (4): 661–675. DOI: 10.1160/TH04-12-0814. PMID: 15841310Croucher D.R., Saunders D.N., Lobov S., Ranson M. Revisiting the biological roles of PAI2 (SERPINB2) in cancer. Nat. Rev. Cancer. 2008; 8 (7): 535–545. DOI: 10.1038/nrc2400. PMID: 18548086Croucher D.R., Saunders D.N., Lobov S., Ranson M. Revisiting the biological roles of PAI2 (SERPINB2) in cancer. Nat. Rev. Cancer. 2008; 8 (7): 535–545. DOI: 10.1038/nrc2400. PMID: 18548086Harris N.L.E., Vennin C., Conway J.R.W., Vine K.L., Pinese M., Cowley M.J., Shearer R.F., Lucas M.C., Herrmann D., Allam A.H., Pajic M., Morton J.P.; Australian Pancreatic Cancer Genome Initiative, Biankin A.V., Ranson M., Timpson P., Saunders D.N. SerpinB2 regulates stromal remodelling and local invasion in pancreatic cancer. Oncogene. 2017; 36 (30): 4288–4298. DOI: 10.1038/onc.2017.63. PMID: 28346421Harris N.L.E., Vennin C., Conway J.R.W., Vine K.L., Pinese M., Cowley M.J., Shearer R.F., Lucas M.C., Herrmann D., Allam A.H., Pajic M., Morton J.P.; Australian Pancreatic Cancer Genome Initiative, Biankin A.V., Ranson M., Timpson P., Saunders D.N. SerpinB2 regulates stromal remodelling and local invasion in pancreatic cancer. Oncogene. 2017; 36 (30): 4288–4298. DOI: 10.1038/onc.2017.63. PMID: 28346421Kumar S., Baglioni C. Protection from tumor necrosis factor mediated cytolysis by overexpression of plasminogen activator inhibitor type-2. J. Biol. Chem. 1991; 266 (31): 20960–20964. PMID: 1939146Kumar S., Baglioni C. Protection from tumor necrosis factor mediated cytolysis by overexpression of plasminogen activator inhibitor type-2. J. Biol. Chem. 1991; 266 (31): 20960–20964. PMID: 1939146Dickinson J.L., Bates E.J., Ferrante A., Antalis T.M. Plasminogen activator inhibitor type 2 inhibits tumor necrosis factor alpha-induced apoptosis. Evidence for an alternate biological function. J. Biol. Chem. 1995; 270 (46): 27894–27904. DOI: 10.1074/jbc.270.46.27894. PMID: 7499264Dickinson J.L., Bates E.J., Ferrante A., Antalis T.M. Plasminogen activator inhibitor type 2 inhibits tumor necrosis factor alpha-induced apoptosis. Evidence for an alternate biological function. J. Biol. Chem. 1995; 270 (46): 27894–27904. DOI: 10.1074/jbc.270.46.27894. PMID: 7499264McMahon B.J., Kwaan H.C. Components of the plasminogen-plasmin as biologic markers for cancer. Adv. Exp. Med. Biol. 2015; 867: 145-156. DOI: 10.1007/978-94-017-7215-0_10. PMID: 26530365McMahon B.J., Kwaan H.C. Components of the plasminogen-plasmin as biologic markers for cancer. Adv. Exp. Med. Biol. 2015; 867: 145-156. DOI: 10.1007/978-94-017-7215-0_10. PMID: 26530365Su S.C., Lin C.W., Yang W.E., Fan W.I., Yang S.F. The urokinase-type hlasminogen activator (uPA) system as a biomarker and therapeutic target in human malignancies. Expert. Opin. Ther. Targets. 2016; 20 (5): 551-566. DOI: 10.1517/14728222.2016.1113260. PMID: 26667094Su S.C., Lin C.W., Yang W.E., Fan W.I., Yang S.F. The urokinase-type hlasminogen activator (uPA) system as a biomarker and therapeutic target in human malignancies. Expert. Opin. Ther. Targets. 2016; 20 (5): 551-566. DOI: 10.1517/14728222.2016.1113260. PMID: 26667094Amar S., Smith I., Fields G.B. Matrix metalloproteinase collagenolysis in health and disease. Biochem. Biophys. Acta. 2017; 1864 (11 Pt A): 1940-1951. DOI: 10.1016/j.bbamcr.2017.04.015. PMID: 28456643Amar S., Smith I., Fields G.B. Matrix metalloproteinase collagenolysis in health and disease. Biochem. Biophys. Acta. 2017; 1864 (11 Pt A): 1940-1951. DOI: 10.1016/j.bbamcr.2017.04.015. PMID: 28456643Воротников А.В. Хемотаксис: движение, направление, управление. Успехи биолог. химии. 2011; 51: 335-4000.Vorotnikov A.V. Chemotaxis: movement, direction, control. Uspekhi Biologicheskoi Khimii. 2011; 51: 335-400. [In Russ.]Del Rosso M., Fibbi G., Pucci M., Margheri F., Serrati S. The plasminogen activationn system in inflammation. Front. Biosci. 2008; 13: 4667-4686. DOI: 10.2741/3032. PMID: 18508538Del Rosso M., Fibbi G., Pucci M., Margheri F., Serrati S. The plasminogen activationn system in inflammation. Front. Biosci. 2008; 13: 4667-4686. DOI: 10.2741/3032. PMID: 18508538Del Rosso M., Margheri F., Serrati S., Chillà A., Laurenzana A., Fibbi G. The urokinase receptor system, a key regulator at the intersection between inflammation, immunity, and coagulation. Curr. Pharm. Des. 2011; 17 (19): 1924-1943. DOI: 10.2174/138161211796718189. PMID: 21711238Del Rosso M., Margheri F., Serrati S., Chillà A., Laurenzana A., Fibbi G. The urokinase receptor system, a key regulator at the intersection between inflammation, immunity, and coagulation. Curr. Pharm. Des. 2011; 17 (19): 1924-1943. DOI: 10.2174/138161211796718189. PMID: 21711238Reichel C.A., Kanse S.M., Krombach F. At the interface of fibrinolysis and inflammation: the role of urokinase-type plasminogen activator in the leukocyte extravasation casrade. Trends Cardiovasc. Med. 2012; 22 (7): 192-196. DOI: /10.1016/j.tcm.2012.07.019. PMID: 23062972Reichel C.A., Kanse S.M., Krombach F. At the interface of fibrinolysis and inflammation: the role of urokinase-type plasminogen activator in the leukocyte extravasation casrade. Trends Cardiovasc. Med. 2012; 22 (7): 192-196. DOI: /10.1016/j.tcm.2012.07.019. PMID: 23062972Schuliga M., Westall G., Xia Y., Stewart A.G. The plasminogen activation system: new targets in lung inflammation and remodeling. Curr. Opin. Pharmacol. 2013; 13 (3): 386-393. DOI: 10.1016/j.coph.2013.05.014. PMID: 23735578Schuliga M., Westall G., Xia Y., Stewart A.G. The plasminogen activation system: new targets in lung inflammation and remodeling. Curr. Opin. Pharmacol. 2013; 13 (3): 386-393. DOI: 10.1016/j.coph.2013.05.014. PMID: 23735578Жалядов А.С., Баландина А.Н., Купраш А.Д., Шривактава А., Шибеко А.М. Современные представления о системе фибринолиза и методах диагностики ее нарушений. Вопросы гематол./онкол. иммунопатол. в педиатрии. 2017; 16 (1): 69-82.Zhalyadov A.S., Balandina A.N., Kuprash A.D., Shrivaktava A., Shibeko A.M. The overview of fibrinolysis system contemporary concepts and of its disorders diagnostic methods. Voprosy Gematologii/Onkologii i Immunopatologii v Pediatrii. 2017; 16 (1): 69-82. [In Russ.]Binder B.R. Physiology and pathophysiology of the fibrinolytic system. Fibrinolysis. 1995; 9 (Suppl. 1): 3–8. DOI: 10.1016/S0268-9499(05)80002-5Binder B.R. Physiology and pathophysiology of the fibrinolytic system. Fibrinolysis. 1995; 9 (Suppl. 1): 3–8. DOI: 10.1016/S0268-9499(05)80002-5Lijnen H.R., Collen D. Mechanisms of physiological fibrinolysis. Baillieres Clin. Haematol. 1995; 8 (2): 277–290. DOI: 10.1016/S0950-3536(05)80268-9. PMID: 7549063Lijnen H.R., Collen D. Mechanisms of physiological fibrinolysis. Baillieres Clin. Haematol. 1995; 8 (2): 277–290. DOI: 10.1016/S0950-3536(05)80268-9. PMID: 7549063Lino N., Fiore L., Rapacioli M., Teruel L., Flores V., Scicolone G., Sánchez V. uPA-uPAR molecular complex is involved in cell signaling during neuronal migration and neuritogenesis. Dev. Dyn. 2014; 243 (5): 676–689. DOI: 10.1002/dvdy.24114. PMID: 24481918Lino N., Fiore L., Rapacioli M., Teruel L., Flores V., Scicolone G., Sánchez V. uPA-uPAR molecular complex is involved in cell signaling during neuronal migration and neuritogenesis. Dev. Dyn. 2014; 243 (5): 676–689. DOI: 10.1002/dvdy.24114. PMID: 24481918Semina E., Rubina K., Sysoeva V., Rysenkova K., Klimovich P., Plekhanova O., Tkachuk V. Urokinase and urokinase receptor participate in regulation of neuronal migration, axon growth and branching. Eur. J. Cell. Biol. 2016; 95 (9): 295–310. DOI: 10.1016/j.ejcb.2016.05.003. PMID: 27324124Semina E., Rubina K., Sysoeva V., Rysenkova K., Klimovich P., Plekhanova O., Tkachuk V. Urokinase and urokinase receptor participate in regulation of neuronal migration, axon growth and branching. Eur. J. Cell. Biol. 2016; 95 (9): 295–310. DOI: 10.1016/j.ejcb.2016.05.003. PMID: 27324124Merino P., Diaz A., Jeanneret V., Wu F., Torre E., Cheng L., Yepes M. Urokinase-type plasminogen activator (uPA) binding to the uPA receptor (uPAR) promotes axonal regeneration in the central nervous system. J. Biol. Chem. 2017; 292 (7): 2741–2753. DOI: 10.1074/jbc.M116.761650. PMID: 27986809Merino P., Diaz A., Jeanneret V., Wu F., Torre E., Cheng L., Yepes M. Urokinase-type plasminogen activator (uPA) binding to the uPA receptor (uPAR) promotes axonal regeneration in the central nervous system. J. Biol. Chem. 2017; 292 (7): 2741–2753. DOI: 10.1074/jbc.M116.761650. PMID: 27986809Diaz A., Merino P., Manrique L.G., Ospina J.P., Cheng L., Wu F., Jeanneret V., Yepes M. A cross talk between neuronal urokinase-type plasminogen activator (uPA) and astrocytic uPA receptor (uPAR) promotes astrocytic activation and synaptic recovery in the ischemic brain. J. Neurosci. 2017; 37 (43): 10310–10322. DOI: 10.1523/JNEUROSCI.1630-17.2017. PMID: 28931568Diaz A., Merino P., Manrique L.G., Ospina J.P., Cheng L., Wu F., Jeanneret V., Yepes M. A cross talk between neuronal urokinase-type plasminogen activator (uPA) and astrocytic uPA receptor (uPAR) promotes astrocytic activation and synaptic recovery in the ischemic brain. J. Neurosci. 2017; 37 (43): 10310–10322. DOI: 10.1523/JNEUROSCI.1630-17.2017. PMID: 28931568

The authors declare that there are no conflicts of interest present.