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CC BY 4.0 · TH Open 2025; 09: a26984219
DOI: 10.1055/a-2698-4219
Review Article

A Contemporary Review of Plasminogen Activator Inhibitor Type 1: Structure, Function, Genetic Architecture, and Intracellular/Extracellular Roles

Authors

  • Jacob Wortley‡   *

    1   Sathyamoorthy Laboratory, Department of Medicine, Burnett School of Medicine at TCU, Fort Worth, Texas, United States

  • Justin Vu‡   *

    1   Sathyamoorthy Laboratory, Department of Medicine, Burnett School of Medicine at TCU, Fort Worth, Texas, United States

  • Neha Soogoor

    1   Sathyamoorthy Laboratory, Department of Medicine, Burnett School of Medicine at TCU, Fort Worth, Texas, United States

  • Mebeli Becerra

    1   Sathyamoorthy Laboratory, Department of Medicine, Burnett School of Medicine at TCU, Fort Worth, Texas, United States

  • Mohanakrishnan Sathyamoorthy 

    1   Sathyamoorthy Laboratory, Department of Medicine, Burnett School of Medicine at TCU, Fort Worth, Texas, United States
    2   Department of Cardiovascular Medicine and Science, Fort Worth Institute for Molecular Medicine and Genomics Research, Fort Worth, Texas, United States
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Abstract

Plasminogen activator inhibitor type 1 (PAI-1) is the key regulator of the fibrinolytic system, thereby acting as a potent mediator in thrombosis. Plasminogen activators such as PAI-1 mediate the conversion of the inactive zymogen plasminogen to plasmin, an active serine protease. As a member of the serpin superfamily, the highly conserved structure of PAI-1 is critical for its regulatory function. This review elucidates PAI-1 structure, function, and genetic architecture, and then discusses intracellular and extracellular functions that have broad implications for proliferative signaling and cell death, angiogenesis, cellular transit, and emerging roles in cancer biology. By understanding the complex and elaborate mechanism of PAI-1 in the fibrinolytic system and as a biomarker, PAI-1 may have broad implications across many disease states not related to its historical roles in fibrinolysis and thrombosis.

Keywords

PAI-1 - extracellular matrix - genetics - fibrinolytic system - cell migration - cell proliferation

Authors' Contributions

Conceptualization, methodology, formal analysis, investigation M.S., J.W., writing—original draft preparation J.W., J.V., N.S., M.B., M.S., writing—review and editing M.S., J.W., J.V., N.S., M.B., visualization, supervision, project administration, and funding acquisition: M.S.. All authors have read and agreed to the published version of the article.


* These authors are co-first authors who contributed equally to this article.




Publikationsverlauf

Eingereicht: 24. Januar 2025

Angenommen: 15. Juli 2025

Accepted Manuscript online:
10. September 2025

Artikel online veröffentlicht:
26. September 2025

© 2025. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)

Georg Thieme Verlag KG
Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany

Bibliographical Record
Jacob Wortley, Justin Vu, Neha Soogoor, Mebeli Becerra, Mohanakrishnan Sathyamoorthy. A Contemporary Review of Plasminogen Activator Inhibitor Type 1: Structure, Function, Genetic Architecture, and Intracellular/Extracellular Roles. TH Open 2025; 09: a26984219.
DOI: 10.1055/a-2698-4219
 

  • References

  • 1 Sottrup-Jensen L, Zajdel M, Claeys H, Petersen TE, Magnusson S. Amino-acid sequence of activation cleavage site in plasminogen: homology with “pro” part of prothrombin. Proc Natl Acad Sci U S A 1975; 72 (07) 2577-2581
    Suche in Google Scholar
  • 2 Choong PFM, Nadesapillai APW. Urokinase plasminogen activator system: a multifunctional role in tumor progression and metastasis. Clin Orthop Relat Res 2003; ;(415 Suppl): S46-S58
    Suche in Google Scholar
  • 3 Macfarlane RG, Pilling J. Fibrinolytic activity of normal urine. Nature 1947; 159 (4049) 779
    Suche in Google Scholar
  • 4 Jung RG, Motazedian P, Ramirez FD. et al. Association between plasminogen activator inhibitor-1 and cardiovascular events: a systematic review and meta-analysis. Thromb J 2018; 16: 12
    Suche in Google Scholar
  • 5 Saes JL, Schols SEM, van Heerde WL, Nijziel MR. Hemorrhagic disorders of fibrinolysis: a clinical review. J Thromb Haemost 2018; (E-pub ahead of print)
    Suche in Google Scholar
  • 6 Wang Y, Dang J, Johnson LK, Selhamer JJ, Doe WF. Structure of the human urokinase receptor gene and its similarity to CD59 and the Ly-6 family. Eur J Biochem 1995; 227 (1-2): 116-122
    Suche in Google Scholar
  • 7 Appella E, Robinson EA, Ullrich SJ. et al. The receptor-binding sequence of urokinase. A biological function for the growth-factor module of proteases. J Biol Chem 1987; 262 (10) 4437-4440
    Suche in Google Scholar
  • 8 Alfano D, Franco P, Vocca I. et al. The urokinase plasminogen activator and its receptor: role in cell growth and apoptosis. Thromb Haemost 2005; 93 (02) 205-211
    Suche in Google Scholar
  • 9 Mahmood N, Mihalcioiu C, Rabbani SA. Multifaceted role of the urokinase-type plasminogen activator (uPA) and its receptor (uPAR): Diagnostic, prognostic, and therapeutic applications. Front Oncol 2018; 8: 24
    Suche in Google Scholar
  • 10 Roldan AL, Cubellis MV, Masucci MT. et al. Cloning and expression of the receptor for human urokinase plasminogen activator, a central molecule in cell surface, plasmin dependent proteolysis. EMBO J 1990; 9 (02) 467-474
    Suche in Google Scholar
  • 11 Alfano D, Franco P, Stoppelli MP. Modulation of cellular function by the urokinase receptor signalling: A mechanistic view. Front Cell Dev Biol 2022; 10: 818616
    Suche in Google Scholar
  • 12 Huai Q, Zhou A, Lin L. et al. Crystal structures of two human vitronectin, urokinase and urokinase receptor complexes. Nat Struct Mol Biol 2008; 15 (04) 422-423
    Suche in Google Scholar
  • 13 Mertens HDT, Kjaergaard M, Mysling S. et al. A flexible multidomain structure drives the function of the urokinase-type plasminogen activator receptor (uPAR). J Biol Chem 2012; 287 (41) 34304-34315
    Suche in Google Scholar
  • 14 Leth JM, Leth-Espensen KZ, Kristensen KK. et al. Evolution and medical significance of LU domain-containing proteins. Int J Mol Sci 2019; 20 (11) 2760
    Suche in Google Scholar
  • 15 Degryse B. The urokinase receptor and integrins constitute a cell migration signalosome. In: Edwards D, Høyer-Hansen G, Blasi F, Sloane BF. eds. The Cancer Degradome: Proteases and Cancer Biology. New York, NY: Springer New York; 2008. :pp. 451–474. Accessed September 11, 2025 at: https://doi.org/10.1007/978-0-387-69057-5_23
    Suche in Google Scholar
  • 16 Sillen M, Miyata T, Vaughan DE, Strelkov SV, Declerck PJ. Structural insight into the two-step mechanism of PAI-1 inhibition by small molecule TM5484. Int J Mol Sci 2021; 22 (03) 1482
    Suche in Google Scholar
  • 17 Sillen M, Declerck PJ. Targeting PAI-1 in cardiovascular disease: Structural insights into PAI-1 functionality and inhibition. Front Cardiovasc Med 2020; 7: 622473 . Accessed September 11, 2025 at: https://www.frontiersin.org/journals/cardiovascular-medicine/articles/10.3389/fcvm.2020.622473
    Suche in Google Scholar
  • 18 Pettersen EF, Goddard TD, Huang CC. et al. UCSF Chimera–a visualization system for exploratory research and analysis. J Comput Chem 2004; 25 (13) 1605-1612
    Suche in Google Scholar
  • 19 van Meijer M, Smilde A, Tans G, Nesheim ME, Pannekoek H, Horrevoets AJG. The suicide substrate reaction between plasminogen activator inhibitor 1 and thrombin is regulated by the cofactors vitronectin and heparin. Blood 1997; 90 (05) 1874-1882
    Suche in Google Scholar
  • 20 Lawrence DA, Strandberg L, Ericson J, Ny T. Structure-function studies of the SERPIN plasminogen activator inhibitor type 1. Analysis of chimeric strained loop mutants. J Biol Chem 1990; 265 (33) 20293-20301
    Suche in Google Scholar
  • 21 Ehrlich HJ, Gebbink RK, Keijer J, Linders M, Preissner KT, Pannekoek H. Alteration of serpin specificity by a protein cofactor. Vitronectin endows plasminogen activator inhibitor 1 with thrombin inhibitory properties. J Biol Chem 1990; 265 (22) 13029-13035
    Suche in Google Scholar
  • 22 Vaughan DE. PAI-1 and atherothrombosis. J Thromb Haemost 2005; 3 (08) 1879-1883
    Suche in Google Scholar
  • 23 Sillen M, Declerck PJ. A narrative review on plasminogen activator inhibitor-1 and its (patho)physiological role: To target or not to target?. Int J Mol Sci 2021; 22 (05) 2721
    Suche in Google Scholar
  • 24 Stefansson S, Lawrence DA. The serpin PAI-1 inhibits cell migration by blocking integrin alpha V beta 3 binding to vitronectin. Nature 1996; 383 (6599) 441-443
    Suche in Google Scholar
  • 25 Nar H, Bauer M, Stassen JM, Lang D, Gils A, Declerck PJ. Plasminogen activator inhibitor 1. Structure of the native serpin, comparison to its other conformers and implications for serpin inactivation. J Mol Biol 2000; 297 (03) 683-695
    Suche in Google Scholar
  • 26 Mottonen J, Strand A, Symersky J. et al. Structural basis of latency in plasminogen activator inhibitor-1. Nature 1992; 355 (6357) 270-273
    Suche in Google Scholar
  • 27 Gong L, Liu M, Zeng T. et al. Crystal structure of the Michaelis complex between tissue-type plasminogen activator and plasminogen activators inhibitor-1. J Biol Chem 2015; 290 (43) 25795-25804 . Accessed September 11, 2025 at: https://www.sciencedirect.com/science/article/pii/S0021925820495602
    Suche in Google Scholar
  • 28 Lin Z, Jiang L, Yuan C. et al. Structural basis for recognition of urokinase-type plasminogen activator by plasminogen activator inhibitor-1. J Biol Chem 2011; 286 (09) 7027-7032 . Accessed September 11, 2025 at: https://www.sciencedirect.com/science/article/pii/S0021925820518978
    Suche in Google Scholar
  • 29 Lawrence DA, Ginsburg D, Day DE. et al. Serpin-protease complexes are trapped as stable acyl-enzyme intermediates. J Biol Chem 1995; 270 (43) 25309-25312 . Accessed September 11, 2025 at: https://www.sciencedirect.com/science/article/pii/S0021925818923203
    Suche in Google Scholar
  • 30 Perron MJ, Blouse GE, Shore JD. Distortion of the catalytic domain of tissue-type plasminogen activator by plasminogen activator inhibitor-1 coincides with the formation of stable serpin-proteinase complexes. J Biol Chem 2003; 278 (48) 48197-48203 . Accessed September 11, 2025 at: https://www.sciencedirect.com/science/article/pii/S0021925820758540
    Suche in Google Scholar
  • 31 Huntington JA, Read RJ, Carrell RW. Structure of a serpin-protease complex shows inhibition by deformation. Nature 2000; 407 (6806) 923-926
    Suche in Google Scholar
  • 32 Gettins PGW, Olson ST. Inhibitory serpins. New insights into their folding, polymerization, regulation and clearance. Biochem J 2016; 473 (15) 2273-2293
    Suche in Google Scholar
  • 33 Dewilde M, Strelkov SV, Rabijns A, Declerck PJ. High quality structure of cleaved PAI-1-stab. J Struct Biol 2009; 165 (02) 126-132 . Accessed September 11, 2025 at: https://www.sciencedirect.com/science/article/pii/S1047847708002670
    Suche in Google Scholar
  • 34 Aertgeerts K, De Bondt HL, De Ranter CJ, Declerck PJ. Mechanisms contributing to the conformational and functional flexibility of plasminogen activator inhibitor-1. Nat Struct Biol 1995; 2 (10) 891-897
    Suche in Google Scholar
  • 35 Declerck PJ, De Mol M, Vaughan DE, Collen D. Identification of a conformationally distinct form of plasminogen activator inhibitor-1, acting as a noninhibitory substrate for tissue-type plasminogen activator. J Biol Chem 1992; 267 (17) 11693-11696
    Suche in Google Scholar
  • 36 Urano T, Strandberg L, Johansson LB, Ny T. A substrate-like form of plasminogen-activator-inhibitor type 1. Conversions between different forms by sodium dodecyl sulphate. Eur J Biochem 1992; 209 (03) 985-992
    Suche in Google Scholar
  • 37 Audenaert AM, Knockaert I, Collen D, Declerck PJ. Conversion of plasminogen activator inhibitor-1 from inhibitor to substrate by point mutations in the reactive-site loop. J Biol Chem 1994; 269 (30) 19559-19564
    Suche in Google Scholar
  • 38 van Meijer M, Smilde A, Tans G, Nesheim ME, Pannekoek H, Horrevoets AJG. The suicide substrate reaction between plasminogen activator inhibitor 1 and thrombin is regulated by the cofactors vitronectin and heparin. Blood 1997; 90 (05) 1874-1882
    Suche in Google Scholar
  • 39 Lawrence DA, Palaniappan S, Stefansson S. et al. Characterization of the binding of different conformational forms of plasminogen activator inhibitor-1 to vitronectin. Implications for the regulation of pericellular proteolysis. J Biol Chem 1997; 272 (12) 7676-7680
    Suche in Google Scholar
  • 40 Declerck PJ, De Mol M, Alessi MC. et al. Purification and characterization of a plasminogen activator inhibitor 1 binding protein from human plasma. Identification as a multimeric form of S protein (vitronectin). J Biol Chem 1988; 263 (30) 15454-15461 . Accessed September 11, 2025 at: https://www.sciencedirect.com/science/article/pii/S0021925819376100
    Suche in Google Scholar
  • 41 Komissarov AA, Andreasen PA, Bødker JS, Declerck PJ, Anagli JY, Shore JD. Additivity in effects of vitronectin and monoclonal antibodies against α-helix F of plasminogen activator inhibitor-1 on its reactions with target proteinases. J Biol Chem 2005; 280 (02) 1482-1489
    Suche in Google Scholar
  • 42 Preissner KT, Grulich-Henn J, Ehrlich HJ. et al. Structural requirements for the extracellular interaction of plasminogen activator inhibitor 1 with endothelial cell matrix-associated vitronectin. J Biol Chem 1990; 265 (30) 18490-18498
    Suche in Google Scholar
  • 43 Jung RG, Simard T, Labinaz A. et al. Role of plasminogen activator inhibitor-1 in coronary pathophysiology. Thromb Res 2018; 164: 54-62
    Suche in Google Scholar
  • 44 Binder BR, Christ G, Gruber F. et al. Plasminogen activator inhibitor 1: physiological and pathophysiological roles. News Physiol Sci 2002; 17: 56-61
    Suche in Google Scholar
  • 45 Carrell RW, Pemberton PA, Boswell DR. The serpins: evolution and adaptation in a family of protease inhibitors. Cold Spring Harb Symp Quant Biol 1987; 52: 527-535
    Suche in Google Scholar
  • 46 Strandberg L, Lawrence D, Ny T. The organization of the human-plasminogen-activator-inhibitor-1 gene. Implications on the evolution of the serine-protease inhibitor family. Eur J Biochem 1988; 176 (03) 609-616
    Suche in Google Scholar
  • 47 Van De Craen B, Declerck PJ, Gils A. The biochemistry, physiology and pathological roles of PAI-1 and the requirements for PAI-1 inhibition in vivo. Thromb Res 2012; 130 (04) 576-585
    Suche in Google Scholar
  • 48 Pannekoek H, Veerman H, Lambers H. et al. Endothelial plasminogen activator inhibitor (PAI): a new member of the Serpin gene family. EMBO J 1986; 5 (10) 2539-2544
    Suche in Google Scholar
  • 49 Ny T, Sawdey M, Lawrence D, Millan JL, Loskutoff DJ. Cloning and sequence of a cDNA coding for the human beta-migrating endothelial-cell-type plasminogen activator inhibitor. Proc Natl Acad Sci U S A 1986; 83 (18) 6776-6780
    Suche in Google Scholar
  • 50 Ginsburg D, Zeheb R, Yang AY. et al. cDNA cloning of human plasminogen activator-inhibitor from endothelial cells. J Clin Invest 1986; 78 (06) 1673-1680
    Suche in Google Scholar
  • 51 Andreasen PA, Riccio A, Welinder KG. et al. Plasminogen activator inhibitor type-1: reactive center and amino-terminal heterogeneity determined by protein and cDNA sequencing. FEBS Lett 1986; 209 (02) 213-218
    Suche in Google Scholar
  • 52 Loskutoff DJ, Linders M, Keijer J, Veerman H, van Heerikhuizen H, Pannekoek H. Structure of the human plasminogen activator inhibitor 1 gene: nonrandom distribution of introns. Biochemistry 1987; 26 (13) 3763-3768
    Suche in Google Scholar
  • 53 Providence KM, White LA, Tang J, Gonclaves J, Staiano-Coico L, Higgins PJ. Epithelial monolayer wounding stimulates binding of USF-1 to an E-box motif in the plasminogen activator inhibitor type 1 gene. J Cell Sci 2002; 115 (Pt 19): 3767-3777
    Suche in Google Scholar
  • 54 Brown NJ, Kim KS, Chen YQ. et al. Synergistic effect of adrenal steroids and angiotensin II on plasminogen activator inhibitor-1 production. J Clin Endocrinol Metab 2000; 85 (01) 336-344
    Suche in Google Scholar
  • 55 van Zonneveld AJ, Curriden SA, Loskutoff DJ. Type 1 plasminogen activator inhibitor gene: functional analysis and glucocorticoid regulation of its promoter. Proc Natl Acad Sci U S A 1988; 85 (15) 5525-5529
    Suche in Google Scholar
  • 56 Skurk T, Lee YM, Hauner H. Angiotensin II and its metabolites stimulate PAI-1 protein release from human adipocytes in primary culture. Hypertension 2001; 37 (05) 1336-1340
    Suche in Google Scholar
  • 57 Eriksson P, Nilsson L, Karpe F, Hamsten A. Very-low-density lipoprotein response element in the promoter region of the human plasminogen activator inhibitor-1 gene implicated in the impaired fibrinolysis of hypertriglyceridemia. Arterioscler Thromb Vasc Biol 1998; 18 (01) 20-26
    Suche in Google Scholar
  • 58 Pont F, Duvillard L, Florentin E, Gambert P, Vergès B. Early kinetic abnormalities of apoB-containing lipoproteins in insulin-resistant women with abdominal obesity. Arterioscler Thromb Vasc Biol 2002; 22 (10) 1726-1732
    Suche in Google Scholar
  • 59 Chen YQ, Su M, Walia RR, Hao Q, Covington JW, Vaughan DE. Sp1 sites mediate activation of the plasminogen activator inhibitor-1 promoter by glucose in vascular smooth muscle cells. J Biol Chem 1998; 273 (14) 8225-8231
    Suche in Google Scholar
  • 60 Song C, Burgess S, Eicher JD, O'Donnell CJ, Johnson AD. Causal effect of plasminogen activator inhibitor type 1 on coronary heart disease. J Am Heart Assoc 2017; 6 (06) e004918
    Suche in Google Scholar
  • 61 Dennler S, Itoh S, Vivien D, ten Dijke P, Huet S, Gauthier JM. Direct binding of Smad3 and Smad4 to critical TGF beta-inducible elements in the promoter of human plasminogen activator inhibitor-type 1 gene. EMBO J 1998; 17 (11) 3091-3100
    Suche in Google Scholar
  • 62 Kunz C, Pebler S, Otte J, von der Ahe D. Differential regulation of plasminogen activator and inhibitor gene transcription by the tumor suppressor p53. Nucleic Acids Res 1995; 23 (18) 3710-3717
    Suche in Google Scholar
  • 63 Boekholdt SM, Bijsterveld NR, Moons AH, Levi M, Büller HR, Peters RJ. Genetic variation in coagulation and fibrinolytic proteins and their relation with acute myocardial infarction: a systematic review. Circulation 2001; 104 (25) 3063-3068
    Suche in Google Scholar
  • 64 Huang J, Sabater-Lleal M, Asselbergs FW. et al; DIAGRAM Consortium, CARDIoGRAM Consortium, C4D Consortium, CARDIOGENICS Consortium. Genome-wide association study for circulating levels of PAI-1 provides novel insights into its regulation. Blood 2012; 120 (24) 4873-4881
    Suche in Google Scholar
  • 65 Koch W, Schrempf M, Erl A. et al. 4G/5G polymorphism and haplotypes of SERPINE1 in atherosclerotic diseases of coronary arteries. Thromb Haemost 2010; 103 (06) 1170-1180
    Suche in Google Scholar
  • 66 Brogren H, Wallmark K, Deinum J, Karlsson L, Jern S. Platelets retain high levels of active plasminogen activator inhibitor 1. PLoS ONE 2011; 6 (11) e26762
    Suche in Google Scholar
  • 67 Culej Bošnjak D, Balent T, Korać P, Antica M, Matulić M. Urokinase plasminogen activation system modulation in transformed cell lines. Int J Mol Sci 2025; 26 (02) 675
    Suche in Google Scholar
  • 68 Ismail AA, Shaker BT, Bajou K. The plasminogen-activator plasmin system in physiological and pathophysiological angiogenesis. Int J Mol Sci 2021; 23 (01) 337
    Suche in Google Scholar
  • 69 De Lorenzi V, Sarra Ferraris GM, Madsen JB, Lupia M, Andreasen PA, Sidenius N. Urokinase links plasminogen activation and cell adhesion by cleavage of the RGD motif in vitronectin. EMBO Rep 2016; 17 (07) 982-998
    Suche in Google Scholar
  • 70 Deng G, Curriden SA, Wang S, Rosenberg S, Loskutoff DJ. Is plasminogen activator inhibitor-1 the molecular switch that governs urokinase receptor-mediated cell adhesion and release?. J Cell Biol 1996; 134 (06) 1563-1571
    Suche in Google Scholar
  • 71 Waltz DA, Natkin LR, Fujita RM, Wei Y, Chapman HA. Plasmin and plasminogen activator inhibitor type 1 promote cellular motility by regulating the interaction between the urokinase receptor and vitronectin. J Clin Invest 1997; 100 (01) 58-67
    Suche in Google Scholar
  • 72 Kjøller L, Kanse SM, Kirkegaard T. et al. Plasminogen activator inhibitor-1 represses integrin- and vitronectin-mediated cell migration independently of its function as an inhibitor of plasminogen activation. Exp Cell Res 1997; 232 (02) 420-429
    Suche in Google Scholar
  • 73 Kozlova N, Jensen JK, Chi TF, Samoylenko A, Kietzmann T. PAI-1 modulates cell migration in a LRP1-dependent manner via β-catenin and ERK1/2. Thromb Haemost 2015; 113 (05) 988-998
    Suche in Google Scholar
  • 74 Binder BR, Mihaly J, Prager GW. uPAR-uPA-PAI-1 interactions and signaling: a vascular biologist's view. Thromb Haemost 2007; 97 (03) 336-342
    Suche in Google Scholar
  • 75 Miszta A, Huskens D, Donkervoort D, Roberts MJM, Wolberg AS, de Laat B. Assessing plasmin generation in health and disease. Int J Mol Sci 2021; 22 (05) 2758 . Accessed September 11, 2025 at: https://research.ebsco.com/linkprocessor/plink?id=5f2e7060-9f50-3319-a570-161dd7908acd
    Suche in Google Scholar
  • 76 Mehic D, Reitsma SE, de Moreuil C. et al. Plasmin generation analysis in patients with bleeding disorder of unknown cause. Blood Adv 2024; 8 (21) 5663-5673
    Suche in Google Scholar
  • 77 Puster LO, Stanley CB, Uversky VN. et al. Characterization of an extensive interface on vitronectin for binding to plasminogen activator inhibitor-1: Adoption of structure in an intrinsically disordered region. Biochemistry 2019; 58 (51) 5117-5134
    Suche in Google Scholar
  • 78 Kihn K, Marchiori E, Spagnolli G. et al. Long-range allostery mediates the regulation of plasminogen activator inhibitor-1 by cell adhesion factor vitronectin. J Biol Chem 2022; 298 (12) 102652
    Suche in Google Scholar
  • 79 Czekay RP, Aertgeerts K, Curriden SA, Loskutoff DJ. Plasminogen activator inhibitor-1 detaches cells from extracellular matrices by inactivating integrins. J Cell Biol 2003; 160 (05) 781-791
    Suche in Google Scholar
  • 80 Webb DJ, Thomas KS, Gonias SL. Plasminogen activator inhibitor 1 functions as a urokinase response modifier at the level of cell signaling and thereby promotes MCF-7 cell growth. J Cell Biol 2001; 152 (04) 741-752
    Suche in Google Scholar
  • 81 Duffy MJ. The urokinase plasminogen activator system: role in malignancy. Curr Pharm Des 2004; 10 (01) 39-49
    Suche in Google Scholar
  • 82 Høyer-Hansen G, Rønne E, Solberg H. et al. Urokinase plasminogen activator cleaves its cell surface receptor releasing the ligand-binding domain. J Biol Chem 1992; 267 (25) 18224-18229
    Suche in Google Scholar
  • 83 Sidenius N, Blasi F. Domain 1 of the urokinase receptor (uPAR) is required for uPAR-mediated cell binding to vitronectin. FEBS Lett 2000; 470 (01) 40-46
    Suche in Google Scholar
  • 84 van Veen M, Matas-Rico E, van de Wetering K. et al. Negative regulation of urokinase receptor activity by a GPI-specific phospholipase C in breast cancer cells. eLife 2017; 6: e23649
    Suche in Google Scholar
  • 85 Fazioli F, Resnati M, Sidenius N, Higashimoto Y, Appella E, Blasi F. A urokinase-sensitive region of the human urokinase receptor is responsible for its chemotactic activity. EMBO J 1997; 16 (24) 7279-7286
    Suche in Google Scholar
  • 86 Bifulco K, Votta G, Ingangi V. et al. Urokinase receptor promotes ovarian cancer cell dissemination through its 84-95 sequence. Oncotarget 2014; 5 (12) 4154-4169
    Suche in Google Scholar
  • 87 Bifulco K, Longanesi-Cattani I, Franco P. et al. Single amino acid substitutions in the chemotactic sequence of urokinase receptor modulate cell migration and invasion. PLoS ONE 2012; 7 (09) e44806
    Suche in Google Scholar
  • 88 Degryse B, Resnati M, Rabbani SA, Villa A, Fazioli F, Blasi F. Src-dependence and pertussis-toxin sensitivity of urokinase receptor-dependent chemotaxis and cytoskeleton reorganization in rat smooth muscle cells. Blood 1999; 94 (02) 649-662
    Suche in Google Scholar
  • 89 Vial D, McKeown-Longo PJ. PAI1 stimulates assembly of the fibronectin matrix in osteosarcoma cells through crosstalk between the alphavbeta5 and alpha5beta1 integrins. J Cell Sci 2008; 121 (Pt 10): 1661-1670
    Suche in Google Scholar
  • 90 Sathyamoorthy M, Matta P, Vaughan DE. Loss of PAI-1 through siRNA increases adhesion of monocytes to vitronectin. 2008
    Suche in Google Scholar
  • 91 Sathyamoorthy M, Matta P, Vaughan DE. PAI-1 deficiency enhances early outgrowth culture expanded and circulating endothelial progenitor cells: Implications for the fibrinolytic system in stem cell biology. 2008
    Suche in Google Scholar
  • 92 Kubala MH, DeClerck YA. The plasminogen activator inhibitor-1 paradox in cancer: a mechanistic understanding. Cancer Metastasis Rev 2019; 38 (03) 483-492
    Suche in Google Scholar
  • 93 McCann JV, Xiao L, Kim DJ. et al. Endothelial miR-30c suppresses tumor growth via inhibition of TGF-β-induced Serpine1. J Clin Invest 2019; 129 (04) 1654-1670
    Suche in Google Scholar
  • 94 Bajou K, Masson V, Gerard RD. et al. The plasminogen activator inhibitor PAI-1 controls in vivo tumor vascularization by interaction with proteases, not vitronectin. Implications for antiangiogenic strategies. J Cell Biol 2001; 152 (04) 777-784
    Suche in Google Scholar
  • 95 Devy L, Blacher S, Grignet-Debrus C. et al. The pro- or antiangiogenic effect of plasminogen activator inhibitor 1 is dose dependent. FASEB J 2002; 16 (02) 147-154
    Suche in Google Scholar
  • 96 Degryse B, Neels JG, Czekay RP, Aertgeerts K, Kamikubo Y, Loskutoff DJ. The low density lipoprotein receptor-related protein is a motogenic receptor for plasminogen activator inhibitor-1. J Biol Chem 2004; 279 (21) 22595-22604
    Suche in Google Scholar
  • 97 Lillis AP, Van Duyn LB, Murphy-Ullrich JE, Strickland DK. LDL receptor-related protein 1: unique tissue-specific functions revealed by selective gene knockout studies. Physiol Rev 2008; 88 (03) 887-918
    Suche in Google Scholar
  • 98 Czekay RP, Loskutoff DJ. Plasminogen activator inhibitors regulate cell adhesion through a uPAR-dependent mechanism. J Cell Physiol 2009; 220 (03) 655-663
    Suche in Google Scholar
  • 99 Gutierrez LS, Schulman A, Brito-Robinson T, Noria F, Ploplis VA, Castellino FJ. Tumor development is retarded in mice lacking the gene for urokinase-type plasminogen activator or its inhibitor, plasminogen activator inhibitor-1. Cancer Res 2000; 60 (20) 5839-5847
    Suche in Google Scholar
  • 100 Estreicher A, Mühlhauser J, Carpentier JL, Orci L, Vassalli JD. The receptor for urokinase type plasminogen activator polarizes expression of the protease to the leading edge of migrating monocytes and promotes degradation of enzyme inhibitor complexes. J Cell Biol 1990; 111 (02) 783-792
    Suche in Google Scholar
  • 101 Kamikubo Y, Neels JG, Degryse B. Vitronectin inhibits plasminogen activator inhibitor-1-induced signalling and chemotaxis by blocking plasminogen activator inhibitor-1 binding to the low-density lipoprotein receptor-related protein. Int J Biochem Cell Biol 2009; 41 (03) 578-585
    Suche in Google Scholar
  • 102 Hou SX, Zheng Z, Chen X, Perrimon N. The Jak/STAT pathway in model organisms: emerging roles in cell movement. Dev Cell 2002; 3 (06) 765-778
    Suche in Google Scholar
  • 103 Czekay RP, Wilkins-Port CE, Higgins SP. et al. PAI-1: An integrator of cell signaling and migration. Int J Cell Biol 2011; 2011: 562481
    Suche in Google Scholar
  • 104 Blasi F, Carmeliet P. uPAR: a versatile signalling orchestrator. Nat Rev Mol Cell Biol 2002; 3 (12) 932-943
    Suche in Google Scholar
  • 105 He Z, Wang G, Wu J, Tang Z, Luo M. The molecular mechanism of LRP1 in physiological vascular homeostasis and signal transduction pathways. Biomed Pharmacother 2021; 139: 111667
    Suche in Google Scholar
  • 106 Ma Z, Thomas KS, Webb DJ. et al. Regulation of Rac1 activation by the low density lipoprotein receptor-related protein. J Cell Biol 2002; 159 (06) 1061-1070
    Suche in Google Scholar
  • 107 Koshelnick Y, Ehart M, Hufnagl P, Heinrich PC, Binder BR. Urokinase receptor is associated with the components of the JAK1/STAT1 signaling pathway and leads to activation of this pathway upon receptor clustering in the human kidney epithelial tumor cell line TCL-598. J Biol Chem 1997; 272 (45) 28563-28567
    Suche in Google Scholar
  • 108 Dumler I, Weis A, Mayboroda OA. et al. The Jak/Stat pathway and urokinase receptor signaling in human aortic vascular smooth muscle cells. J Biol Chem 1998; 273 (01) 315-321
    Suche in Google Scholar
  • 109 Dumler I, Kopmann A, Wagner K. et al. Urokinase induces activation and formation of Stat4 and Stat1-Stat2 complexes in human vascular smooth muscle cells. J Biol Chem 1999; 274 (34) 24059-24065
    Suche in Google Scholar
  • 110 Andreasen PA, Kjøller L, Christensen L, Duffy MJ. The urokinase-type plasminogen activator system in cancer metastasis: a review. Int J Cancer 1997; 72 (01) 1-22
    Suche in Google Scholar
  • 111 Hundsdorfer B, Zeilhofer HF, Bock KP, Dettmar P, Schmitt M, Horch HH. [The prognostic importance of urinase type plasminogen activators (uPA) and plasminogen activator inhibitors (PAI-1) in the primary resection of oral squamous cell carcinoma]. Mund Kiefer Gesichtschir 2004; 8 (03) 173-179
    Suche in Google Scholar
  • 112 Durand MKV, Bødker JS, Christensen A. et al. Plasminogen activator inhibitor-I and tumour growth, invasion, and metastasis. Thromb Haemost 2004; 91 (03) 438-449
    Suche in Google Scholar
  • 113 Kelly TE, Spillane CL, Ward MP. et al. Plasminogen activator inhibitor 1 is associated with high-grade serous ovarian cancer metastasis and is reduced in patients who have received neoadjuvant chemotherapy. Front Cell Dev Biol 2023; 11: 1150991
    Suche in Google Scholar
  • 114 Chen SC, Henry DO, Reczek PR, Wong MKK. Plasminogen activator inhibitor-1 inhibits prostate tumor growth through endothelial apoptosis. Mol Cancer Ther 2008; 7 (05) 1227-1236
    Suche in Google Scholar
  • 115 Morita Y, Hayashi Y, Kanamaru T. et al. Inhibitory role of plasminogen activator inhibitor-1 in invasion and proliferation of HLE hepatocellular carcinoma cells. Jpn J Cancer Res 1999; 90 (07) 747-752
    Suche in Google Scholar
  • 116 Giacoia EG, Miyake M, Lawton A, Goodison S, Rosser CJ. PAI-1 leads to G1-phase cell-cycle progression through cyclin D3/cdk4/6 upregulation. Mol Cancer Res 2014; 12 (03) 322-334
    Suche in Google Scholar
  • 117 Mashiko S, Kitatani K, Toyoshima M. et al. Inhibition of plasminogen activator inhibitor-1 is a potential therapeutic strategy in ovarian cancer. Cancer Biol Ther 2015; 16 (02) 253-260
    Suche in Google Scholar
  • 118 Li CF, Kandel C, Baliko F, Nadesan P, Brünner N, Alman BA. Plasminogen activator inhibitor-1 (PAI-1) modifies the formation of aggressive fibromatosis (desmoid tumor). Oncogene 2005; 24 (09) 1615-1624
    Suche in Google Scholar
  • 119 Vial D, Monaghan-Benson E, McKeown-Longo PJ. Coordinate regulation of fibronectin matrix assembly by the plasminogen activator system and vitronectin in human osteosarcoma cells. Cancer Cell Int 2006; 6: 8
    Suche in Google Scholar
  • 120 McEachron TA, Pawlinski R, Richards KL, Church FC, Mackman N. Protease-activated receptors mediate crosstalk between coagulation and fibrinolysis. Blood 2010; 116 (23) 5037-5044
    Suche in Google Scholar
  • 121 McEachron TA, Church FC, Mackman N. Regulation of thrombin-induced plasminogen activator inhibitor-1 in 4T1 murine breast cancer cells. Blood Coagul Fibrinolysis 2011; 22 (07) 576-582
    Suche in Google Scholar
  • 122 Mazzieri R, Blasi F. The urokinase receptor and the regulation of cell proliferation. Thromb Haemost 2005; 93 (04) 641-646
    Suche in Google Scholar
  • 123 Soeda S, Shinomiya K, Ochiai T. et al. Plasminogen activator inhibitor-1 aids nerve growth factor-induced differentiation and survival of pheochromocytoma cells by activating both the extracellular signal-regulated kinase and c-Jun pathways. Neuroscience 2006; 141 (01) 101-108
    Suche in Google Scholar
  • 124 Kortlever RM, Higgins PJ, Bernards R. Plasminogen activator inhibitor-1 is a critical downstream target of p53 in the induction of replicative senescence. Nat Cell Biol 2006; 8 (08) 877-884
    Suche in Google Scholar
  • 125 Rana T, Jiang C, Banerjee S. et al. PAI-1 regulation of p53 expression and senescence in type II alveolar epithelial cells. Cells 2023; 12 (15) 2008
    Suche in Google Scholar
  • 126 Vaughan DE, Rai R, Khan SS, Eren M, Ghosh AK. Plasminogen activator inhibitor-1 is a marker and a mediator of senescence. Arterioscler Thromb Vasc Biol 2017; 37 (08) 1446-1452
    Suche in Google Scholar
  • 127 Aguirre-Ghiso JA, Estrada Y, Liu D, Ossowski L. ERK(MAPK) activity as a determinant of tumor growth and dormancy; regulation by p38(SAPK). Cancer Res 2003; 63 (07) 1684-1695
    Suche in Google Scholar
  • 128 Beaulieu LM, Whitley BR, Wiesner TF. et al. Breast cancer and metabolic syndrome linked through the plasminogen activator inhibitor-1 cycle. BioEssays 2007; 29 (10) 1029-1038
    Suche in Google Scholar
  • 129 Schneider DJ, Chen Y, Sobel BE. The effect of plasminogen activator inhibitor type 1 on apoptosis. Thromb Haemost 2008; 100 (06) 1037-1040
    Suche in Google Scholar
  • 130 Fang H, Placencio VR, DeClerck YA. Protumorigenic activity of plasminogen activator inhibitor-1 through an antiapoptotic function. J Natl Cancer Inst 2012; 104 (19) 1470-1484
    Suche in Google Scholar
  • 131 Valiente M, Obenauf AC, Jin X. et al. Serpins promote cancer cell survival and vascular co-option in brain metastasis. Cell 2014; 156 (05) 1002-1016
    Suche in Google Scholar
  • 132 Kwaan HC, McMahon B. The role of plasminogen-plasmin system in cancer. Cancer Treat Res 2009; 148: 43-66
    Suche in Google Scholar
  • 133 Balsara RD, Ploplis VA. Plasminogen activator inhibitor-1: the double-edged sword in apoptosis. Thromb Haemost 2008; 100 (06) 1029-1036
    Suche in Google Scholar
  • 134 Balsara RD, Castellino FJ, Ploplis VA. A novel function of plasminogen activator inhibitor-1 in modulation of the AKT pathway in wild-type and plasminogen activator inhibitor-1-deficient endothelial cells. J Biol Chem 2006; 281 (32) 22527-22536
    Suche in Google Scholar
  • 135 Alfano D, Iaccarino I, Stoppelli MP. Urokinase signaling through its receptor protects against anoikis by increasing BCL-xL expression levels. J Biol Chem 2006; 281 (26) 17758-17767
    Suche in Google Scholar
  • 136 Tsuruta F, Masuyama N, Gotoh Y. The phosphatidylinositol 3-kinase (PI3K)-Akt pathway suppresses Bax translocation to mitochondria. J Biol Chem 2002; 277 (16) 14040-14047
    Suche in Google Scholar
  • 137 Balsara RD, Xu Z, Ploplis VA. Targeting plasminogen activator inhibitor-1: role in cell signaling and the biology of domain-specific knock-in mice. Curr Drug Targets 2007; 8 (09) 982-995
    Suche in Google Scholar
  • 138 Cajot JF, Bamat J, Bergonzelli GE. et al. Plasminogen-activator inhibitor type 1 is a potent natural inhibitor of extracellular matrix degradation by fibrosarcoma and colon carcinoma cells. Proc Natl Acad Sci U S A 1990; 87 (18) 6939-6943
    Suche in Google Scholar
  • 139 Alizadeh H, Ma D, Berman M. et al. Tissue-type plasminogen activator-induced invasion and metastasis of murine melanomas. Curr Eye Res 1995; 14 (06) 449-458
    Suche in Google Scholar
  • 140 Bajou K, Maillard C, Jost M. et al. Host-derived plasminogen activator inhibitor-1 (PAI-1) concentration is critical for in vivo tumoral angiogenesis and growth. Oncogene 2004; 23 (41) 6986-6990
    Suche in Google Scholar
  • 141 Chen H, Peng H, Liu W. et al. Silencing of plasminogen activator inhibitor-1 suppresses colorectal cancer progression and liver metastasis. Surgery 2015; 158 (06) 1704-1713
    Suche in Google Scholar
  • 142 Kwaan HC, Mazar AP, McMahon BJ. The apparent uPA/PAI-1 paradox in cancer: more than meets the eye. Semin Thromb Hemost 2013; 39 (04) 382-391
    Suche in Google Scholar
  • 143 Bajou K, Peng H, Laug WE. et al. Plasminogen activator inhibitor-1 protects endothelial cells from FasL-mediated apoptosis. Cancer Cell 2008; 14 (04) 324-334
    Suche in Google Scholar
  • 144 Olander JV, Bremer ME, Marasa JC, Feder J. Fibrin-enhanced endothelial cell organization. J Cell Physiol 1985; 125 (01) 1-9
    Suche in Google Scholar
  • 145 Qi J, Goralnick S, Kreutzer DL. Fibrin regulation of interleukin-8 gene expression in human vascular endothelial cells. Blood 1997; 90 (09) 3595-3602
    Suche in Google Scholar
  • 146 Inoue M, Sawada T, Uchima Y. et al. Plasminogen activator inhibitor-1 (PAI-1) gene transfection inhibits the liver metastasis of pancreatic cancer by preventing angiogenesis. Oncol Rep 2005; 14 (06) 1445-1451
    Suche in Google Scholar
  • 147 Marshall LJ, Ramdin LSP, Brooks T, DPhil PC, Shute JK. Plasminogen activator inhibitor-1 supports IL-8-mediated neutrophil transendothelial migration by inhibition of the constitutive shedding of endothelial IL-8/heparan sulfate/syndecan-1 complexes. J Immunol 2003; 171 (04) 2057-2065
    Suche in Google Scholar
  • 148 Kubala MH, Punj V, Placencio-Hickok VR. et al. Plasminogen activator inhibitor-1 promotes the recruitment and polarization of macrophages in cancer. Cell Rep 2018; 25 (08) 2177-2191.e7
    Suche in Google Scholar