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Thromb Haemost 2015; 113(05): 988-998
DOI: 10.1160/TH14-08-0678
Coagulation and Fibrinolysis
Schattauer GmbH

PAI-1 modulates cell migration in a LRP1-dependent manner via β-catenin and ERK1/2

Nina Kozlova
1   Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, University of Oulu, Oulu, Finland
,
Jan K. Jensen
2   Department of Molecular Biology and Genetics - Aarhus University; Aarhus C, Denmark
,
Tabughang Franklin Chi
1   Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, University of Oulu, Oulu, Finland
,
Anatoly Samoylenko   *
1   Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, University of Oulu, Oulu, Finland
3   Laboratory of Cell Signalling, Palladin Institute of Biochemistry, National Academy of Sciences of Ukraine, Kyiv, Ukraine
,
Thomas Kietzmann   *
1   Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, University of Oulu, Oulu, Finland
› Author Affiliations Financial support: The study was supported by grants from the Finnish Academy of Science, Biocenter Oulu, the Sigrid Juselius Foundation, the Centre for International Mobility (CIMO) to TK and from the Ministry of Education and Research of Ukraine (№170–2009) to AS.
Further Information

Publication History

Received: 22 August 2014

Accepted after major revision: 06 January 2015

Publication Date:
24 November 2017 (online)

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Summary

Plasminogen activator inhibitor-1 (PAI-1) is the major and most specific acting urokinase (uPA) and tissue plasminogen activator (tPA) inhibitor. Apart from its function in the fibrinolytic system, PAI-1 was also found to contribute to processes like tissue remodelling, angiogenesis, and tumour progression. However, the role of PAI-1 in those processes remains largely controversial with respect to the influence of PAI-1 on cell signalling pathways. Although PAI-1 does not possess its own cellular receptor, it can be bound to low-density lipoprotein receptor- related protein 1 (LRP1) which was proposed to modulate the β-catenin pathway. Therefore, we used wild-type mouse embryonic fibroblasts (MEFs), and MEFs deficient of LRP1 to study PAI-1 as modulator of the β-catenin pathway. We found that PAI-1 influences MEF proliferation and motility in a LRP1-dependent manner and that β-catenin is important for that response. In addition, expression of β-catenin and β-catenin-dependent transcriptional activity were induced by PAI-1 in wild type MEFs, but not in LRP1-deficient cells. Moreover, PAI-1-induced ERK1/2 activation was more prominent in the LRP1-deficient cells and interestingly knockdown of β-catenin abolished this effect. Together, the data of the current study show that PAI-1 can promote cell migration via LRP1-dependent activation of the β-catenin and ERK1/2 MAPK pathway which may be important in stage-specific treatment of human diseases associated with high PAI-1 levels.

Keywords

PAI-1 - LRP1 - beta-catenin - cell migration

* AS and TK share last authorship on this paper.


 

  • References

  • 1 Andreasen PA, Egelund R, Petersen HH. The plasminogen activation system in tumour growth, invasion, and metastasis. Cell Mol Life Sci 2000; 57: 25-40.
    CrossrefPubMedGoogle Scholar
  • 2 Janicke F, Schmitt M, Pache L. et al. Urokinase (uPA) and its inhibitor PAI-1 are strong and independent prognostic factors in node-negative breast cancer. Breast Cancer Res Treat 1993; 24: 195-208.
    CrossrefPubMedGoogle Scholar
  • 3 Harbeck N, Kates RE, Gauger K. et al. Urokinase-type plasminogen activator (uPA) and its inhibitor PAI-I: novel tumour-derived factors with a high prognostic and predictive impact in breast cancer. Thromb Haemost 2004; 91: 450-456.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 4 Kietzmann T, Andreasen P. Plasminogen activator inhibitor-1 (PAI-1): a molecule at the crossroads to cell survival or cell death. Thromb Haemost 2008; 100: 965-968.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 5 Dupont DM, Madsen JB, Kristensen T. et al. Biochemical properties of plasminogen activator inhibitor-1. Front Biosci 2009; 14: 1337-1361.
    PubMedGoogle Scholar
  • 6 Lillis AP, Mikhailenko I, Strickland DK. Beyond endocytosis: LRP function in cell migration, proliferation and vascular permeability. J Thromb Haemost 2005; 03: 1884-1893.
    CrossrefPubMedGoogle Scholar
  • 7 Herz J, Strickland DK. LRP: a multifunctional scavenger and signalling receptor. J Clin Invest 2001; 108: 779-784.
    CrossrefPubMedGoogle Scholar
  • 8 Degryse B, Neels JG, Czekay RP. et al. The low density lipoprotein receptor-related protein is a motogenic receptor for plasminogen activator inhibitor-1. J Biol Chem 2004; 279: 22595-22604.
    CrossrefPubMedGoogle Scholar
  • 9 Zilberberg A, Yaniv A, Gazit A. The low density lipoprotein receptor-1, LRP1, interacts with the human frizzled-1 (HFz1) and down-regulates the canonical Wnt signalling pathway. J Biol Chem 2004; 279: 17535-17542.
    CrossrefPubMedGoogle Scholar
  • 10 Moon RT, Kohn AD, De Ferrari GV. et al. WNT and beta-catenin signalling: diseases and therapies. Nat Rev Genet 2004; 05: 691-701.
    CrossrefPubMedGoogle Scholar
  • 11 Jensen JK, Thompson LC, Bucci JC. et al. Crystal structure of plasminogen activator inhibitor-1 in an active conformation with normal thermodynamic stability. J Biol Chem 2011; 286: 29709-29717.
    CrossrefPubMedGoogle Scholar
  • 12 Molenaar M, van de Wetering M, Oosterwegel M. et al. XTcf-3 transcription factor mediates beta-catenin-induced axis formation in Xenopus embryos. Cell 1996; 86: 391-399.
    CrossrefPubMedGoogle Scholar
  • 13 Tron K, Samoylenko A, Musikowski G. et al. Regulation of rat heme oxygenase-1 expression by interleukin-6 via the Jak/STAT pathway in hepatocytes. J Hepatol 2006; 45: 72-80.
    CrossrefPubMedGoogle Scholar
  • 14 Wijayanti N, Huber S, Samoylenko A. et al. Role of NF-kappaB and p38 MAP kinase signalling pathways in the lipopolysaccharide-dependent activation of heme oxygenase-1 gene expression. Antioxid Redox Signal 2004; 06: 802-810.
    PubMedGoogle Scholar
  • 15 Kietzmann T, Roth U, Jungermann K. Induction of the plasminogen activator inhibitor-1 gene expression by mild hypoxia via a hypoxia response element binding the hypoxia-inducible factor-1 in rat hepatocytes. Blood 1999; 94: 4177-4185.
    PubMedGoogle Scholar
  • 16 Ganjam GK, Dimova EY, Unterman TG. et al. FoxO1 and HNF-4 are involved in regulation of hepatic glucokinase gene expression by resveratrol. J Biol Chem 2009; 284: 30387-30397.
    PubMedGoogle Scholar
  • 17 Flugel D, Gorlach A, Kietzmann T. GSK-3beta regulates cell growth, migration, and angiogenesis via Fbw7 and USP28-dependent degradation of HIF-1alpha. Blood 2012; 119: 1292-1301.
    CrossrefPubMedGoogle Scholar
  • 18 Weaver AM, Hussaini IM, Mazar A. et al. Embryonic Fibroblasts That Are Genetically Deficient in Low Density Lipoprotein Receptor-related Protein Demonstrate Increased Activity of the Urokinase Receptor System and Accelerated Migration on Vitronectin. J Biol Chem 1997; 272: 14372-14379.
    CrossrefPubMedGoogle Scholar
  • 19 Czekay R-. Plasminogen activator inhibitor-1 detaches cells from extracellular matrices by inactivating integrins. J Cell Biol 2003; 160: 781-791.
    CrossrefPubMedGoogle Scholar
  • 20 Andreasen P. PAI-1 – A Potential Therapeutic Target in Cancer. Curr Drug Targets 2007; 08: 1030-1041.
    CrossrefPubMedGoogle Scholar
  • 21 Stahl A, Mueller BM. Melanoma cell migration on vitronectin: regulation by components of the plasminogen activation system. Int J Cancer 1997; 71: 116-122.
    CrossrefPubMedGoogle Scholar
  • 22 Palmieri D, Lee JW, Juliano RL. et al. Plasminogen activator inhibitor-1 and –3 increase cell adhesion and motility of MDA-MB-435 breast cancer cells. J Biol Chem 2002; 277: 40950-40957.
    CrossrefPubMedGoogle Scholar
  • 23 Stefansson S, Lawrence DA. The serpin PAI-1 inhibits cell migration by blocking integrin alpha V beta 3 binding to vitronectin. Nature 1996; 383: 441-443.
    CrossrefPubMedGoogle Scholar
  • 24 Kirchheimer JC, Binder BR, Remold HG. Matrix-bound plasminogen activator inhibitor type 1 inhibits the invasion of human monocytes into interstitial tissue. J Immunol 1990; 145: 1518-1522.
    PubMedGoogle Scholar
  • 25 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: 578-585.
    CrossrefPubMedGoogle Scholar
  • 26 Czekay R, Wilkins-Port CE, Higgins SP. et al. PAI-1: An Integrator of Cell Signalling and Migration. International Journal of Cell Biology 2011; 2011: 1-9.
    PubMedGoogle Scholar
  • 27 Wehrli M, Dougan ST, Caldwell K. et al. arrow encodes an LDL-receptor-related protein essential for Wingless signalling. Nature 2000; 407: 527-530.
    CrossrefPubMedGoogle Scholar
  • 28 Salic A, Lee E, Mayer L. et al. Control of beta-catenin stability: reconstitution of the cytoplasmic steps of the wnt pathway in Xenopus egg extracts. Mol Cell 2000; 05: 523-532.
    CrossrefPubMedGoogle Scholar
  • 29 He X, Semenov M, Tamai K. et al. LDL receptor-related proteins 5 and 6 in Wnt/ beta-catenin signalling: arrows point the way. Development 2004; 131: 1663-1677.
    CrossrefPubMedGoogle Scholar
  • 30 MacDonald BT, Tamai K, He X. Wnt/beta-catenin signalling: components, mechanisms, and diseases. Dev Cell 2009; 17: 9-26.
    CrossrefPubMedGoogle Scholar
  • 31 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: 1061-1070.
    CrossrefPubMedGoogle Scholar
  • 32 Kuang HB, Miao CL, Guo WX. et al. Dickkopf-1 enhances migration of HEK293 cell by beta-catenin/E-cadherin degradation. Front Biosci (Landmark Ed) 2009; 14: 2212-2220.
    PubMedGoogle Scholar
  • 33 Kishida S, Yamamoto H, Kikuchi A. Wnt-3a and Dvl induce neurite retraction by activating Rho-associated kinase. Mol Cell Biol 2004; 24: 4487-4501.
    CrossrefPubMedGoogle Scholar
  • 34 Mantuano E, Jo M, Gonias SL. et al. Low Density Lipoprotein Receptor-related Protein (LRP1) Regulates Rac1 and RhoA Reciprocally to Control Schwann Cell Adhesion and Migration. J Biol Chem 2010; 285: 14259-14266.
    CrossrefPubMedGoogle Scholar
  • 35 Shi Y, Mantuano E, Inoue G. et al. Ligand binding to LRP1 transactivates Trk receptors by a Src family kinase-dependent pathway. Sci Signal 2009; 02: ra18.
    PubMedGoogle Scholar
  • 36 Bikkavilli RK, Feigin ME, Malbon CC. p38 mitogen-activated protein kinase regulates canonical Wnt-beta-catenin signalling by inactivation of GSK3beta. J Cell Sci 2008; 121: 3598-3607.
    CrossrefPubMedGoogle Scholar
  • 37 Caverzasio J, Manen D. Essential role of Wnt3a-mediated activation of mitogenactivated protein kinase p38 for the stimulation of alkaline phosphatase activity and matrix mineralisation in C3H10T1/2 mesenchymal cells. Endocrinology 2007; 148: 5323-5330.
    CrossrefPubMedGoogle Scholar
  • 38 Hildesheim J, Salvador JM, Hollander MC. et al. Casein kinase 2– and protein kinase A-regulated adenomatous polyposis coli and beta-catenin cellular localisation is dependent on p38 MAPK. J Biol Chem 2005; 280: 17221-17226.
    CrossrefPubMedGoogle Scholar
  • 39 Keren A, Bengal E, Frank D. p38 MAP kinase regulates the expression of XMyf5 and affects distinct myogenic programs during Xenopus development. Dev Biol 2005; 288: 73-86.
    CrossrefPubMedGoogle Scholar
  • 40 Jeon SH, Yoon JY, Park YN. et al. Axin Inhibits Extracellular Signal-regulated Kinase Pathway by Ras Degradation via ETX-Catenin. J. Biol. Chem. 2007; 282: 14482-14492.
    CrossrefPubMedGoogle Scholar
  • 41 Gortazar AR, Martin-Millan M, Bravo B. et al. Crosstalk between caveolin-1/extracellular signal-regulated kinase (ERK) and beta-catenin survival pathways in osteocyte mechanotransduction. J Biol Chem 2013; 288: 8168-8175.
    CrossrefPubMedGoogle Scholar
  • 42 Shin SSY, Young S, Rath O. et al. Functional Roles of Multiple Feedback Loops in Extracellular Signal-Regulated Kinase and Wnt Signalling Pathways That Regulate Epithelial-Mesenchymal Transition. Cancer Res 2010; 70: 6715-6724.
    CrossrefPubMedGoogle Scholar
  • 43 Gallagher SJ, Rambow F, Kumasaka M. et al. Beta-catenin inhibits melanocyte migration but induces melanoma metastasis. Oncogene 2013; 32: 2230-2238.
    CrossrefPubMedGoogle Scholar
  • 44 Beaulieu LM, Whitley BR, Wiesner TF. et al. Breast cancer and metabolic syndrome linked through the plasminogen activator inhibitor-1 cycle. Bioessays 2007; 29: 1029-1038.
    CrossrefPubMedGoogle Scholar
  • 45 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; 08: 877-884.
    CrossrefPubMedGoogle Scholar