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

Nina Kozlova; Jan K. Jensen; Tabughang Franklin Chi; Anatoly Samoylenko; Thomas Kietzmann

doi:10.1160/TH14-08-0678

Thrombosis and Haemostasis, Table of Contents

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

¹Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, University of Oulu, Oulu, Finland

,

Jan K. Jensen

²Department of Molecular Biology and Genetics - Aarhus University; Aarhus C, Denmark

,

Tabughang Franklin Chi

¹Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, University of Oulu, Oulu, Finland

,

Anatoly Samoylenko^*

¹Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, University of Oulu, Oulu, Finland

³Laboratory of Cell Signalling, Palladin Institute of Biochemistry, National Academy of Sciences of Ukraine, Kyiv, Ukraine

,

Thomas Kietzmann^*

¹Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, University of Oulu, Oulu, Finland

› Author Affiliations

Abstract

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

Full Text

References

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.
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.
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.
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.
5 Dupont DM, Madsen JB, Kristensen T. et al. Biochemical properties of plasminogen activator inhibitor-1. Front Biosci 2009; 14: 1337-1361.
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.
7 Herz J, Strickland DK. LRP: a multifunctional scavenger and signalling receptor. J Clin Invest 2001; 108: 779-784.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
19 Czekay R-. Plasminogen activator inhibitor-1 detaches cells from extracellular matrices by inactivating integrins. J Cell Biol 2003; 160: 781-791.
20 Andreasen P. PAI-1 – A Potential Therapeutic Target in Cancer. Curr Drug Targets 2007; 08: 1030-1041.
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.
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.
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.
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.
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.
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.
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.
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.
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.
30 MacDonald BT, Tamai K, He X. Wnt/beta-catenin signalling: components, mechanisms, and diseases. Dev Cell 2009; 17: 9-26.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
43 Gallagher SJ, Rambow F, Kumasaka M. et al. Beta-catenin inhibits melanocyte migration but induces melanoma metastasis. Oncogene 2013; 32: 2230-2238.
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.
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.