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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.


 

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