title: PAI-1 modulates cell migration in a LRP1-dependent manner via β-catenin and ERK1/2.
abstract: 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.
authors.forename: Nina
authors.initials: N
authors.lastname: Kozlova
authors.forename: Jan K
authors.initials: JK
authors.lastname: Jensen
authors.forename: Tabughang Franklin
authors.initials: TF
authors.lastname: Chi
authors.affiliation: Anatoly Samoylenko, Faculty of Biochemistry and Molecular Medicine, University of Oulu, P. O.Box 3000, FI-90014 Oulu, Finland, E-mail: anatoliy.samoylenko@oulu.fi.
authors.forename: Anatoly
authors.initials: A
authors.lastname: Samoylenko
authors.affiliation: Thomas Kietzmann, Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, University of Oulu, P. O.Box 3000, FI-90014 Oulu, Finland, Tel : +358 2 9448 7713, Email: tkietzm@gwdg.de.
authors.forename: Thomas
authors.initials: T
authors.lastname: Kietzmann
mesh_terms: D000818:Animals; D002465:Cell Movement; D049109:Cell Proliferation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D051379:Mice; D034741:RNA, Small Interfering / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D011973:Receptors, LDL / Q000378:metabolism*; D058258:Serpin E2 / Q000378:metabolism*; D015398:Signal Transduction; D010959:Tissue Plasminogen Activator / Q000378:metabolism*; D014158:Transcription, Genetic; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism*
chemical_list: C495267:CTNNB1 protein, mouse; D026503:Low Density Lipoprotein Receptor-Related Protein-1; C486645:Lrp1 protein, mouse; D034741:RNA, Small Interfering; D011973:Receptors, LDL; D058258:Serpin E2; C511869:Serpine2 protein, mouse; D025521:Tumor Suppressor Proteins; D051176:beta Catenin; D048049:Extracellular Signal-Regulated MAP Kinases; D010959:Tissue Plasminogen Activator; D014568:Urokinase-Type Plasminogen Activator
keywords: LRP1; PAI-1; beta-catenin; cell migration