PAI-1 modulates cell migration in a LRP1-dependent manner via β-catenin and ERK1/2
PAI-1 modulates cell migration in a LRP1-dependent manner via β-catenin and ERK1/2
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DOI：
10.1160/th14-08-0678
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发表时间：
2015-05-01
影响因子：
6.7
通讯作者：
Kietzmann, Thomas
中科院分区：
文献类型：
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作者：
Kozlova, Nina;Jensen, Jan K.;Kietzmann, Thomas
纤溶酶原激活物抑制剂-1（派-1）是尿激酶（uPA）和组织纤溶酶原激活物（tPA）的主要和最特异的抑制剂。除了其在纤维蛋白溶解系统中的功能外，还发现派-1有助于组织重塑、血管生成和肿瘤进展等过程。然而，派-1在这些过程中的作用在很大程度上仍然是有争议的派-1对细胞信号通路的影响。虽然派-1不具有其自身的细胞受体，但它可以与低密度脂蛋白受体相关蛋白1（LRP 1）结合，后者被认为调节β-连环蛋白途径。因此，我们使用野生型小鼠胚胎成纤维细胞（MEFs）和缺乏LRP 1的MEFs来研究派-1作为β-连环蛋白途径的调节剂。我们发现派-1以LRP 1依赖的方式影响MEF的增殖和运动，β-连环蛋白对这种反应很重要。此外，β-连环蛋白和β-连环蛋白依赖的转录活性的表达诱导派-1在野生型MEFs中，但不是在LRP 1缺陷的细胞。此外，派-1诱导的ERK 1/2激活在LRP 1缺陷细胞中更为突出，有趣的是，β-连环蛋白的敲低消除了这种作用。总之，本研究的数据表明，派-1可以通过β-连环蛋白和ERK 1/2 MAPK通路的LRP 1依赖性激活来促进细胞迁移，这在与高派-1水平相关的人类疾病的阶段特异性治疗中可能是重要的。
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 p-catenin pathway. Therefore, we used wild-type mouse embryonic fibroblasts (MEFs), and MEFs deficient of LRP1 to study PAI-1 as modulator of the beta-catenin pathway. We found that PAI-1 influences MEF proliferation and motility in a LRP1-dependent manner and that beta-catenin is important for that response. In addition, expression of beta-catenin and beta-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 beta-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 beta-catenin and ERK1/2 MAPK pathway which may be important in stage-specific treatment of human diseases associated with high PAI-1 levels.