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LRP6 mediated signal transduction pathway triggered by tissue plasminogen activator acts through lipid rafts in neuroblastoma cells.
Journal of Cell Communication and Signaling ( IF 4.1 ) Pub Date : 2020-02-15 , DOI: 10.1007/s12079-020-00551-w
Gloria Riitano 1 , Valeria Manganelli 1 , Antonella Capozzi 1 , Vincenzo Mattei 2 , Serena Recalchi 1 , Stefano Martellucci 2 , Agostina Longo 1 , Roberta Misasi 1 , Tina Garofalo 1 , Maurizio Sorice 1
Affiliation  

LDL receptor-related proteins 6 (LRP6) is a type I transmembrane receptor (C-terminus in cytosol), which appears to be essential in numerous biological processes, since it is an essential co-receptor of Wnt ligands for canonical β-catenin dependent signal transduction. It was shown that tissue plasminogen activator (tPA), physically interacting with LRP6, induces protein phosphorylation, which may have large implication in the regulation of neural processes. In this investigation we analyzed whether LRP6 is associated with lipid rafts following tPA triggering in neuroblastoma cells and the role of raft integrity in LRP6 cell signaling. Sucrose gradient separation revealed that phosphorylated LRP6 was mainly, but not exclusively present in lipid rafts; this enrichment became more evident after triggering with tPA. In these microdomains LRP6 is strictly associated with ganglioside GM1, a paradigmatic component of these plasma membrane compartments, as revealed by coimmunoprecipitation experiments. As expected, tPA triggering induced LRP6 phosphorylation, which was independent of LRP1, as revealed by knockdown experiments by siRNA, but strictly dependent on raft integrity. Moreover, tPA induced β-catenin phosphorylation was also significantly prevented by previous pretreatment with methyl-β-cyclodextrin. Our results demonstrate that LRP6 mediated signal transduction pathway triggered by tPA acts through lipid rafts in neuroblastoma cells. These findings introduce an additional task for identifying new molecular target(s) of pharmacological agents. Indeed, these data, pointing to the key role of lipid rafts in tPA triggered signaling involving β-catenin, may have pharmacological implications, suggesting that cyclodextrins, and potentially other drugs, such as statins, may represent an useful tool.

中文翻译:

由组织纤溶酶原激活物触发的LRP6介导的信号转导途径通过神经母细胞瘤细胞中的脂质筏起作用。

LDL受体相关蛋白6(LRP6)是I型跨膜受体(胞质中的C端),在许多生物学过程中似乎都是必不可少的,因为它是Wnt配体对β-catenin依赖的重要共受体信号转导。研究表明,与LRP6发生物理相互作用的组织纤溶酶原激活物(tPA)诱导蛋白质磷酸化,这可能对神经过程的调节具有重要意义。在这项研究中,我们分析了神经母细胞瘤细胞中tPA触发后LRP6是否与脂质筏相关,以及筏完整性在LRP6细胞信号传导中的作用。蔗糖梯度分离表明磷酸化的LRP6主要但不是仅存在于脂质筏中。用tPA触发后,这种富集变得更加明显。在这些微区中,LRP6与神经节苷脂GM1紧密相关,神经节苷脂GM1是这些质膜区室的典型组成部分,如共免疫沉淀实验所揭示。正如预期的那样,tPA触发了诱导的LRP6磷酸化,这独立于LRP1,如siRNA的敲除实验所揭示的,但严格依赖于筏的完整性。此外,以前用甲基-β-环糊精进行预处理也可以显着防止tPA诱导的β-catenin磷酸化。我们的结果表明,tPA触发的LRP6介导的信号转导途径通过神经母细胞瘤细胞中的脂质筏起作用。这些发现引入了鉴定药理学分子新靶标的额外任务。实际上,这些数据指出了脂筏在tPA中的关键作用触发了涉及β-catenin的信号传导,
更新日期:2020-04-21
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