Proteinase-activated receptor-1 - Triggered activation of tumor progression locus-2 promotes actin cytoskeleton reorganization and cell migration
Proteinase-activated receptor-1 - Triggered activation of tumor progression locus-2 promotes actin cytoskeleton reorganization and cell migration
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DOI：
10.1158/0008-5472.can-07-5793
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发表时间：
2008-03-15
期刊：
影响因子：
11.2
通讯作者：
Tsichlis, Philip N.
中科院分区：
文献类型：
--
作者：
Hatziapostolou, Maria;Polytarchou, Christos;Tsichlis, Philip N.
肿瘤进展基因2(Tpl2)是一种有丝分裂原激活的蛋白激酶(MAP3K)，在逆转录病毒诱导的啮齿动物淋巴瘤和乳腺癌中被激活，它可以传递Toll样受体、白介素1、肿瘤坏死因子α和CD40信号，并在炎症中发挥重要作用。在这里，我们发现Tpl2也是细胞迁移和基因表达信号转导所必需的，这些信号起源于G蛋白偶联受体蛋白酶激活受体1(PAR1)。由Tpl2转导的PAR1信号激活了rac1和粘着斑激酶，它们是肌动蛋白细胞骨架重组和细胞迁移所必需的。PAR1在成纤维细胞中的表达可由肿瘤细胞产生的蛋白酶触发，而PAR1在肿瘤细胞中的表达可由成纤维细胞产生的蛋白酶触发。这些数据表明，调控细胞迁移和基因表达的信号在间质细胞和肿瘤细胞之间双向流动，Tpl2在这一过程中发挥关键作用。
Tumor progression locus 2 (Tpl2), a mitogen-activated protein kinase kinase kinase (MAP3K) that is activated by provirus insertion in retrovirus-induced rodent lymphomas and mammary adenocarcinomas, is known to transduce Toll-like receptor, interleukin 1, tumor necrosis factor alpha, and CD40 signals and to play an important role in inflammation. Here we show that Tpl2 is also required for the transduction of cell migration and gene expression signals originating in the G-protein-coupled receptor proteinase-activated receptor 1 (PAR1). PAR1 signals transduced by Tpl2 activate Rac1 and focal adhesion kinase, and they are required for reorganization of the actin cytoskeleton and cell migration. PAR1 expressed in fibroblasts can be triggered by proteinases produced by tumor cells, and PAR1 expressed in tumor cells can be triggered by proteinases produced by fibroblasts. These data suggest that signals that regulate cell migration and gene expression flow between stromal and tumor cells in both directions and that Tpl2 plays a pivotal role in this process.