Loss of the Tumor Suppressor Gene NF2, Encoding Merlin, Constitutively Activates Integrin-Dependent mTORC1 Signaling
Loss of the Tumor Suppressor Gene NF2, Encoding Merlin, Constitutively Activates Integrin-Dependent mTORC1 Signaling
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DOI：
10.1128/mcb.01578-08
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发表时间：
2009-08-01
影响因子：
5.3
通讯作者：
Giancotti, Filippo G.
中科院分区：
文献类型：
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作者：
Lopez-Lago, Miguel A.;Okada, Tomoyo;Giancotti, Filippo G.
整联蛋白信号通过p21激活激酶促进肿瘤抑制因子merlin的磷酸化和失活，从而消除了正常细胞中有丝分裂发生的阻碍。然而，merlin的生化功能以及对恶性间皮瘤和其他与NF2相关的恶性肿瘤发病机制至关重要的效应通路尚不清楚。我们报道整联蛋白特异性信号促进mTORC1的激活以及依赖帽子结构的mRNA翻译。merlin的缺失可挽救在缺乏与适宜的细胞外基质附着的细胞中的mTORC1信号，这表明整联蛋白信号通过使merlin失活来控制mTORC1。该信号通路控制细胞周期蛋白D1 mRNA的翻译，进而控制细胞周期进程。此外，它还促进细胞存活。对一组恶性间皮瘤细胞系的分析显示，merlin的缺失与mTORC1的激活之间存在很强的相关性。merlin阴性的细胞系对雷帕霉素的生长抑制作用敏感，重组merlin的表达使其对雷帕霉素产生部分抗性。相反，merlin的缺失可恢复merlin阳性细胞系对雷帕霉素的敏感性。这些结果表明整联蛋白介导的黏附通过使merlin失活来促进mTORC1信号。此外，它们还揭示merlin阴性的间皮瘤表现出不受调控的mTORC1信号，并且对雷帕霉素敏感，从而为在这些肿瘤中进行基于生物标志物驱动的mTORC1抑制剂的前瞻性临床研究提供了临床前的理论基础。
Integrin signaling promotes, through p21-activated kinase, phosphorylation and inactivation of the tumor suppressor merlin, thus removing a block to mitogenesis in normal cells. However, the biochemical function of merlin and the effector pathways critical for the pathogenesis of malignant mesothelioma and other NF2-related malignancies are not known. We report that integrin-specific signaling promotes activation of mTORC1 and cap-dependent mRNA translation. Depletion of merlin rescues mTORC1 signaling in cells deprived of anchorage to a permissive extracellular matrix, suggesting that integrin signaling controls mTORC1 through inactivation of merlin. This signaling pathway controls translation of the cyclin D1 mRNA and, thereby, cell cycle progression. In addition, it promotes cell survival. Analysis of a panel of malignant mesothelioma cell lines reveals a strong correlation between loss of merlin and activation of mTORC1. Merlin-negative lines are sensitive to the growth-inhibitory effect of rapamycin, and the expression of recombinant merlin renders them partially resistant to rapamycin. Conversely, depletion of merlin restores rapamycin sensitivity in merlin-positive lines. These results indicate that integrin-mediated adhesion promotes mTORC1 signaling through the inactivation of merlin. Furthermore, they reveal that merlin-negative mesotheliomas display unregulated mTORC1 signaling and are sensitive to rapamycin, thus providing a preclinical rationale for prospective, biomarker-driven clinical studies of mTORC1 inhibitors in these tumors.