Regulation of mTOR Complex 2 Signaling in Neurofibromatosis 2-Deficient Target Cell Types
Regulation of mTOR Complex 2 Signaling in Neurofibromatosis 2-Deficient Target Cell Types
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DOI：
10.1158/1541-7786.mcr-11-0425-t
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发表时间：
2012-05-01
影响因子：
5.2
通讯作者：
Ramesh, Vijaya
中科院分区：
文献类型：
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作者：
James, Marianne F.;Stivison, Elizabeth;Ramesh, Vijaya
神经纤维瘤病 2 (NF2) 肿瘤抑制基因的失活突变会导致神经鞘瘤和脑膜瘤的发生。使用缺乏 NF2 的脑膜瘤细胞和肿瘤，以及脑膜瘤衍生的正常细胞对应物（蛛网膜细胞），我们确定 merlin 是 mTOR 复合物 1 (mTORC1) 的新型负调节因子。我们现在表明，merlin 正向调节 mTORC2（第二种功能独特的 mTOR 复合物）的激酶活性，并且在细胞中急性 merlin 缺陷时，mTORC2 底物（包括 Akt）的下游磷酸化会减少。响应一般生长因子刺激，在 merlin merlin RNA 干扰抑制的人蛛网膜细胞和雪旺细胞中，Akt 信号传导通过高活性 TORC1 和受损 mTORC2 介导的机制减弱。此外，Akt 信号传导因响应不同的生长因子刺激而以细胞类型依赖性方式受到差异性损害。然而，与 mTORC1 的激活相反，正常蛛网膜和雪旺细胞响应急性 merlin 缺失而表现出的 mTORC2 信号传导谱减弱，在 NF2 缺陷的脑膜瘤和神经鞘瘤中并未得到一致反映，这表明在最初的 merlin 缺失后，肿瘤中可能获得了额外的遗传事件。这一发现与另一种良性肿瘤疾病——结节性硬化症形成鲜明对比，后者在细胞和肿瘤中均表现出减弱的 mTORC2 信号传导谱。最后，我们检查了雷帕霉素以及 mTOR 激酶抑制剂 Torin1，以两种 mTOR 复合物为靶点，以确定最有效的一类化合物，用于阻断 merlin 缺陷型脑膜瘤细胞中 mTOR 介导的信号传导和增殖。这些研究最终可能有助于开发针对 NF2 相关肿瘤的合适疗法。摩尔癌症研究中心； 10（5）； 649-59。 (C) 2012 年 AACR。
Inactivating mutations in the neurofibromatosis 2 (NF2) tumor suppressor gene results in the development of schwannomas and meningiomas. Using NF2-deficient meningioma cells and tumors, together with the normal cellular counterparts that meningiomas derive, arachnoid cells, we identified merlin as a novel negative regulator of mTOR complex 1 (mTORC1). We now show that merlin positively regulates the kinase activity of mTORC2, a second functionally distinct mTOR complex, and that downstream phosphorylation of mTORC2 substrates, including Akt, is reduced upon acute merlin deficiency in cells. In response to general growth factor stimulation, Akt signaling is attenuated in merlin merlin RNA interference-suppressed human arachnoid and Schwann cells by mechanisms mediated by hyperactivem TORC1 and impaired mTORC2. Moreover, Akt signaling is impaired differentially in a cell type-dependent manner in response to distinct growth factor stimuli. However, contrary to activation of mTORC1, the attenuated mTORC2 signaling profiles exhibited by normal arachnoid and Schwann cells in response to acute merlin loss were not consistently reflected in NF2-deficient meningiomas and schwannomas, suggesting additional genetic events may have been acquired in tumors after initial merlin loss. This finding contrasts with another benign tumor disorder, tuberous sclerosis complex, which exhibits attenuated mTORC2 signaling profiles in both cells and tumors. Finally, we examined rapamycin, as well as the mTOR kinase inhibitor, Torin1, targeting both mTOR complexes to identify the most efficacious class of compounds for blocking mTOR-mediated signaling and proliferation in merlin-deficient meningioma cells. These studies may ultimately aid in the development of suitable therapeutics for NF2-associated tumors. Mol Cancer Res; 10(5); 649-59. (C) 2012 AACR.