Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
J Exp Med. 2012 Apr 9;209(4):713-28. doi: 10.1084/jem.20111470. Epub 2012 Apr 2.
Notch plays critical roles in both cell fate decisions and tumorigenesis. Notch receptor engagement initiates signaling cascades that include a phosphatidylinositol 3-kinase/target of rapamycin (TOR) pathway. Mammalian TOR (mTOR) participates in two distinct biochemical complexes, mTORC1 and mTORC2, and the relationship between mTORC2 and physiological outcomes dependent on Notch signaling is unknown. In this study, we report contributions of mTORC2 to thymic T-cell acute lymphoblastic leukemia (T-ALL) driven by Notch. Conditional deletion of Rictor, an essential component of mTORC2, impaired Notch-driven proliferation and differentiation of pre-T cells. Furthermore, NF-κB activity depended on the integrity of mTORC2 in thymocytes. Active Akt restored NF-κB activation, a normal rate of proliferation, and differentiation of Rictor-deficient pre-T cells. Strikingly, mTORC2 depletion lowered CCR7 expression in thymocytes and leukemic cells, accompanied by decreased tissue invasion and delayed mortality in T-ALL driven by Notch. Collectively, these findings reveal roles for mTORC2 in promoting thymic T cell development and T-ALL and indicate that mTORC2 is crucial for Notch signaling to regulate Akt and NF-κB.
Notch 在细胞命运决定和肿瘤发生中都起着关键作用。Notch 受体的结合启动了信号级联反应，包括磷酸肌醇 3-激酶/雷帕霉素靶蛋白 (TOR) 途径。哺乳动物 TOR（mTOR）参与两个不同的生化复合物，mTORC1 和 mTORC2，而 mTORC2 与依赖 Notch 信号的生理结果之间的关系尚不清楚。在这项研究中，我们报告了 mTORC2 对 Notch 驱动的胸腺 T 细胞急性淋巴细胞白血病（T-ALL）的贡献。条件性删除 mTORC2 的必需成分 Rictor，会损害 Notch 驱动的前 T 细胞的增殖和分化。此外，NF-κB 活性依赖于胸腺细胞中 mTORC2 的完整性。活性 Akt 恢复了 NF-κB 的激活、Rictor 缺陷前 T 细胞的正常增殖率和分化。引人注目的是，mTORC2 的耗竭降低了胸腺细胞和白血病细胞中的 CCR7 表达，同时减少了 Notch 驱动的 T-ALL 中的组织侵袭和延迟死亡。总的来说，这些发现揭示了 mTORC2 在促进胸腺 T 细胞发育和 T-ALL 中的作用，并表明 mTORC2 对于 Notch 信号调节 Akt 和 NF-κB 至关重要。
