Discrete signaling mechanisms of mTORC1 and mTORC2: Connected yet apart in cellular and molecular aspects
Discrete signaling mechanisms of mTORC1 and mTORC2: Connected yet apart in cellular and molecular aspects
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DOI：
10.1016/j.jbior.2016.12.001
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发表时间：
2017-01-01
影响因子：
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通讯作者：
Murali, Raj
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文献类型：
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作者：
Jhanwar-Uniyal, Meena;Amin, Anubhav G.;Murali, Raj
PI 3 K/Akt/mTOR（雷帕霉素的机械靶点）信号级联的激活已经在包括胶质母细胞瘤（GB）在内的许多恶性肿瘤的肿瘤发生中显示。由于肿瘤抑制因子PTEN（一种对PI 3 K起拮抗作用的磷酸酶）的缺失，该信号级联常常上调。mTOR通过形成两种多蛋白复合物mTORC 1和mTORC 2来调节细胞的生长、运动和代谢，这两种复合物由特殊的结合伴侣组成。这些复合物对不同的刺激敏感。mTORC 1对营养物质敏感，mTORC 2通过PI 3 K和生长因子信号传导调节。mTORC 1通过下游分子4 E-BP 1（也称为EIF 4 E-BP 1）和S6 K调节蛋白质合成和细胞生长。此外，mTORC 2通过磷酸化某些AGC激酶（如Akt和SGK）的C-末端疏水基序来响应生长因子信号传导。mTORC 2通过与核糖体结合在正常细胞和癌细胞的维持中起关键作用，并参与细胞代谢调节。这两种复合物相互控制，因为Akt调节PRAS 40磷酸化，其解除mTORC 1活性的抑制，而S6 K调节Sin]以调节mTORC 2活性。mTORC 2的另一个重要组成部分是Sin 1，它对mTORC 2复合物的形成和功能至关重要。mTOR的别构抑制剂、雷帕霉素和雷帕霉素类似物在GB患者的临床试验中基本上是无效的，这是由于它们对mTORC 1的不完全抑制或经由负反馈回路的损失而意外激活mTOR。mTORC 1和mTORC 2的新型ATP结合抑制剂通过其下游底物pS 6 K（Ser 235/236）的完全去磷酸化完全抑制mTORC 1活性，同时有效抑制mTORC 2活性，如通过pAK-T-Ser 473的完全去磷酸化所证明的。此外，GB癌干细胞的增殖和自我更新可被这些新型mTORC 1和mTORC 2抑制剂有效靶向。因此，mTOR复合物抑制剂的有效性可以通过其抑制mTORC 1和2的能力以及其阻止细胞增殖和迁移的能力来评估。(C)2017爱思唯尔有限公司版权所有
Activation of PI3K/Akt/mTOR (mechanistic target of rapamycin) signaling cascade has been shown in tumorigenesis of numerous malignancies including glioblastoma (GB). This signaling cascade is frequently upregulated due to loss of the tumor suppressor PTEN, a phosphatase that functions antagonistically to PI3K. mTOR regulates cell growth, motility, and metabolism by forming two multiprotein complexes, mTORC1 and mTORC2, which are composed of special binding partners. These complexes are sensitive to distinct stimuli. mTORC1 is sensitive to nutrients and mTORC2 is regulated via PI3K and growth factor signaling. mTORC1 regulates protein synthesis and cell growth through downstream molecules: 4E-BP1 (also called EIF4E-BP1) and S6K. Also, mTORC2 is responsive to growth factor signaling by phosphorylating the C-terminal hydrophobic motif of some AGC kinases like Akt and SGK. mTORC2 plays a crucial role in maintenance of normal and cancer cells through its association with ribosomes, and is involved in cellular metabolic regulation. Both complexes control each other as Akt regulates PRAS40 phosphorylation, which disinhibits mTORC1 activity, while S6K regulates Sin] to modulate mTORC2 activity. Another significant component of mTORC2 is Sin 1, which is crucial for mTORC2 complex formation and function. Allosteric inhibitors of mTOR, rapamycin and rapalogs, have essentially been ineffective in clinical trials of patients with GB due to their incomplete inhibition of mTORC1 or unexpected activation of mTOR via the loss of negative feedback loops. Novel ATP binding inhibitors of mTORC1 and mTORC2 suppress mTORC1 activity completely by total dephosphorylation of its downstream substrate pS6K(Ser235/236), while effectively suppressing mTORC2 activity, as demonstrated by complete dephosphorylation of pAK-T-Ser473. Furthermore, proliferation and self-renewal of GB cancer stem cells are effectively targetable by these novel mTORC1 and mTORC2 inhibitors. Therefore, the effectiveness of inhibitors of mTOR complexes can be estimated by their ability to suppress both mTORC1 and 2 and their ability to impede both cell proliferation and migration. (C) 2017 Elsevier Ltd. All rights reserved.