A complex interplay between Akt, TSC2 and the two mTOR complexes.
A complex interplay between Akt, TSC2 and the two mTOR complexes.
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DOI：
10.1042/bst0370217
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发表时间：
2009-02
影响因子：
3.9
通讯作者：
Manning BD
中科院分区：
文献类型：
--
作者：
Huang J;Manning BD
Akt/PKB既调节TSC 1-TSC 2复合物，又受其调节。在磷酸肌醇3-激酶（PI 3 K）的下游，Akt直接在多个位点磷酸化TSC 2。虽然分子机制尚未完全理解，但这些磷酸化事件缓解了TSC 1-TSC 2复合物对Rheb和mTOR复合物1（mTORC 1）的抑制作用，从而响应生长因子激活mTORC 1。通过负反馈机制，mTORC 1活性抑制生长因子对PI 3 K的刺激。这在缺乏TSC 1-TSC 2复合物的细胞和肿瘤中尤其明显，其中Akt信号传导至少部分地由于mTORC 1的组成性激活而严重减弱。Akt和TSC 1-TSC 2复合体之间的关系的另一个复杂性水平最近被发现。mTOR复合物2（mTORC 2或mTOR-Rictor复合物）的生长因子刺激的激酶活性通常通过磷酸化其疏水基序（Ser 473）来增强Akt信号传导，发现在缺乏TSC 1-TSC 2复合物的细胞中是有缺陷的。这种对mT 0 RC 2的作用可以与TSC 1-TSC 2复合物对Rheb和mT 0 RC 1的抑制作用分开。这篇综述讨论了我们目前对Akt，TSC 1-TSC 2复合物和mTOR之间日益复杂的功能相互作用的理解，这些相互作用在各种人类疾病中具有根本性的重要作用。
Akt/PKB both regulates and is regulated by the TSC1-TSC2 complex. Downstream of phosphoinositide 3-kinase (PI3K), Akt directly phosphorylates TSC2 on multiple sites. While the molecular mechanism is not well understood, these phosphorylation events relieve the inhibitory effects of the TSC1-TSC2 complex on Rheb and mTOR complex 1 (mTORC1), thereby activating mTORC1 in response to growth factors. Through negative feedback mechanisms, mTORC1 activity inhibits growth factor stimulation of PI3K. This is particularly evident in cells and tumors lacking the TSC1-TSC2 complex, where Akt signalling is severely attenuated due, at least in part, to constitutive activation of mTORC1. An additional level of complexity in the relationship between Akt and the TSC1-TSC2 complex has recently been uncovered. The growth factor-stimulated kinase activity of mTOR complex 2 (mTORC2 or the mTOR-Rictor complex), which normally enhances Akt signalling by phosphorylating its hydrophobic motif (Ser473), was found to be defective in cells lacking the TSC1-TSC2 complex. This effect on mTORC2 can be separated from the inhibitory effects of the TSC1-TSC2 complex on Rheb and mTORC1. This review discusses our current understanding of the increasingly complex functional interactions between Akt, the TSC1-TSC2 complex and mTOR, which are fundamentally important players in a large variety of human diseases.