Regulation of insulin receptor substrate-1 by mTORC2 (mammalian target of rapamycin complex 2).
Regulation of insulin receptor substrate-1 by mTORC2 (mammalian target of rapamycin complex 2).
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DOI：
10.1042/bst20130018
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发表时间：
2013-08
影响因子：
3.9
通讯作者：
Jacinto E
中科院分区：
文献类型：
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作者：
Destefano MA;Jacinto E
mTOR（雷帕霉素的哺乳动物靶标）对营养物质、能量和生长因子的存在做出反应，将细胞代谢、生长和增殖联系起来。雷帕霉素敏感的 mTORC（mTOR 复合物）1 激活翻译调节因子 S6K（S6 激酶），导致营养物存在下蛋白质合成增加。另一方面，对雷帕霉素不敏感的 mTORC2 通过磷酸化 Akt 来响应胰岛素等生长因子的存在，以促进其成熟和变构激活。我们最近发现 mTORC2 还可以在 IRS-1（胰岛素受体底物-1）水平上调节胰岛素信号传导。虽然 mTORC1 促进与 IRS-1 下调相关的 IRS-1 丝氨酸磷酸化，但我们发现 mTORC2 介导其降解。在 mTORC2 破坏的细胞中，尽管 mTORC1 介导的丝氨酸位点发生磷酸化，但无活性的 IRS-1 仍在积累。 IRS-1 降解缺陷是由于 CUL7 (Cullin 7) 泛素连接酶底物靶向亚基 Fbw8 的表达减弱所致。 mTORC2 和 Fbw8 在膜上共定位，其中 mTORC2 磷酸化 Ser86 以稳定 Fbw8，并在胰岛素刺激下促进其胞质定位。在慢性胰岛素暴露的条件下，失活的丝氨酸磷酸化 IRS-1 和 Fbw8 共定位于细胞质，其中前者通过 CUL7/Fbw8 泛素化。因此，mTORC2 通过控制 Fbw8 稳定性和定位向 IRS-1 负反馈。我们的研究结果表明，除了持续的 mTORC1 信号传导之外，mTORC2 信号的增加还可以由于 mTORC2 介导的 IRS-1 降解而促进胰岛素抵抗。
mTOR (mammalian target of rapamycin) responds to the presence of nutrients, energy and growth factors to link cellular metabolism, growth and proliferation. The rapamycin-sensitive mTORC (mTOR complex) 1 activates the translational regulator S6K (S6 kinase), leading to increased protein synthesis in the presence of nutrients. On the other hand, the rapamycin-insensitive mTORC2 responds to the presence of growth factors such as insulin by phosphorylating Akt to promote its maturation and allosteric activation. We recently found that mTORC2 can also regulate insulin signalling at the level of IRS-1 (insulin receptor substrate-1). Whereas mTORC1 promotes IRS-1 serine phosphorylation that is linked to IRS-1 down-regulation, we uncovered that mTORC2 mediates its degradation. In mTORC2-disrupted cells, inactive IRS-1 accumulated despite undergoing phosphorylation at the mTORC1-mediated serine sites. Defective IRS-1 degradation was due to attenuated expression of the CUL7 (Cullin 7) ubiquitin ligase substrate-targeting subunit Fbw8. mTORC2 and Fbw8 co-localize at the membrane where mTORC2 phosphorylates Ser86 to stabilize Fbw8 and promotes its cytosolic localization upon insulin stimulation. Under conditions of chronic insulin exposure, inactive serine-phosphorylated IRS-1 and Fbw8 co-localize to the cytosol where the former becomes ubiquitylated via CUL7/Fbw8. Thus mTORC2 negatively feeds back to IRS-1 via control of Fbw8 stability and localization. Our findings reveal that, in addition to persistent mTORC1 signalling, increased mTORC2 signals can promote insulin resistance due to mTORC2-mediated degradation of IRS-1.