mTORC1-Activated S6K1 Phosphorylates Rictor on Threonine 1135 and Regulates mTORC2 Signaling
mTORC1-Activated S6K1 Phosphorylates Rictor on Threonine 1135 and Regulates mTORC2 Signaling
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DOI：
10.1128/mcb.00601-09
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发表时间：
2010-02-15
影响因子：
5.3
通讯作者：
Roux, Philippe P.
中科院分区：
文献类型：
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作者：
Julien, Louis-Andre;Carriere, Audrey;Roux, Philippe P.
哺乳动物雷帕霉素靶蛋白（mTOR）是一种保守的丝氨酸/苏氨酸激酶，它形成两种功能不同的复合物，对营养和生长因子信号传导很重要。mTOR复合物1 （mTORC1）调控mRNA翻译和核糖体生物发生，而mTORC2在Akt的磷酸化和随后的激活中发挥重要作用。有趣的是，mTORC1负调控Akt的激活，但mTORC1信号是否直接靶向mTORC2仍然未知。在这里，我们发现生长因子促进了mTORC2的一个重要亚基Rictor （mTOR的雷帕霉素不敏感伴侣）的磷酸化。我们发现Rictor磷酸化需要mTORC1活性，更具体地说，需要p70核糖体S6激酶1 （S6K1）。我们在Rictor中鉴定了几个磷酸化位点，发现Thr1135在体外和体内都以雷帕霉素敏感的方式被S6K1直接磷酸化。Rictor在Thr1135上的磷酸化不影响mTORC2的组装、激酶活性或细胞定位。然而，我们发现表达Rictor T1135A突变体的细胞增加了mtorc2依赖性的Akt磷酸化。此外，Akt底物fox01 /3a和糖原合成酶激酶3 α / β (GSK3 α / β)的磷酸化在这些细胞中被发现增加，表明s6k1介导的Rictor磷酸化抑制了mTORC2和Akt信号传导。总之，我们的研究结果揭示了两个mTOR复合物之间的新调控联系，其中Rictor整合了mtorc1依赖性信号。
The mammalian target of rapamycin (mTOR) is a conserved Ser/Thr kinase that forms two functionally distinct complexes important for nutrient and growth factor signaling. While mTOR complex 1 (mTORC1) regulates mRNA translation and ribosome biogenesis, mTORC2 plays an important role in the phosphorylation and subsequent activation of Akt. Interestingly, mTORC1 negatively regulates Akt activation, but whether mTORC1 signaling directly targets mTORC2 remains unknown. Here we show that growth factors promote the phosphorylation of Rictor (rapamycin-insensitive companion of mTOR), an essential subunit of mTORC2. We found that Rictor phosphorylation requires mTORC1 activity and, more specifically, the p70 ribosomal S6 kinase 1 (S6K1). We identified several phosphorylation sites in Rictor and found that Thr1135 is directly phosphorylated by S6K1 in vitro and in vivo, in a rapamycin-sensitive manner. Phosphorylation of Rictor on Thr1135 did not affect mTORC2 assembly, kinase activity, or cellular localization. However, cells expressing a Rictor T1135A mutant were found to have increased mTORC2-dependent phosphorylation of Akt. In addition, phosphorylation of the Akt substrates FoxO1/3a and glycogen synthase kinase 3 alpha/beta (GSK3 alpha/beta) was found to be increased in these cells, indicating that S6K1-mediated phosphorylation of Rictor inhibits mTORC2 and Akt signaling. Together, our results uncover a new regulatory link between the two mTOR complexes, whereby Rictor integrates mTORC1-dependent signaling.