Ablation in mice of the mTORC components raptor, rictor, or mLST8 reveals that mTORC2 is required for signaling to Akt-FOXO and PKCα but not S6K1
Ablation in mice of the mTORC components raptor, rictor, or mLST8 reveals that mTORC2 is required for signaling to Akt-FOXO and PKCα but not S6K1
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DOI：
10.1016/j.devcel.2006.10.007
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发表时间：
2006-12-01
影响因子：
11.8
通讯作者：
Sabatini, David M.
中科院分区：
文献类型：
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作者：
Guertin, David A.;Stevens, Deanna M.;Sabatini, David M.
mTOR激酶通过两种不同的多蛋白复合物mTORC 1和mTORC 2控制细胞生长、增殖和存活。mTOR和mLST 8在两个复合物中，而raptor和rictor分别是mTORC 1和mTORC 2的一部分。为了研究mTORC 1和mTORC 2在体内的功能，我们产生了raptor、rictor或mLST 8缺陷的小鼠。就像mTOR缺失的小鼠一样，缺乏raptor的小鼠在发育早期死亡。然而，mLST 8缺失胚胎存活至e10.5，并且类似于缺失rictor的胚胎。mLST 8是维持rictor-mTOR相互作用所必需的，但不是raptor-mTOR相互作用所必需的，并且mLST 8和rictor两者都是Akt/PKB和PKC α的疏水基序磷酸化所必需的，但不是S6 K1。此外，胰岛素信号传导至FOXO 3，而不是TSC 2或GSK 3 β，需要mLST 8和rictor。因此，mTORC 1功能在早期发育中是必不可少的，mLST 8仅为mTORC 2信号传导所需，mTORC 2是Akt-FOXO和PKC α通路的必要组分。
The mTOR kinase controls cell growth, proliferation, and survival through two distinct multiprotein complexes, mTORC1 and mTORC2. mTOR and mLST8 are in both complexes, while raptor and rictor are part of only mTORC1 and mTORC2, respectively. To investigate mTORC1 and mTORC2 function in vivo, we generated mice deficient for raptor, rictor, or mLST8. Like mice null for mTOR, those lacking raptor die early in development. However, mLST8 null embryos survive until e10.5 and resemble embryos missing rictor. mLST8 is necessary to maintain the rictor-mTOR, but not the raptor-mTOR, interaction, and both mLST8 and rictor are required for the hydrophobic motif phosphorylation of Akt/PKB and PKC alpha, but not S6K1. Furthermore, insulin signaling to FOXO3, but not to TSC2 or GSK3 beta, requires mLST8 and rictor. Thus, mTORC1 function is essential in early development, mLST8 is required only for mTORC2 signaling, and mTORC2 is a necessary component of the Akt-FOXO and PKC alpha pathways.