The definitive genetic 'dissection' of the two complexes in living mice. Deleting Raptor was lethal early (mTORC1 essential); deleting Rictor or mLST8 selectively knocked out mTORC2 signaling to Akt and PKCalpha but spared S6K1. This cleanly assigned jobs to each complex and proved mLST8 is an mTORC2-specific requirement.
| Evidence tier | D Mechanistic / in vitro / review |
| Study type | 5 - Mechanistic / In Vitro |
| Model system | Knockout mice (raptor/rictor/mLST8) |
| Journal | Developmental Cell |
| Year | 2006 |
| Peer reviewed | Yes |
| Source | DOI 10.1016/j.devcel.2006.10.007 · PMID 17141160 |
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 PKCalpha, but not S6K1. Furthermore, insulin signaling to FOXO3, but not to TSC2 or GSK3beta, 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 PKCalpha pathways.
| Intervention | Genetic (raptor / rictor / mLST8 knockout mice) |
| Target | mTORC1 vs mTORC2 / Akt-FOXO / PKCα |
| Model | Knockout mice |
| Effect | mTORC2 (rictor/mLST8) is required for Akt-FOXO and PKCα signaling but not S6K1; raptor/mTOR-null mice die early |