1. 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
- Author
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David A. Guertin, Nada Y. Kalaany, Carson C. Thoreen, Jason Moffat, Michael S. Brown, Deanna Stevens, Aurora A. Burds, Kevin Fitzgerald, and David M. Sabatini
- Subjects
DEVBIO ,mTORC1 ,mTORC2 ,Fetal Development ,Glycogen Synthase Kinase 3 ,Mice ,0302 clinical medicine ,Insulin ,TOR complex ,Phosphorylation ,Cytoskeleton ,Mice, Knockout ,0303 health sciences ,TOR Serine-Threonine Kinases ,Forkhead Box Protein O3 ,digestive, oral, and skin physiology ,Forkhead Transcription Factors ,SIGNALING ,030220 oncology & carcinogenesis ,Gene Targeting ,FOXO3 ,biological phenomena, cell phenomena, and immunity ,Signal transduction ,Protein Binding ,Signal Transduction ,Protein Kinase C-alpha ,P70-S6 Kinase 1 ,Mechanistic Target of Rapamycin Complex 1 ,Biology ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,Tuberous Sclerosis Complex 2 Protein ,Animals ,Fetal Viability ,Molecular Biology ,Protein kinase B ,PI3K/AKT/mTOR pathway ,030304 developmental biology ,Glycogen Synthase Kinase 3 beta ,Ribosomal Protein S6 Kinases ,Tumor Suppressor Proteins ,Proteins ,Cell Biology ,Embryo, Mammalian ,Multiprotein Complexes ,Trans-Activators ,Cancer research ,Proto-Oncogene Proteins c-akt ,Transcription Factors ,Developmental Biology - Abstract
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.
- Published
- 2006