Editors' ChoiceCell Biology

mTORC Acid Test

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Sci. Signal.  08 Mar 2011:
Vol. 4, Issue 163, pp. ec68
DOI: 10.1126/scisignal.4163ec68

Signaling through the mammalian target of rapamycin complexes 1 and 2 (mTORC1 and mTORC2) controls various cellular growth, metabolic, and survival processes. Whereas activation of mTORC1 regulates growth and metabolism, activation of mTORC2 regulates cellular survival. Hormones and growth factors induce signaling through both complexes, but amino acids have only been reported to activate mTORC1. Tato et al. report that amino acids are also capable of activating mTORC2 under starvation conditions. Insulin signaling through phosphatidylinositol 3-kinase (PI3K) causes phosphorylation of the kinase Akt on Thr308, which leads to activation of both mTORCs; Akt is further phosphorylated by mTORC2 to reach its maximal activity. In six different mammalian cell lines, amino acid treatment after serum starvation induced phosphorylation of Akt on Thr308 and on Ser473. The PI3K inhibitor wortmannin blocked both phosphorylation events, but the mTORC1 inhibitor rapamycin did not, suggesting that amino acids and insulin activated signaling through the same mechanism. Knocking down the mTORC2-specific component rictor using small interfering RNA (siRNA) eliminated amino acid–induced Ser473 phosphorylation but did not affect the phosphorylation of mTORC1 targets. Both mTOR and mTORC2 purified from lysates of amino acid–stimulated cells induced phosphorylation of Ser473 in an in vitro kinase assay. mTORC2-mediated phosphorylation of the Forkhead family transcription factor FOXO3a causes FOXO3a to be excluded from nuclei, thereby preventing it from stimulating expression of proapoptotic genes. Amino acid stimulation induced phosphorylation of FOXO3a, and this effect was blocked by wortmannin and by the Akt inhibitor Akti-1/2. The authors also noted that the ability of amino acids to stimulate Akt phosphorylation downstream of mTORC2 depended on the starvation conditions and duration of starvation, suggesting that this pathway may be significant in the interplay between nutrient sensing and insulin signaling observed in diseases such as obesity and cancer. The observation that mTORC2 can be activated by amino acids highlights a link between amino acids and cell survival and apoptosis, which may also have implications in aging and tumor progression.

I. Tato, R. Bartrons, F. Ventura, J. L. Rosa, Amino acids activate mammalian target of rapamycin complex 2 (mTORC2) via PI3K/Akt signaling. J. Biol. Chem. 286, 6128–6142 (2011). [Abstract] [Full Text]

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