The mechanistic target of rapamycin (mTOR) functions as a component of two large 
complexes, mTORC1 and mTORC2, which play crucial roles in regulating cell growth 
and homeostasis. However, the molecular mechanisms by which mTOR controls cell 
proliferation remain elusive. Here we show that the FoxO3a transcription factor 
is coordinately regulated by mTORC1 and mTORC2, and plays a crucial role in 
controlling cell proliferation. To dissect mTOR signaling, mTORC1 was 
specifically inactivated by depleting p18, an essential anchor of mTORC1 on 
lysosomes. mTORC1 inactivation caused a marked retardation of cell 
proliferation, which was associated with upregulation of cyclin-dependent kinase 
inhibitors (CDKIs). Although Akt was activated by mTORC1 inactivation, FoxO3a 
was upregulated via an epigenetic mechanism and hypophosphorylated at Ser314, 
which resulted in its nuclear accumulation. Consistently, mTORC1 inactivation 
induced downregulation of serum- and glucocorticoid-inducible kinase 1 (SGK1), 
the kinase responsible for Ser314 phosphorylation. Expression of FoxO3a mutated 
at Ser314 suppressed cell proliferation by inducing CDKI expression. SGK1 
overexpression suppressed CDKI expression in p18-deficient cells, whereas SGK1 
knockdown induced CDKI expression in wild-type cells, resulting in the 
suppression of cell proliferation. These results suggest that mTORC1, in 
coordination with mTORC2, controls cell proliferation by regulating FoxO3a gene 
expression and SGK1-mediated phosphorylation of FoxO3a at Ser314.