TOR signaling in mammals

Abstract

MTOR activation depends on several inputs, including nutrients (amino acids), energy (ATP) and growth factors (Schmelzle and Hall, 2000). Both ATP and amino acid deprivation result in mTOR inactivation, even in the presence of growth factors such as insulin (Schmelzle and Hall, 2000, Gingras et al., 2004; Dufner and Thomas, 1999). The mechanism by which amino acids and ATP activate mTOR is not completely clear. Nonetheless, under energy starvation conditions, the AMP-activated protein kinase (AMPK) phosphorylates and activates tuberous sclerosis protein 2 (TSC2, also termed tuberin) (Inoki et al., 2003), which inhibits mTOR in combination with TSC1 (hamartin) (Inoki et al., 2003; Potter et al., 2003; Gao et al., 2002). Amino acid deprivation has also been shown to regulate mTOR via the TSC complex (Gao et al., 2002). Restoration of ATP or amino acids induces mTOR activation, which is further increased by growth factor addition. Growth factors regulate mTOR via phosphoinositide 3-kinase (PI3K), protein kinase B (PKB/Akt) and TSC.⇓