The mechanism by which amino acids and ATP activate mTOR is not completely clear. 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).
MTOR activation depends on several inputs, including nutrients (amino acids), energy (ATP) and growth factors ( Schmelzle and Hall, 2000). mTOR is found in a highly conserved complex that includes Raptor ( Kim et al., 2002 Hara et al., 2002) and a protein of unknown function called mLST8 ( Chen and Kaiser, 2003). To recognize 4EBP1 and S6K, mTOR must associate with a protein adaptor termed Raptor (for regulatory associated protein of mTOR). By acting on S6K, mTOR facilitates ribosome biogenesis and translation elongation ( Gingras et al., 2004 Dufner and Thomas, 1999). 5′-TOP transcripts encode several ribosomal proteins and translation elongation factors. This Ser/Thr kinase phosphorylates the ribosomal S6 protein, facilitating recruitment and translation of a specific mRNA subset that contains a 5′ polypyrimidine tract (5′-TOP) ( Dufner and Thomas, 1999). In addition to 4EBP1, mTOR also regulates translation via S6 kinase (S6K, formerly known as p70 s6K). Phosphorylation of 4EBP1 releases eIF4E, allowing initiation of translation ( Gingras et al., 2004). mTOR exerts its effects by phosphorylating eukaryotic initiation factor 4E binding protein 1 (4EBP1), which inhibits 5′-cap-dependent mRNA translation (the majority of cellular translation) by binding and inactivating eIF4E. Central to the pathways that induce cell growth in mammals is the murine target of rapamycin (mTOR), a multi-domain, 298 kDa, evolutionarily-conserved Ser/Thr kinase that is inhibited by the drug rapamycin ( Schmelzle and Hall, 2000).
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