TOR signaling in mammals.

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). 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. Phosphorylation of 4EBP1 releases eIF4E, allowing initiation of translation (Gingras et al., 2004). In addition to 4EBP1, mTOR also regulates translation via S6 kinase (S6K, formerly known as p70s6K). 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). 5′-TOP transcripts encode several ribosomal proteins and translation elongation factors. By acting on S6K, mTOR facilitates ribosome biogenesis and translation elongation (Gingras et al., 2004; Dufner and Thomas, 1999). To recognize 4EBP1 and S6K, mTOR must associate with a protein adaptor termed Raptor (for regulatory associated protein of mTOR). 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).