Background The Complexes of mTOR Kinase and Their Activities

mTOR kinase is found in two complexes that differ in their major binding partner (Fig. 1): raptor (regulatory associated protein of TOR) in mTORC1 and rictor (rapamycin-msensitive companion of mTOR) in mTORC2 (Kim et al. 2002; Sarbassov et al. 2004). Both complexes contain a small protein called GpL that binds to the kinase domain of mTOR kinase and stabilizes the interaction with raptor and rictor (Kim et al. 2003). An additional protein, SIN1, found in mTORC2, maintains the integrity of the complex and regulates activity and substrate specificity (Jacinto et al. 2006; Polak and Hall 2006; Yang et al. 2006a). It is important to note that under normal conditions the two complexes differ in their sensitivity to the drug rapamycin; mTORC1 is sensitive and mTORC2 is insensitive (Sarbassov et al. 2004).

The role of mTORC1 in the control of cap-dependent translation has been extensively studied (Sarbassov et al. 2005a; Reiling and Sabatini 2006). Under conditions of adequate nutrients and oxygen, mTORC1 is activated, permitting phosphorylation of key substrates, p70S6 kinase (S6K) and 4E-BP (Fig. 1). S6K phosphorylation triggers events that promote the formation of translation initiation complexes (reviewed in Mamane et al. 2006); among these is the phosphorylation of ribosomal protein S6, which is often used as a marker for S6K activity. To understand the role of 4E-BP phosphorylation in the control of cap-dependent translation, we must consider its binding partner, eIF4E, and the eIF4F translation initiation complex (Figs. 1 and 2), which binds to the 5'-cap of an mRNA (Fig. 2), the first step in initiation of cap-dependent translation. Functional eIF4F complex consists of the scaffolding protein eIF4G bound to (1) eIF4E, the protein in the complex that directly binds the 5'-cap; (2) Mnk1, a kinase which phosphorylates eIF4E; and (3) eIF4A, an RNA helicase. As indicated in Fig. 2, the functionality of eIF4F depends on eIF4E being bound to eIF4G. However, eIF4E can be removed from eIF4G by binding to 4E-BP, this inhibits cap-dependent translation. It is the role of mTORC1 to control whether or not eIF4E is bound to 4E-BP. Under positive growth conditions, mTORC1 is active and phosphorylates 4E-BP, making 4E-BP unable to bind eIF4E. Thus eIF4E binds eIF4G and completes the eIF4F complex on the 5'-cap. Under these conditions, the polyA binding protein (PABP), bound to the 3'-poly A tail of the mRNA, can also interact with eIF4G (Fig. 2),

Active Cap-Dependen Translational Initiation

Inactive Cap-Dependen Translational Initiation

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