Biology Reference
In-Depth Information
The role of mTORC1 in the control of cap-dependent translation has been exten-
sively studied (Sarbassov et al. 2005a; Reiling and Sabatini 2006). Under condi-
tions 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 posi-
tive 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),
Fig. 2
The control of cap-dependent translation mediated by the activation or inactivation of
mTORC1. Details are discusses in the text
