Molecular mechanisms of mTOR-mediated translational control

Abstract

Mammalian cells have evolved elaborate mechanisms for translational control, most of which are sensitive to nutrient availability, cellular energy, stress, hormones and growth factor stimuli. A key pathway that integrates and responds to environmental cues involves the target of rapamycin (TOR). In mammals, the form of TOR that directly regulates protein synthesis is mammalian TOR complex 1 (mTORC1). Growth factors or related hormones activate several key signal transduction pathways. In particular, the phosphoinositide 3-kinase (PI3K)–AKT pathway and the Ras–ERK (extracellular signal-regulated kinase) pathway stimulate mTORC1 signalling by inhibiting the tumour suppressor complex tuberous sclerosis 1 (TSC1)–TSC2, a negative regulator of mTORC1. AMP-activated protein kinase is the energy sensor for mTORC1, whereas the Rag family of small GTPases mediate amino acid signalling to mTORC1. mTORC1 signalling regulates eukaryotic translation initiation factor 4G (eIF4G), eIF4B and 4E-binding protein 1 (4E-BP1), as well as the 40S ribosomal S6 kinases (S6Ks), including S6K1 and S6K2. Some mRNA species contain inhibitory secondary structures in the 5′ untranslated region, which prevents efficient scanning of the small ribosome subunit to the start codon. The initiation factor eIF4A is an RNA helicase that is capable of unwinding mRNA secondary structures; the helicase activity can be modulated by S6K1. The multisubunit initiation factor complex eIF3 functions as a dynamic scaffold for mTORC1 and S6K1 binding, and the scaffold protein SKAR recruits activated S6K1 to newly generated mRNAs.