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Molecular mechanisms of mTOR-mediated translational control

Key Points

  • 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.

Abstract

The process of translation requires substantial cellular resources. Cells have therefore evolved complex mechanisms to control overall protein synthesis as well as the translation of specific mRNAs that are crucial for cell growth and proliferation. At the heart of this process is the mammalian target of rapamycin (mTOR) signalling pathway, which senses and responds to nutrient availability, energy sufficiency, stress, hormones and mitogens to modulate protein synthesis. Here, we highlight recent findings on the regulators and effectors of mTOR and discuss specific cases that serve as paradigms for the different modes of mTOR regulation and its control of translation.

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Figure 1: Regulating cap-dependent translation initiation.
Figure 2: The mTORC1 signalling regulatory network.
Figure 3: Regulation of PDCD4.
Figure 4: mTORC1 and S6K associate with mRNAs.

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Acknowledgements

We thank N. Kubica and M. Mendoza in the Blenis laboratory and L. Friedman and D. Dornan of Genentech Inc. for critical reading of the manuscript. We regret not being able to cite all of the relevant references owing to space limitations.

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Glossary

RNA helicase

An enzyme that resolves RNA base pairing through ATP hydrolysis, which leads to unfolding of structured RNAs.

PIKK family

(Phosphoinositide 3-kinase-related kinase). This family comprises high-molecular-weight signalling proteins, including mammalian target of rapamycin (mTOR), DNA protein kinase (DNA-PK), ataxia telangiectasia (A-T) mutated (ATM), ATR (A-T and RAD5-related) and SMG1. These kinases have central roles in the control of cell growth, gene expression, and genome surveillance and repair in eukaryotic cells.

GTPase-activating protein

(GAP). A protein that stimulates the intrinsic ability of a GTPase to hydrolyse GTP to GDP. Therefore, GAPs negatively regulate GTPases by converting them from active (GTP bound) to inactive (GDP bound) forms.

Wnt signalling

Wnt proteins are highly conserved secreted signalling molecules that regulate interactions between cells during embryogenesis. Wnt proteins bind to the Frizzled and low density lipoprotein receptor-related protein (LRP) families of receptors, and the signal is transduced to β-catenin, which then drives the transcription of Wnt target genes. Mutations in Wnt genes or Wnt pathway components lead to developmental defects and cancer.

Hypoxic stress

A lack of oxygen induces numerous changes in cell metabolism. Under hypoxic stress, inadequate ATP production leads to the downregulation of energy-consuming processes, such as protein synthesis. Hypoxia-inducible factor 1α (HIF1α) is the key transcription factor involved in cellular adaptation to hypoxia.

Rag proteins

In mammals, the Rag subfamily of Ras small GTPases comprises four members. They form heterodimers of RAGA or RAGB with RAGC or RAGD. Recent studies show that Rag proteins are required for amino acids to stimulate mammalian target of rapamycin complex 1 (mTORC1) signalling.

Ternary complex

A complex that comprises eIF2, Met-tRNA and GTP. During cap-dependent translation initiation, the complex associates with 40S ribosomal subunit, eIF3 and eIF1A to form the 43S pre-initiation complex. The assembly of the ternary complex is regulated by eIF2B.

Internal ribosome entry site

A structure in the 5′ untranslated region or open reading frame of some mRNAs of cellular or viral origin. This site mediates translation initiation independently of the cap structure by recruiting the ribosome directly to an internal position of the mRNA.

Polysome

Two or more ribosomes attached to different points on the same strand of mRNA. Also known as a polyribosome.

Exon-junction complex

A complex of proteins that is deposited as a consequence of pre-mRNA splicing 20–24 nucleotides upstream of splicing-generated exon–exon junctions of newly synthesized mRNA. These proteins are thought to mediate the enhanced accuracy and efficiency of gene expression of spliced mRNAs.

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Ma, X., Blenis, J. Molecular mechanisms of mTOR-mediated translational control. Nat Rev Mol Cell Biol 10, 307–318 (2009). https://doi.org/10.1038/nrm2672

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