The Translational Regulation in mTOR Pathway

Abstract

The mechanistic/mammalian target of rapamycin (mTOR) plays a master role in cell proliferation and growth in response to insulin, amino acids, energy levels, and oxygen. mTOR can coordinate upstream signals with downstream effectors, including transcriptional and translational apparatuses to regulate fundamental cellular processes such as energy utilization, protein synthesis, autophagy, cell growth, and proliferation. Of the above, protein synthesis is highly energy-consuming; thus, mRNA translation is under the tight and immediate control of mTOR signaling. The translational regulation driven by mTOR signaling mainly relies on eukaryotic translation initiation factor 4E (eIF4E)-binding protein (4E-BP), ribosomal protein S6 kinase (S6K), and its downstream players, which are significant in rapid cellular response to environmental change. mTOR signaling not only controls the general mRNA translation, but preferential mRNA translation as well. This means that mTOR signaling shows the stronger selectivity to particular target mRNAs. Some evidence has supported the contribution of 4E-BP and La-related proteins 1 (LARP1) to such translational regulation. In this review, we summarize the mTOR pathway and mainly focus on mTOR-mediated mRNA translational regulation. We introduce the major components of mTOR signaling and their functions in translational control in a general or particular manner, and describe how the specificity of regulation is coordinated. Furthermore, we summarize recent research progress and propose additional ideas for reference. Because the mTOR pathway is on the center of cell growth and metabolism, comprehensively understanding this pathway will contribute to the therapy of related diseases, including cancers, type 2 diabetes, obesity, and neurodegeneration.

Keywords: 4E-BP; LARP1; S6K; mTOR; translational regulation.

Figure 1

mTOR pathway. The major signaling pathways of mTORC1 and mTORC2. Arrows indicate facilitation and activation, and blocks indicate inhibition.

Figure 2

The main downstream signaling pathways of mTORC1. Arrows indicate facilitation and activation, and blocks indicate inhibition.

Figure 3

S6K and 4E-BP in mRNA translation. When mTORC1 is activated, 4E-BP is phosphorylated and inactive, and LARP1 is phosphorylated and binds to the 3′ UTRs of RP mRNAs, promoting their translation. When mTORC1 is inactivated, 4E-BP binds to eIF4E and inhibits eIF4F complex formation. S6K1 binds to eIF3 complex to block translation initiation. LARP1 directly binds to 5′ caps, 5′ TOP sequences, and 3′ UTRs of RP mRNAs and inhibits their translation.