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Review
. 2013 Jun;35(6):463-73.
doi: 10.1007/s10059-013-0138-2. Epub 2013 May 20.

Nutrient regulation of the mTOR complex 1 signaling pathway

Sang Gyun Kim  1 , Gwen R Buel, John Blenis
Affiliations
Review

Nutrient regulation of the mTOR complex 1 signaling pathway

Sang Gyun Kim et al. Mol Cells. 2013 Jun.

Abstract

The mammalian target of rapamycin (mTOR) is an evolutionally conserved kinase which exists in two distinct structural and functional complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). Of the two complexes, mTORC1 couples nutrient abundance to cell growth and proliferation by sensing and integrating a variety of inputs arising from amino acids, cellular stresses, energy status, and growth factors. Defects in mTORC1 regulation are implicated in the development of many metabolic diseases, including cancer and diabetes. Over the past decade, significant advances have been made in deciphering the complexity of the signaling processes contributing to mTORC1 regulation and function, but the mechanistic details are still not fully understood. In particular, how amino acid availability is sensed by cells and signals to mTORC1 remains unclear. In this review, we discuss the current understanding of nutrient-dependent control of mTORC1 signaling and will focus on the key components involved in amino acid signaling to mTORC1.

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Figures

Fig. 1
Fig. 1
The mTOR signaling pathway. The key signaling pathways that regulate mTORC1 and mTORC2 and the composition of each mTOR complex are depicted. Multiple inputs from growth factors, amino acids, cellular energy status, and stress are integrated into mTORC1 through the mechanisms shown. When mTORC1 is active, it plays a major role in promoting cell growth and proliferation by stimulating various anabolic processes such as protein, lipid, and nucleotide synthesis and ribosome biogenesis, and by inhibiting catabolic processes such as autophagy. mTORC2 is regulated by growth factors through a poorly identified mechanism, but unlike mTORC1, it does not respond to other upstream signals derived from nutrients or stress.
Fig. 2
Fig. 2
Amino acid signaling to mTORC1. The key mechanisms by which amino acids activate mTORC1 on the lysosomal surface are depicted. Under amino acid deficiency, the inactive state of the v-ATPase-Ragulator complex is unable to activate Rag GTPases on the lysosomal surface, thus mTORC1 cannot be recruited to the lysosome. In addition, LRS is inactive due to low level of leucine. Under amino acid sufficiency, the v-ATPase-Ragulator complex is activated through a lysosomal ‘inside-out’ mechanism, which in turn promotes the GTP-charging of RagA/B via a GEF function of the Ragulator. Activated Rags then recruit mTORC1 to the lysosomal surface, where mTORC1 can be activated by Rheb by integrating amino acid signals with other upstream signals converging on the Rheb GTPase. Under conditions of leucine availability, activated LRS signals to the Rags through the cytoplasmic face of the lysosome.
Fig. 3
Fig. 3
Nutrient signaling to mTORC1. The involvement of glutamine in nutrient regulation of mTORC1 signaling is depicted. Glutamine, as a free amino acid, promotes amino acid-induced mTORC1 activation by enhancing the uptake of essential amino acids including leucine. In addition, through metabolism to αKG, glutamine is able to activate Rag GTPases through a leucine/GDH-dependent mechanism. Leucine can also signal to the Rags by activating LRS and/or inhibiting SH3BP4, which is proposed to inhibit leucine signaling to mTORC1 by preventing the formation of the active Rags (Kim et al., 2012). The metabolism of the critical nutrients glucose and glutamine contribute to generating cellular energy, which is required for the assembly of a functional, dimeric mTORC1 via the TTT-RUVBL1/2 complex and its subsequent amino acid/Rag-dependent lysosomal localization.
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