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Review
. 2014 Nov 13;15(11):20753-69.
doi: 10.3390/ijms151120753.

Current models of mammalian target of rapamycin complex 1 (mTORC1) activation by growth factors and amino acids

Xu Zheng  1 , Yan Liang  2 , Qiburi He  3 , Ruiyuan Yao  4 , Wenlei Bao  5 , Lili Bao  6 , Yanfeng Wang  7 , Zhigang Wang  8
Affiliations
Review

Current models of mammalian target of rapamycin complex 1 (mTORC1) activation by growth factors and amino acids

Xu Zheng et al. Int J Mol Sci. .

Abstract

Mammalian target of rapamycin (mTOR), which is now referred to as mechanistic target of rapamycin, integrates many signals, including those from growth factors, energy status, stress, and amino acids, to regulate cell growth and proliferation, protein synthesis, protein degradation, and other physiological and biochemical processes. The mTOR-Rheb-TSC-TBC complex co-localizes to the lysosome and the phosphorylation of TSC-TBC effects the dissociation of the complex from the lysosome and activates Rheb. GTP-bound Rheb potentiates the catalytic activity of mTORC1. Under conditions with growth factors and amino acids, v-ATPase, Ragulator, Rag GTPase, Rheb, hVps34, PLD1, and PA have important but disparate effects on mTORC1 activation. In this review, we introduce five models of mTORC1 activation by growth factors and amino acids to provide a comprehensive theoretical foundation for future research.

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Figures

Figure 1
Figure 1
The Rhebulator-Rheb model of mTORC1 activation by growth factors. mTOR, Rheb, and the TSC-TBC complex colocalize on the lysosomal surface, and the GAP activity of TSC2 inhibits the function of GTP-bound Rheb. Growth factors induce the phosphorylation of the TSC-TBC complex, resulting in its dissociation from the lysosome, although TSC2 continues to have GAP activity. This separation of the TSC-TBC complex prevents TSC2 from interacting with Rheb-GTP on the lysosome to inhibit its activity. Under the effects of GEFs or its own activity, GDP-bound Rheb converts into GTP-bound Rheb, stimulating the kinase activity of mTORC1.
Figure 2
Figure 2
The Ragulator-Rags model of mTORC1 activation by amino acids. Ragulator, a GEF, comprises p14, MP1, p18, LAMTOR4, and LAMTOR5, which localize to the lysosomal surface through p18. Under sufficient amino acids, Ragulator recruits Rag GTPases to the lysosome. Concurrently, amino acids promote the GEF activity of Ragulator for GDP-bound RagA/B and the GAP activity of FLCN-FNIP1/2 and LRS for GTP-bound RagC/D, and active Rag GTPases can recruit mTORC1 to the lysosome to interact with GTP-bound Rheb, which localizes to lysosome, initiating mTORC1 signaling. SH3BP5 is a negative regulator of Rags that interacts with inactive Rag GTPases under amino acid starvation to impede the formation of an active Rag GTPase complex, which inhibits mTORC1 activation. In contrast, p62 binds to Rag proteins to favor the formation and localization of active Rag GTPases, which regulate mTORC1.
Figure 3
Figure 3
The “inside-out” model of mTORC1 activation by amino acids. Ragulator, PAT1, v-ATPase, and Rheb localize on the lysosomal surface. The amino acid signals in the lysosome are sensed by v-ATPase and PAT1, which actively export amino acids from the lumen to the cytosol and induce structural rearrangement of the v-ATPase-Ragulator-Rag GTPase by hydrolyzing ATP. This process activates the Ragulator and Rag GTPases, which colocalize mTORC1 to the lysosome to interact with active Rheb-GTP on the surface, initiating mTORC1 signaling.
Figure 4
Figure 4
The“hVps34/Rheb-PLD1” model of mTORC1 activation by amino acids. Amino acids stimulate Ca2+/CaM or hVps15, interacting with hVps34 to activate it. The activated hVps34 complex catalyzes PI to produce PI3P, which associates with the PX domain of PLD1 to stimulate PLD1. Concurrently, active GTP-bound Rheb that is stimulated by amino acids also promotes PLD1 activity. Subsequently, the product of phosphatidylcholine (PC) hydrolysis by PLD1, PA, binds directly to the FRB domain of mTOR and competitively inhibits rapamycin-FKBP12 to complex with mTOR. This process can activate mTORC1 directly.
Figure 5
Figure 5
Model of mTORC1 activation by amino acids: “Rheb binds to FKBP38 and mTOR is unleashed.” Under conditions of ample amino acids, Rheb-GTP might interact with FKBP38 and induce the release and activation of mTOR.
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