Next Article in Journal
Analysis of Protein–Protein Interactions in MCF-7 and MDA-MB-231 Cell Lines Using Phthalic Acid Chemical
Previous Article in Journal
Structures of the Inducer-Binding Domain of Pentachlorophenol-Degrading Gene Regulator PcpR from Sphingobium chlorophenolicum
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
IJMS
Volume 15
Issue 11
10.3390/ijms151120753
ijms-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Current Models of Mammalian Target of Rapamycin Complex 1 (mTORC1) Activation by Growth Factors and Amino Acids

by
Xu Zheng
1,2,†,
Yan Liang
1,†,
Qiburi He
1,
Ruiyuan Yao
1,
Wenlei Bao
1,
Lili Bao
1,3,
Yanfeng Wang
1,* and
Zhigang Wang
1,*
1
College of Life Sciences, Inner Mongolia University, Hohhot 010021, China
2
Department of Clinical Laboratory, Hulunbeir Municipal People's Hospital, Hailar 021008, China
3
College of Basic Medical Science, Inner Mongolia Medical University, Hohhot 010110, China
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Int. J. Mol. Sci. 2014, 15(11), 20753-20769; https://doi.org/10.3390/ijms151120753
Submission received: 4 September 2014 / Revised: 24 September 2014 / Accepted: 29 October 2014 / Published: 13 November 2014
(This article belongs to the Section Biochemistry)
Browse Figures
Versions Notes

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.

1. Introduction

TOR (target of rapamycin) is an evolutionarily highly conserved serine/threonine kinase that belongs to the phosphatidylinositol kinase-related kinase (PIKK) family [1,2]. Shortly after its identification in Saccharomyces cerevisiae, a mammalian ortholog of TOR was identified and named FK506-binding protein 12 (FABP12)-rapamycin-associated protein (FRAP), or rapamycin and FKBP12 target (RAFT). Later, it was officially named mammalian target of rapamycin (mTOR) [3,4,5,6,7]. Recently, mTOR was renamed mechanistic target of rapamycin (MTOR) by the HUGO Gene Nomenclature Committee (HGNC). Rapamycin, a specific inhibitor of mTOR, inhibits cell growth and proliferation [5,8,9].
mTOR combines with various components to form two mTOR complexes, mTORC1 and mTORC2. mTORC1 comprises mTOR, Raptor (regulator-associated protein of mTOR), PRAS40 (proline-rich Akt substrate, 40 kDa), Deptor, mLst8 (mammalian lethal with SEC13 protein 8), Tti1, and Tel2. mTORC2 is composed of mTOR, Rictor, mSin1 (mammalian stress-activated protein kinase-interacting protein 1), Protor1/2, Deptor, mLst8, Tti1, and Tel2. Raptor in mTORC1 and Rictor in mTORC2 have equivalent significance. The phosphorylation or acetylation of Rictor influences generation of mTORC2 [10,11,12]. Raptor and PRAS40 are unique to mTORC1, as Rictor, mSin1, and Protor1/2 are to mTORC2; the difference between Raptor and Rictor is likely the basis for their disparate functions.
The consensus over the past several decades is that mTORC1 is sensitive to rapamycin, whereas mTORC2 is rapamycin insensitive, although recent reports indicate that prolonged rapamycin treatment prevents the de novo generation of mTORC2 [8,13,14,15,16,17]. Consequently, mTORC1 has been studied in greater detail, due to its sensitivity to rapamycin.
The six components of mTORC1 have varying influences on mTORC1 signaling. Raptor, mLST8, Tti1, and Tel2 are positive regulators, whereas PRAS40 and Deptor are negative regulators. Raptor interacts with mTOR at multiple points and binds to downstream effectors of mTOR, including S6K1 (ribosomal protein S6 kinase 1) and 4E-BP1 (eukaryotic translation initiation factor 4E-binding protein 1), which are the chief downstream factors in protein synthesis and ribosome formation [18,19,20,21,22,23]. S6K1 is a kinase of S6, which controls protein synthesis, and 4E-BP1 governs the release of the translation initiation factor eIF4E [1,24,25].
In addition, ULK1 (unc-51-like autophagy activating kinase 1), a homolog of yeast ATG1, is believed to be another downstream effector of mTORC1. ULK1 is a key initiator of mammalian autophagy, and its activation is prevented by mTORC1 under nutrient sufficiency [26]. mLST8 interacts specifically with the kinase domain of mTOR and regulates the stability of mTOR-Raptor association under various nutritional conditions [18,27]. mLST8 receives upstream signals, including nutrient factors and growth factors, and overexpression of mLST8 stimulates mTOR kinase activity [18,27]. However, deletion of mLST8 does not affect mTORC1 activity in mice [28,29]. Tti1, a putative novel mTOR-binding protein, positively regulates mTOR activity and interacts with Tel2, a common partner in the assembly of the mTOR complex, to maintain its activity [30,31]. Raptor, mLTS8, Tti1, and Tel2 are essential for activating mTORC1 signaling by growth factors and amino acids.
PRAS40 was isolated as a substrate of AKT (also known as protein kinase B, PKB) [32]. The phosphorylation of PRAS40 leads to the interaction between it and 14-3-3 protein, which associates with transcription factors, signaling molecules, apoptosis factors, and tumor suppressors to promote cell survival as a phosphoserine-/phosphothreonine-binding protein [32,33]. PRAS40 is phosphorylated by mTOR. By binding to mTORC1 via Raptor, PRAS40 inhibits mTORC1 autophosphorylation and mTORC1 kinase activity toward 4EBP1 and itself [34,35]. Knockdown of PRAS40 impairs the amino acid- and insulin-stimulated phosphorylation of 4EBP1 and S6K1, demonstrating that PRAS40 is required for signaling downstream of mTORC1 [36,37,38].
Deptor, an mTOR inhibitor, is also negatively regulated by mTOR. Knockdown of Deptor ameliorates disuse muscle atrophy [39,40,41]. Deptor phosphorylation by mTOR in response to growth signals cooperates with casein kinase I (CK I) to generate a degron that binds to an F box protein, βTrCP, for subsequent ubiquitination and degradation [42,43,44]. Consequently, mTOR generates an autoamplification loop to stimulate its activity.

2. Model of mTORC1 Activation by Growth Factors

Growth factors, such as insulin and insulin-like growth factors (IGFs), stimulate mTORC1 through the PI3K (phosphatidylinositol-4,5-bisphosphate 3-kinase) and Ras signaling pathways [2,29,45], which enhances the phosphorylation of the TSC-TBC complex by protein kinase B (AKT), extracellular signal-regulated kinase 1/2 (ERK1/2), and p90 ribosomal S6 kinase (RSK1) [29,46,47,48,49,50]. The TSC-TBC complex, also known as Rhebulator, comprises TSC1 (tuberous sclerosis 1), TSC2 (tuberous sclerosis 2), and TBC1D7 (TBC1 domain family, member 7) [46,51]. TSC2 is a GTPase-activating protein (GAP) that induces GTP hydrolysis of Rheb (Ras homolog enriched in brain), which is a Ras-like small guanosine triphosphatase (GTPase) that shuttles between an active GTP-bound form and an inactive GDP-bound form [52,53]. Thus, TSC2 hydrolyzes Rheb-GTP to Rheb-GDP and in turn inhibits mTORC1 kinase activity [54].
Conversely, recent reports have demonstrated that mTOR, Rheb, and TSC2 colocalize with a lysosomal marker, called LAMP2 (lysosome-associated membrane protein 2) [46,55]. When the TSC-TBC complex is phosphorylated by upstream regulators, it dissociates from the lysosome, preventing TSC2 from hydrolyzing Rheb-GTP on the lysosome, although the GAP activity of TSC2 remains [46,56,57]. A recent study noted that insulin stimulates acute dissociation of the TSC-TBC complex from the lysosomal surface, on which subpopulations of Rheb and mTORC1 reside, showing that Akt-mediated phosphorylation of TSC2 effects the dissociation of the TSC-TBC complex from the lysosome in response to insulin [58]. As discussed, phosphorylation of the TSC-TBC complex activates Rheb and mTORC1 signaling. TSC-TBC and Rheb have a significant effect on the activation of mTORC1, in what we refer to as the Rhebulator-Rheb model, shown in Figure 1.
Ijms 15 20753 g001 1024
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 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.
Ijms 15 20753 g001
Rheb needs a guanine exchange factor (GEF) to transition from its GDP-bound to GTP-bound form [59], but GEF for Rheb has not been determined. Although Hsu et al. [60,61,62,63] suggested that Drosophila translationally controlled tumor protein (dTCTP) is a GEF of dRheb and that TCTP is essential for growth and proliferation through regulation of the dRhebGTPase, other groups have reported that deletion and overexpression of TCTP have no effect on mTORC1 activity and that TCTP does not have GTP exchange activity toward Rheb in mammalian cells. Recent studies have demonstrated that E3 ubiquitin ligase associates with Myc (PAM) and activate Rheb directly as a GEF and that deacetylated αβ-tubulin increases the GTP-loading of Rheb as a positive regulator [64,65]. However, these findings must be validated.

3. Models of mTORC1 Activation by Amino Acids

3.1. Ragulator-Rags Model

Ragulator is a pentameric complex in which LAMTOR4 and LAMTOR5 form a heterodimer that interacts with the MP1-p14 heterodimer through p18 on the lysosomal membrane [66,67]. Ragulator is believed to have GEF activity toward RagA and RagB, which belong to the Ras-related GTPase (Rag GTPase) family. There are four mammalian Rags: RagA, RagB, RagC, and RagD [68,69,70]. GTP-bound RagA/B and GDP-bound RagC/D are central to the amino acid-sensitive mTORC1 pathway [69,71,72].
Rag GTPases localize to the lysosomal membrane to recruit mTORC1 by interacting with Raptor [66,71]. The activated GTP bound-RagA/B and GDP bound-RagC/D Rag GTPases can activate mTORC1, but it is unknown how they are converted from the GDP-bound and GTP-bound forms, respectively. Minimally, these processes require GEFs and GAPs. Recent findings have demonstrated Ragulator to be a GEF for RagA/B, and FLCN (also known as folliculin) and its binding partner, FNIP1/2 (FLCN-interacting protein 1/2), are Rag-binding proteins with GAP activity for RagC/D [67,73]. Also, leucyl-tRNA synthetase (LRS) is a GAP for RagD only [74,75].
SH3 domain-binding protein 4 (SH3BP4), Gator1, and the adaptor protein p62 are key factors in the mTORC1 signaling pathway. SH3BP4 interacts with inactive Rags through its Src homology 3 (SH3) domain under amino acid starvation to impede the formation of an active Rag GTPase complex, and Gator1 acts as a GAP, promoting transition of the active GTP-bound RagA/B to its inactive GDP-bound form, which inhibits mTORC1 activation [76,77,78,79,80,81]. In contrast, p62 binds to Rag proteins to favor the formation and translocation of active Rag GTPases, and it is a positive regulator of Rag GTPases [82].
In summary, amino acids enter the cell through specific channels and promote the GEF activity of Ragulator and the GAP activity of FLCN-FNIP1/2 and LRS to stimulate Rag GTPase. Subsequently, the activated Rags recruit mTORC1 to the lysosome to interact with Rheb-GTP, initiating mTORC1 signaling [66,67,71,73,74,75,83,84,85].
Menon et al. [58] and Demetriades et al. [86] have provided additional insight into the regulation of mTORC1 by amino acids. When cells have sufficient amino acids, TORC1 is active, due to its lysosomal relocalization, mediated by Rag GTPases. Upon depletion of amino acids, Rag GTPases release TORC1, causing it to become cytoplasmic and inactive [58,86]. Although this model comprises many unknown mechanisms, it provides an overall framework of mTORC1 activation by amino acids, which we have named the Ragulator-Rags model, shown in Figure 2.

3.2. Amino Acids “inside-out” Model

The mechanism through which amino acid signals are sensed by mTORC1 remains unknown. Recent findings show that amino acids initiate signals within the lysosome, constituting the “inside-out” mechanism. In the egress of amino acids from the lysosome, vacuolar H+-adenosine triphosphatase (v-ATPase) resides on the lysosome, recruiting Rag GTPases by hydrolyzing ATP [83,84,87,88]. The amino acids within the lysosome induce structural rearrangement of the v-ATPase-Ragulator-Rag GTPase [87]. However, the factor that senses amino acids is unknown.
Ijms 15 20753 g002 1024
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 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.
Ijms 15 20753 g002
As early as 2001, some findings demonstrated that lysosome amino acid transporter 1 (LYAAT1), also known as proton-coupled amino acid transporter 1 (PAT1), actively exports amino acids from lysosomes by chemiosmotic coupling to v-ATPase on the lysosomal membrane [89]. Recent research has shown that PAT1 is required for mTORC1 activation by amino acids, exporting amino acids from the lysosomal lumen to the cytosol to activate mTORC1 during this process [84,89,90,91,92,93]. PAT1 senses the changes in amino acid concentrations in the lysosomal lumen and exports amino acids. This process induces rearrangement of the v-ATPase-Ragulator-Rag GTPase and colocalization of mTORC1 with Rag GTPase at the lysosome and its interaction with Rheb-GTP.
We refer to this model as the amino acids “inside-out” model, as shown in Figure 3. This process is initiated in lysosomes, for which PAT1 is an amino acid sensor and v-ATPase is a key factor. Nevertheless, several mechanisms in this model remain unknown. For example, the transporter that amino acids use to enter lysosomes.
Ijms 15 20753 g003 1024
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 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.
Ijms 15 20753 g003

3.3. The “hVps34/Rheb-PLD1” Model

Human vacuolar protein sorting 34 (hVps34), the sole class III member of the PI3 Kinase family, participates in mTORC1 activation by amino acids [94,95,96,97]. Gulati et al. [98] provided evidence that stimulation by amino acids raises intracellular Ca2+ levels, which enhances the interaction between Ca2+/CaM and hVps34, resulting in hVps34 activation. However, another group believes that hVps34 activity is regulated through its interactions with human vacuolar protein sorting 15 (hVps15) and is independent of Ca2+/CaM [99].
Nevertheless, activated hVps34 is an important kinase that catalyzes phosphatidylinositol (PI) phosphorylation to form phosphatidylinositol 3-phosphate (PI3P). PI3P binds to the PX domain of phospholipase D1 (PLD1) to activate it [100,101,102,103]. Activated PLD1 hydrolyzes phosphatidylcholine (PC) to produce phosphatidic acid (PA). PA then competes with rapamycin/FKBP12, binding to the FRB domain of mTOR to promote mTORC1 signaling [18,104,105,106,107].
Recently, the crystal structures of mTOR kinase and mTORC1 were solved, demonstrating that the binding of rapamycin/FKBP12 to mTORC1 restricts substrate access to the active site, such as S6K1, and causes the disintegration of mTORC1 to abolish the phosphorylation of 4E-BP1 [2,108]. New evidence indicates that Rheb binds and activates PLD1 in a GTP-dependent manner, suggesting that PLD1 is an effector of Rheb in the mTORC1 pathway and is a positive regulator of mTORC1 activation by amino acids [109].
Based on these results, we proposed the “hVps34/Rheb-PLD1” model, in which amino acids stimulate the interaction between Ca2+/CaM and hVps34 or between hVps15 and hVps34 to activate hVps34. Then, the product of hVps34, PI3P, interacts with the PX domain of PLD1 to promote its activity. Subsequently, the product of phosphatidylcholine hydrolysis by PLD1, PA, binds directly to the FRB domain of mTOR and competitively inhibits rapamycin-FKBP12 to complex with mTORC1 (Figure 4).
Ijms 15 20753 g004 1024
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 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.
Ijms 15 20753 g004

3.4. Rheb Binds to FKBP38 and mTOR Is Unleashed

As a unique member of the FKBP (FK506-binding protein) family, FKBP38 contains three types of domains: FKBP_C, TPR, and TM. In the absence of growth factors and nutrition, the FKBP_C domain can bind to mTOR to suppress the phosphorylation of S6K1 and 4EBP1 [53]. In the current model of the Rheb–FKBP38–mTOR relationship, FKBP38 is an endogenous inhibitor of mTOR. Under amino acid or serum starvation, this mTOR inhibitor binds to and interferes with mTORC1 function, similar to the FKBP12-rapamycin complex. Under conditions of ample growth factors and nutrients, the FKBP_C domain might interact with Rheb-GTP to activate downstream mTOR signaling by releasing mTOR from FKBP38 [53,110] (Figure 5).
Ijms 15 20753 g005 1024
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.
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.
Ijms 15 20753 g005
Activation of mTORC1 could be impaired by FKBP38, and FKBP38*#x2013;Rheb interactions have been confirmed experimentally [53,111], but other data do not support this model. Overexpression or knockdown of FKBP38 does not affect the phosphorylation of mTORC1 substrates [112,113]. Subsequent studies have shown that FKBP38 is not involved in the Rheb-dependent activation of mTORC1 in vitro [114], and the interaction between Rheb and FKBP38 could not be detected by three separate in vitro assays [115]. It remains unknown how Rheb-GTP activates mTORC1 and how FKBP38 inhibits mTORC1 signaling.

4. Conclusions

mTOR signaling is critical in many processes and human diseases, but it remains poorly characterized. Although we have developed basic models of mTORC1 activation by growth factors and amino acids, certain mechanisms in mTORC1 signaling are unknown. For example, how inositol polyphosphate multikinase (IPMK) and mitogen-activated protein 4 kinase 3 (MAP4K3) positively regulate amino acid-induced mTORC1 signaling. However, we do not know in which models these molecules participate or whether they constitute a new model. As a core signaling pathway, mTORC1 is regulated by many upstream factors and pathways. It is likely that other models of mTORC1 activation by growth factors and amino acids exist. Thus, examining the mTORC1 signaling pathway further is paramount, and future research should focus on determining the GEF of Rheb, amino acid sensors, how amino acids enter lysosome, and the mechanisms of mTORC1 activation.

Acknowledgments

This work was supported by grants from the Natural Sciences Foundation of China (NO.31160469, 31360561); a graduate student research project of Inner Mongolia University; and Major Projects for New Varieties of Genetically Modified Organisms (No. 2014ZX08008-002).

Author Contributions

Xu Zheng and Yan Liang obtain the materials and wrote the preliminary draft. Qiburi He, Ruiyuan Yao, Wenlei Bao, and Lili Bao helped acquire the materials and revise the manuscript. Yanfeng Wang and Zhigang Wang revised the manuscript and provided overall supervision. All authors have read and approved the final manuscript.

Abbreviations

mTOR: mammalian target of rapamycin; S6K1: ribosomal protein S6 kinase 1; 4E-BP1: eukaryotic translation initiation factor 4E-binding protein 1; ULK1: unc-51 like autophagy activating kinase 1; IGFs: insulin-like growth factors; PI3K: phosphatidylinositol-4, 5-bisphosphate 3-kinase; AKT: protein kinase B; ERK1/2: extracellular signal-regulated kinase 1/2; RSK1: p90 ribosomal S6 kinase; TSC: tuberous sclerosis; TBC1D7: TBC1 domain family, member 7; GAP: GTPase-activating protein; GEF: guanine exchange factor; PAT1: proton-coupled amino acid transporter 1; hVps34: human vacuolar protein sorting 34; PLD1: phospholipase D 1; Rheb: Ras homolog enriched in brain; FKBP: FK506-binding protein.

Conflicts of Interest

The authors declare that they have no competing interests.

References

  1. Wullschleger, S.; Loewith, R.; Hall, M.N. Tor signaling in growth and metabolism. Cell 2006, 124, 471–484. [Google Scholar]
  2. Yang, H.; Rudge, D.G.; Koos, J.D.; Vaidialingam, B.; Yang, H.J.; Pavletich, N.P. Mtor kinase structure, mechanism and regulation. Nature 2013, 497, 217–223. [Google Scholar]
  3. Brown, E.J.; Albers, M.W.; Shin, T.B.; Ichikawa, K.; Keith, C.T.; Lane, W.S.; Schreiber, S.L. A mammalian protein targeted by G1-arresting rapamycin-receptor complex. Nature 1994, 369, 756–758. [Google Scholar]
  4. Heitman, J.; Movva, N.R.; Hall, M.N. Targets for cell cycle arrest by the immunosuppressant rapamycin in yeast. Science 1991, 253, 905–909. [Google Scholar]
  5. Laplante, M.; Sabatini, D.M. mTOR signaling in growth control and disease. Cell 2012, 149, 274–293. [Google Scholar]
  6. Sabatini, D.M.; Erdjument-Bromage, H.; Lui, M.; Tempst, P.; Snyder, S.H. Raft1: A mammalian protein that binds to FKBP12 in a rapamycin-dependent fashion and is homologous to yeast TORs. Cell 1994, 78, 35–43. [Google Scholar]
  7. Sabers, C.J.; Martin, M.M.; Brunn, G.J.; Williams, J.M.; Dumont, F.J.; Wiederrecht, G.; Abraham, R.T. Isolation of a protein target of the FKBP12-rapamycin complex in mammalian cells. J. Biol. Chem. 1995, 270, 815–822. [Google Scholar]
  8. Vezina, C.; Kudelski, A.; Sehgal, S. Rapamycin (AY-22,989), a new antifungal antibiotic. I. Taxonomy of the producing streptomycete and isolation of the active principle. J. Antibiot. 1975, 28, 721–726. [Google Scholar]
  9. Sekulić, A.; Hudson, C.C.; Homme, J.L.; Yin, P.; Otterness, D.M.; Karnitz, L.M.; Abraham, R.T. A direct linkage between the phosphoinositide 3-kinase-AKT signaling pathway and the mammalian target of rapamycin in mitogen-stimulated and transformed cells. Cancer Res. 2000, 60, 3504–3513. [Google Scholar]
  10. Sarbassov, D.D.; Ali, S.M.; Kim, D.-H.; Guertin, D.A.; Latek, R.R.; Erdjument-Bromage, H.; Tempst, P.; Sabatini, D.M. Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr. Biol. 2004, 14, 1296–1302. [Google Scholar]
  11. Glidden, E.J.; Gray, L.G.; Vemuru, S.; Li, D.; Harris, T.E.; Mayo, M.W. Multiple site acetylation of rictor stimulates mammalian target of rapamycin complex 2 (mTORC2)-dependent phosphorylation of akt protein. J. Biol. Chem. 2012, 287, 581–588. [Google Scholar]
  12. Akcakanat, A.; Singh, G.; Hung, M.-C.; Meric-Bernstam, F. Rapamycin regulates the phosphorylation of rictor. Biochem. Biophys. Res. Commun. 2007, 362, 330–333. [Google Scholar]
  13. Jacinto, E.; Loewith, R.; Schmidt, A.; Lin, S.; Rüegg, M.A.; Hall, A.; Hall, M.N. Mammalian tor complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat. Cell. Biol. 2004, 6, 1122–1128. [Google Scholar]
  14. Barlow, A.; Xie, J.; Moore, C.; Campbell, S.; Shaw, J.; Nicholson, M.; Herbert, T. Rapamycin toxicity in MIN6 cells and rat and human islets is mediated by the inhibition of mTOR complex 2 (mTORC2). Diabetologia 2012, 55, 1355–1365. [Google Scholar]
  15. Lamming, D.W.; Ye, L.; Katajisto, P.; Goncalves, M.D.; Saitoh, M.; Stevens, D.M.; Davis, J.G.; Salmon, A.B.; Richardson, A.; Ahima, R.S. Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity. Science 2012, 335, 1638–1643. [Google Scholar]
  16. Loewith, R.; Jacinto, E.; Wullschleger, S.; Lorberg, A.; Crespo, J.L.; Bonenfant, D.; Oppliger, W.; Jenoe, P.; Hall, M.N. Two TOR complexes, only one of which is rapamycin sensitive, have distinct roles in cell growth control. Mol. Cell 2002, 10, 457–468. [Google Scholar]
  17. Sarbassov, D.D.; Ali, S.M.; Sengupta, S.; Sheen, J.-H.; Hsu, P.P.; Bagley, A.F.; Markhard, A.L.; Sabatini, D.M. Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol. Cell 2006, 22, 159–168. [Google Scholar]
  18. Hay, N.; Sonenberg, N. Upstream and downstream of mtor. Genes Dev. 2004, 18, 1926–1945. [Google Scholar]
  19. Hara, K.; Maruki, Y.; Long, X.; Yoshino, K.; Oshiro, N.; Hidayat, S.; Tokunaga, C.; Avruch, J.; Yonezawa, K. Raptor, a binding partner of target of rapamycin (TOR), mediates tor action. Cell 2002, 110, 177–189. [Google Scholar]
  20. Kim, D.-H.; Sarbassov, D.D.; Ali, S.M.; King, J.E.; Latek, R.R.; Erdjument-Bromage, H.; Tempst, P.; Sabatini, D.M. mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell 2002, 110, 163–175. [Google Scholar]
  21. Nojima, H.; Tokunaga, C.; Eguchi, S.; Oshiro, N.; Hidayat, S.; Yoshino, K.; Hara, K.; Tanaka, N.; Avruch, J.; Yonezawa, K. The mammalian target of rapamycin (mTOR) partner, raptor, binds the mtor substrates p70 S6 kinase and 4E-BP1 through their TOR signaling (TOS) motif. J. Biol. Chem. 2003, 278, 15461–15464. [Google Scholar]
  22. Schalm, S.S.; Blenis, J. Identification of a conserved motif required for mtor signaling. Curr. Biol. 2002, 12, 632–639. [Google Scholar]
  23. Schalm, S.S.; Fingar, D.C.; Sabatini, D.M.; Blenis, J. Tos motif-mediated raptor binding regulates 4E-BP1 multisite phosphorylation and function. Curr. Biol. 2003, 13, 797–806. [Google Scholar]
  24. Brunn, G.J.; Hudson, C.C.; Sekulić, A.; Williams, J.M.; Hosoi, H.; Houghton, P.J.; Lawrence, J.C.; Abraham, R.T. Phosphorylation of the translational repressor PHAS-I by the mammalian target of rapamycin. Science 1997, 277, 99–101. [Google Scholar]
  25. Dann, S.G.; Thomas, G. The amino acid sensitive tor pathway from yeast to mammals. FEBS Lett. 2006, 580, 2821–2829. [Google Scholar]
  26. Kim, J.; Kundu, M.; Viollet, B.; Guan, K.L. AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat. Cell. Biol. 2011, 13, 132–141. [Google Scholar]
  27. Kim, D.-H.; Sarbassov, D.D.; Ali, S.M.; Latek, R.R.; Guntur, K.V.; Erdjument-Bromage, H.; Tempst, P.; Sabatini, D.M. GβL, a positive regulator of the rapamycin-sensitive pathway required for the nutrient-sensitive interaction between raptor and mTOR. Mol. Cell 2003, 11, 895–904. [Google Scholar]
  28. Guertin, D.A.; Stevens, D.M.; Thoreen, C.C.; Burds, A.A.; Kalaany, N.Y.; Moffat, J.; Brown, M.; Fitzgerald, K.J.; Sabatini, D.M. Ablation in mice of the mTORC components raptor, rictor, or mLST8 reveals that mTORC2 is required for signaling to Akt-FOXO and PKCalpha, but not S6K1. Dev. Cell 2006, 11, 859–871. [Google Scholar]
  29. Laplante, M.; Sabatini, D.M. mTOR signaling at a glance. J. Cell. Sci. 2009, 122, 3589–3594. [Google Scholar]
  30. Kaizuka, T.; Hara, T.; Oshiro, N.; Kikkawa, U.; Yonezawa, K.; Takehana, K.; Iemura, S.; Natsume, T.; Mizushima, N. Tti1 and Tel2 are critical factors in mammalian target of rapamycin complex assembly. J. Biol. Chem. 2010, 285, 20109–20116. [Google Scholar]
  31. Kanoh, J.; Yanagida, M. Tel2: A common partner of PIK‐related kinases and a link between DNA checkpoint and nutritional response? Genes Cells 2007, 12, 1301–1304. [Google Scholar]
  32. Kovacina, K.S.; Park, G.Y.; Bae, S.S.; Guzzetta, A.W.; Schaefer, E.; Birnbaum, M.J.; Roth, R.A. Identification of a proline-rich Akt substrate as a 14-3-3 binding partner. J. Biol. Chem. 2003, 278, 10189–10194. [Google Scholar]
  33. Morrison, D.K. The 14-3-3 proteins: Integrators of diverse signaling cues that impact cell fate and cancer development. Trends Cell. Biol. 2009, 19, 16–23. [Google Scholar]
  34. Thedieck, K.; Polak, P.; Kim, M.L.; Molle, K.D.; Cohen, A.; Jenö, P.; Arrieumerlou, C.; Hall, M.N. PRAS40 and PRR5-like protein are new mtor interactors that regulate apoptosis. PLoS One 2007, 2, e1217. [Google Scholar]
  35. Wang, L.; Harris, T.E.; Roth, R.A.; Lawrence, J.C. PRAS40 regulates mTORC1 kinase activity by functioning as a direct inhibitor of substrate binding. J. Biol. Chem. 2007, 282, 20036–20044. [Google Scholar]
  36. Fonseca, B.D.; Smith, E.M.; Lee, V.H.-Y.; MacKintosh, C.; Proud, C.G. Pras40 is a target for mammalian target of rapamycin complex 1 and is required for signaling downstream of this complex. J. Biol. Chem. 2007, 282, 24514–24524. [Google Scholar]
  37. Oshiro, N.; Takahashi, R.; Yoshino, K.; Tanimura, K.; Nakashima, A.; Eguchi, S.; Miyamoto, T.; Hara, K.; Takehana, K.; Avruch, J. The proline-rich Akt substrate of 40 kDa (pras40) is a physiological substrate of mammalian target of rapamycin complex 1. J. Biol. Chem. 2007, 282, 20329–20339. [Google Scholar]
  38. Sancak, Y.; Thoreen, C.C.; Peterson, T.R.; Lindquist, R.A.; Kang, S.A.; Spooner, E.; Carr, S.A.; Sabatini, D.M. PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinase. Mol. Cell 2007, 25, 903–915. [Google Scholar]
  39. Kazi, A.A.; Hong-Brown, L.; Lang, S.M.; Lang, C.H. Deptor knockdown enhances mtor activity and protein synthesis in myocytes and ameliorates disuse muscle atrophy. Mol. Med. 2011, 17, 925–936. [Google Scholar]
  40. Liu, M.; Wilk, S.A.; Wang, A.; Zhou, L.; Wang, R.-H.; Ogawa, W.; Deng, C.; Dong, L.Q.; Liu, F. Resveratrol inhibits mtor signaling by promoting the interaction between mTOR and DEPTOR. J. Biol. Chem. 2010, 285, 36387–36394. [Google Scholar]
  41. Peterson, T.R.; Laplante, M.; Thoreen, C.C.; Sancak, Y.; Kang, S.A.; Kuehl, W.M.; Gray, N.S.; Sabatini, D.M. DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival. Cell 2009, 137, 873–886. [Google Scholar]
  42. Duan, S.; Skaar, J.R.; Kuchay, S.; Toschi, A.; Kanarek, N.; Ben-Neriah, Y.; Pagano, M. mTOR generates an auto-amplification loop by triggering the βTrCP-and CK1α-dependent degradation of DEPTOR. Mol. Cell 2011, 44, 317–324. [Google Scholar]
  43. Gao, D.; Inuzuka, H.; Tan, M.-K.M.; Fukushima, H.; Locasale, J.W.; Liu, P.; Wan, L.; Zhai, B.; Chin, Y.R.; Shaik, S. mTOR drives its own activation viaSCF(βTrCP)-dependent degradation of the mTOR inhibitor DEPTOR. Mol. Cell 2011, 44, 290–303. [Google Scholar]
  44. Zhao, Y.; Xiong, X.; Sun, Y. DEPTOR, an mtor inhibitor, is a physiological substrate of SCF (βTrCP) E3 ubiquitin ligase and regulates survival and autophagy. Mol. Cell 2011, 44, 304–316. [Google Scholar]
  45. Laplante, M.; Sabatini, D.M. An emerging role of mTOR in lipid biosynthesis. Curr. Biol. 2009, 19, R1046–R1052. [Google Scholar]
  46. Dibble, C.C.; Elis, W.; Menon, S.; Qin, W.; Klekota, J.; Asara, J.M.; Finan, P.M.; Kwiatkowski, D.J.; Murphy, L.O.; Manning, B.D. TBC1D7 is a third subunit of the TSC1-TSC2 complex upstream of mTORC1. Mol. Cell 2012, 47, 535–546. [Google Scholar]
  47. Inoki, K.; Ouyang, H.; Zhu, T.; Lindvall, C.; Wang, Y.; Zhang, X.; Yang, Q.; Bennett, C.; Harada, Y.; Stankunas, K. TSC2 integrates wnt and energy signals via a coordinated phosphorylation by AMPK and GSK3 to regulate cell growth. Cell 2006, 126, 955–968. [Google Scholar]
  48. Ma, L.; Chen, Z.; Erdjument-Bromage, H.; Tempst, P.; Pandolfi, P.P. Phosphorylation and functional inactivation of TSC2 by Erk: Implications for tuberous sclerosisand cancer pathogenesis. Cell 2005, 121, 179–193. [Google Scholar]
  49. Potter, C.J.; Pedraza, L.G.; Xu, T. Akt regulates growth by directly phosphorylating Tsc2. Nat. Cell. Biol. 2002, 4, 658–665. [Google Scholar]
  50. Roux, P.P.; Ballif, B.A.; Anjum, R.; Gygi, S.P.; Blenis, J. Tumor-promoting phorbol esters and activated ras inactivate the tuberous sclerosis tumor suppressor complex via p90 ribosomal s6 kinase. Proc. Natl. Acad. Sci. USA 2004, 101, 13489–13494. [Google Scholar]
  51. Capo-Chichi, J.M.; Tcherkezian, J.; Hamdan, F.F.; Décarie, J.C.; Dobrzeniecka, S.; Patry, L.; Nadon, M.A.; Mucha, B.E.; Major, P.; Shevell, M. Disruption of TBC1D7, a subunit of the TSC1-TSC 2 protein complex, in intellectual disability and megalencephaly. J. Med. Genet. 2013, 50, 740–744. [Google Scholar]
  52. Yamagata, K.; Sanders, L.K.; Kaufmann, W.E.; Yee, W.; Barnes, C.A.; Nathans, D.; Worley, P.F. rheb, a growth factor-and synaptic activity-regulated gene, encodes a novel Ras-related protein. J. Biol. Chem. 1994, 269, 16333–16339. [Google Scholar]
  53. Bai, X.; Ma, D.; Liu, A.; Shen, X.; Wang, Q.J.; Liu, Y.; Jiang, Y. Rheb activates mTOR by antagonizing its endogenous inhibitor, FKBP38. Science 2007, 318, 977–980. [Google Scholar]
  54. Zhang, Y.; Gao, X.; Saucedo, L.J.; Ru, B.; Edgar, B.A.; Pan, D. Rheb is a direct target of the tuberous sclerosis tumour suppressor proteins. Nat. Cell. Biol. 2003, 5, 578–581. [Google Scholar]
  55. Jacobs, B.L.; You, J.S.; Frey, J.W.; Goodman, C.A.; Gundermann, D.M.; Hornberger, T.A. Eccentric contractions increase TSC2 phosphorylation and alter the targeting of TSC 2 and mTOR to the lysosome. J. Physiol. 2013, 591, 4611–4620. [Google Scholar]
  56. Cai, S.L.; Tee, A.R.; Short, J.D.; Bergeron, J.M.; Kim, J.; Shen, J.; Guo, R.; Johnson, C.L.; Kiguchi, K.; Walker, C.L. Activity of TSC2 is inhibited by akt-mediated phosphorylation and membrane partitioning. J. Cell. Biol. 2006, 173, 279–289. [Google Scholar]
  57. Miyazaki, M.; McCarthy, J.J.; Esser, K.A. Insulin like growth factor‐1‐induced phosphorylation and altered distribution of tuberous sclerosis complex (TSC)1/TSC2 in C2C12 myotubes. FEBS J. 2010, 277, 2180–2191. [Google Scholar]
  58. Menon, S.; Dibble, C.C.; Talbott, G.; Hoxhaj, G.; Valvezan, A.J.; Takahashi, H.; Cantley, L.C.; Manning, B.D. Spatial control of the TSC complex integrates insulin and nutrient regulation of mTORC1 at the lysosome. Cell 2014, 156, 771–785. [Google Scholar]
  59. Li, Y.; Inoki, K.; Guan, K.L. Biochemical and functional characterizations of small GTPase Rheb and TSC2 GAP activity. Mol. Cell. Biol. 2004, 24, 7965–7975. [Google Scholar]
  60. Amson, R.; Pece, S.; Marine, J.C.; Fiore, P.P.D.; Telerman, A. TPT1/TCTP-regulated pathways in phenotypic reprogramming. Trends. Cell. Biol. 2012, 23, 37–46. [Google Scholar]
  61. Hsu, Y.C.; Chern, J.J.; Cai, Y.; Liu, M.; Choi, K.W. Drosophila TCTP is essential for growth and proliferation through regulation of dRheb GTPase. Nature 2007, 445, 785–788. [Google Scholar]
  62. Polak, P.; Hall, M.N. mTOR and the control of whole body metabolism. Curr. Opin. Cell. Biol. 2009, 21, 209–218. [Google Scholar]
  63. Rehmann, H.; Brüning, M.; Berghaus, C.; Schwarten, M.; Köhler, K.; Stocker, H.; Stoll, R.; Zwartkruis, F.; Wittinghofer, A. Biochemical characterisation of TCTP questions its function as a guanine nucleotide exchange factor for Rheb. FEBS Lett. 2008, 582, 3005–3010. [Google Scholar]
  64. Lee, M.N.; Koh, A.; Park, D.; Jang, J.-H.; Kwak, D.; Jeon, H.; Kim, J.; Choi, E.-J.; Jeong, H.; Suh, P.-G. Deacetylated αβ-tubulin acts as a positive regulator of Rheb GTPase through increasing its GTP-loading. Cell. Signal. 2012, 25, 535–551. [Google Scholar]
  65. Maeurer, C.; Holland, S.; Pierre, S.; Potstada, W.; Scholich, K. Sphingosine-1-phosphate induced mTOR-activation is mediated by the E3-ubiquitin ligase PAM. Cell. Signal. 2009, 21, 293–300. [Google Scholar]
  66. Sancak, Y.; Bar-Peled, L.; Zoncu, R.; Markhard, A.L.; Nada, S.; Sabatini, D.M. Ragulator-Rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids. Cell 2010, 141, 290–303. [Google Scholar]
  67. Bar-Peled, L.; Schweitzer, L.D.; Zoncu, R.; Sabatini, D.M. Ragulator is a GEF for the rag GTPases that signal amino acid levels to mTORC1. Cell 2012, 150, 1196–1208. [Google Scholar]
  68. Sancak, Y.; Sabatini, D.M. Rag proteins regulate amino-acid-induced mTORC1 signalling. Biochem. Soc. Trans. 2009, 37, 289–290. [Google Scholar]
  69. Schürmann, A.; Brauers, A.; Maßmann, S.; Becker, W.; Joost, H.-G. Cloning of a novel family of mammalian GTP-binding proteins (RagA, RagBs, RagB1) with remote similarity to the Ras-related GTPases. J. Biol. Chem. 1995, 270, 28982–28988. [Google Scholar]
  70. Sekiguchi, T.; Hirose, E.; Nakashima, N.; Ii, M.; Nishimoto, T. Novel G proteins, Rag C and Rag D, interact with GTP-binding proteins, Rag A and Rag B. J. Biol. Chem. 2001, 276, 7246–7257. [Google Scholar]
  71. Sancak, Y.; Peterson, T.R.; Shaul, Y.D.; Lindquist, R.A.; Thoreen, C.C.; Bar-Peled, L.; Sabatini, D.M. The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1. Science 2008, 320, 1496–1501. [Google Scholar]
  72. Hirose, E.; Nakashima, N.; Sekiguchi, T.; Nishimoto, T. RagA is a functional homologue of S. Cerevisiae Gtr1p involved in the Ran/Gsp1-GTPase pathway. J. Cell. Sci. 1998, 111, 11–21. [Google Scholar]
  73. Hong, S.-B.; Oh, H.; Valera, V.A.; Baba, M.; Schmidt, L.S.; Linehan, W.M. Inactivation of the FLCN tumor suppressor gene induces TFE3 transcriptional activity by increasing its nuclear localization. PLoS One 2010, 5, e15793. [Google Scholar]
  74. Durán, R.V.; Hall, M.N. Leucyl-tRNA synthetase: Double duty in amino acid sensing. Cell. Res. 2012, 22, 1207–1209. [Google Scholar]
  75. Han, J.M.; Jeong, S.J.; Park, M.C.; Kim, G.; Kwon, N.H.; Kim, H.K.; Ha, S.H.; Ryu, S.H.; Kim, S. Leucyl-tRNA synthetase is an intracellular leucine sensor for the mTORC1-signaling pathway. Cell 2012, 149, 410–424. [Google Scholar]
  76. Hsieh, A. mTOR: The master regulator. Cell 2012, 149, 955–957. [Google Scholar]
  77. Kim, S.G.; Buel, G.R.; Blenis, J. Nutrient regulation of the mTOR complex 1 signaling pathway. Mol. Cells 2013, 35, 1–11. [Google Scholar]
  78. Kim, Y.M.; Kim, D.H. dRAGging amino acid-mTORC1 signaling by SH3BP4. Mol. Cells 2013, 35, 1–6. [Google Scholar]
  79. Kim, Y.M.; Stone, M.; Hwang, T.H.; Kim, Y.G.; Dunlevy, J.R.; Griffin, T.J.; Kim, D.H. SH3BP4 is a negative regulator of amino acid-Rag GTPase-mTORC1 signaling. Mol. Cell 2012, 46, 833–846. [Google Scholar]
  80. Shaw, R.J. GATORS take a bite out of mTOR. Science 2013, 340, 1056–1057. [Google Scholar]
  81. Bar-Peled, L.; Chantranupong, L.; Cherniack, A.D.; Chen, W.W.; Ottina, K.A.; Grabiner, B.C.; Spear, E.D.; Carter, S.L.; Meyerson, M.; Sabatini, D.M. A tumor suppressor complex with GAP activity for the Rag GTPases that signal amino acid sufficiency to mTORC1. Science 2013, 340, 1100–1106. [Google Scholar]
  82. Duran, A.; Amanchy, R.; Linares, J.F.; Joshi, J.; Abu-Baker, S.; Porollo, A.; Hansen, M.; Moscat, J.; Diaz-Meco, M.T. P62 is a key regulator of nutrient sensing in the mTORC1 pathway. Mol. Cell 2011, 44, 134–146. [Google Scholar]
  83. Bar-Peled, L.; Sabatini, D.M. Snapshot: mTORC1 signaling at the lysosomal surface. Cell 2012, 151, 1390–1390.e1. [Google Scholar]
  84. Jewell, J.L.; Guan, K.-L. Nutrient signaling to mTOR and cell growth. Trends Biochem. Sci. 2013, 38, 233–242. [Google Scholar]
  85. Yang, H.; Gong, R.; Xu, Y. Control of cell growth: Rag GTPases in activation of TORC1. Cell. Mol. Life Sci. 2013, 70, 2873–2875. [Google Scholar]
  86. Demetriades, C.; Doumpas, N.; Teleman, A.A. Regulation of TORC1 in response to amino acid starvation via lysosomal recruitment of TSC2. Cell. 2014, 156, 786–799. [Google Scholar]
  87. Zoncu, R.; Bar-Peled, L.; Efeyan, A.; Wang, S.; Sancak, Y.; Sabatini, D.M. mTORC1 senses lysosomal amino acids through an inside-out mechanism that requires the vacuolar H+-ATPase. Science 2011, 334, 678–683. [Google Scholar]
  88. Efeyan, A.; Zoncu, R.; Sabatini, D.M. Amino acids and mTORC1: From lysosomes to disease. Trends Mol. Med. 2012, 18, 524–533. [Google Scholar]
  89. Sagné, C.; Agulhon, C.; Ravassard, P.; Darmon, M.; Hamon, M.; El Mestikawy, S.; Gasnier, B.; Giros, B. Identification and characterization of a lysosomal transporter for small neutral amino acids. Proc. Natl. Acad. Sci. USA 2001, 98, 7206–7211. [Google Scholar]
  90. Goberdhan, D.C.; Meredith, D.; Boyd, C.R.; Wilson, C. PAT-related amino acid transporters regulate growth via a novel mechanism that does not require bulk transport of amino acids. Development 2005, 132, 2365–2375. [Google Scholar]
  91. Heublein, S.; Kazi, S.; Ögmundsdóttir, M.; Attwood, E.; Kala, S.; Boyd, C.; Wilson, C.; Goberdhan, D. Proton-assisted amino-acid transporters are conserved regulators of proliferation and amino-acid-dependent mTORC1 activation. Oncogene 2010, 29, 4068–4079. [Google Scholar]
  92. Ögmundsdóttir, M.H.; Heublein, S.; Kazi, S.; Reynolds, B.; Visvalingam, S.M.; Shaw, M.K.; Goberdhan, D.C. Proton-assisted amino acid transporter PAT1 complexes with Rag GTPases and activates TORC1 on late endosomal and lysosomal membranes. PLoS One 2012, 7, e36616. [Google Scholar]
  93. Ruivo, R.; Bellenchi, G.C.; Chen, X.; Zifarelli, G.; Sagné, C.; Debacker, C.; Pusch, M.; Supplisson, S.; Gasnier, B. Mechanism of proton/substrate coupling in the heptahelical lysosomal transporter cystinosin. Proc. Natl. Acad. Sci. USA 2012, 109, E210–E217. [Google Scholar]
  94. Byfield, M.P.; Murray, J.T.; Backer, J.M. hVps34 is a nutrient-regulated lipid kinase required for activation of p70 S6 kinase. J. Biol. Chem. 2005, 280, 33076–33082. [Google Scholar]
  95. Nobukuni, T.; Joaquin, M.; Roccio, M.; Dann, S.G.; Kim, S.Y.; Gulati, P.; Byfield, M.P.; Backer, J.M.; Natt, F.; Bos, J.L. Amino acids mediate mTOR/raptor signaling through activation of class 3 phosphatidylinositol 3OH-kinase. Proc. Natl. Acad. Sci. USA 2005, 102, 14238–14243. [Google Scholar]
  96. Nobukuni, T.; Kozma, S.C.; Thomas, G. hVps34, an ancient player, enters a growing game: mTOR Complex1/S6K1 signaling. Curr. Opin. Cell. Biol. 2007, 19, 135–141. [Google Scholar]
  97. Zhou, X.; Takatoh, J.; Wang, F. The mammalian class 3 PI3K (PIK3C3) is required for early embryogenesis and cell proliferation. PLoS One 2011, 6, e16358. [Google Scholar]
  98. Gulati, P.; Gaspers, L.D.; Dann, S.G.; Joaquin, M.; Nobukuni, T.; Natt, F.; Kozma, S.C.; Thomas, A.P.; Thomas, G. Amino acids activate mTOR complex 1 via Ca2+/CaM signaling to hVps34. Cell. MeTable 2008, 7, 456–465. [Google Scholar]
  99. Yan, Y.; Flinn, R.; Wu, H.; Schnur, R.; Backer, J. hVps15, but not Ca2+/CaM, is required for the activity and regulation of hVps34 in mammalian cells. Biochem. J. 2009, 417, 747–755. [Google Scholar]
  100. Hodgkin, M.N.; Masson, M.R.; Powner, D.; Saqib, K.M.; Ponting, C.P.; Wakelam, M.J. Phospholipase D regulation and localisation is dependent upon a phosphatidylinositol 4,5-bisphosphate-specific PH domain. Curr. Biol. 2000, 10, 43–46. [Google Scholar]
  101. Stahelin, R.V.; Ananthanarayanan, B.; Blatner, N.R.; Singh, S.; Bruzik, K.S.; Murray, D.; Cho, W. Mechanism of membrane binding of the phospholipase D1 PX domain. J. Biol. Chem. 2004, 279, 54918–54926. [Google Scholar]
  102. Vanhaesebroeck, B.; Leevers, S.J.; Ahmadi, K.; Timms, J.; Katso, R.; Driscoll, P.C.; Woscholski, R.; Parker, P.J.; Waterfield, M.D. Synthesis and function of 3-phosphorylated inositol lipids. Annu. Rev. Biochem. 2001, 70, 535–602. [Google Scholar]
  103. Volinia, S.; Dhand, R.; Vanhaesebroeck, B.; MacDougall, L.; Stein, R.; Zvelebil, M.; Domin, J.; Panaretou, C.; Waterfield, M. A human phosphatidylinositol 3-kinase complex related to the yeast Vps34p-Vps15p protein sorting system. EMBO J. 1995, 14, 3339–3348. [Google Scholar]
  104. Chen, J.; Fang, Y. A novel pathway regulating the mammalian target of rapamycin (mTOR) signaling. Biochem. Pharmacol. 2002, 64, 1071–1077. [Google Scholar]
  105. Fang, Y.; Vilella-Bach, M.; Bachmann, R.; Flanigan, A.; Chen, J. Phosphatidic acid-mediated mitogenic activation of mTOR signaling. Sci. Signal. 2001, 294, 1942–1950. [Google Scholar]
  106. Foster, D.A. Regulation of mTOR by phosphatidic acid? Cancer Res. 2007, 67, 1–4. [Google Scholar]
  107. Choi, J.; Chen, J.; Schreiber, S.L.; Clardy, J. Structure of the FKBP12-rapamycin complex interacting with binding domain of human FRAP. Science 1996, 273, 239–242. [Google Scholar]
  108. Yip, C.K.; Murata, K.; Walz, T.; Sabatini, D.M.; Kang, S.A. Structure of the human mTOR complex I and its implications for rapamycin inhibition. Mol. Cell. 2010, 38, 768–774. [Google Scholar]
  109. Sun, Y.; Fang, Y.; Yoon, M.-S.; Zhang, C.; Roccio, M.; Zwartkruis, F.; Armstrong, M.; Brown, H.; Chen, J. Phospholipase D1 is an effector of Rheb in the mTOR pathway. Proc. Natl. Acad. Sci. USA 2008, 105, 8286–8291. [Google Scholar]
  110. Proud, C.G. mTOR, unleashed. Science 2007, 318, 926–927. [Google Scholar]
  111. Dunlop, E.A.; Dodd, K.M.; Seymour, L.A.; Tee, A.R. Mammalian target of rapamycin complex 1-mediated phosphorylation of eukaryotic initiation factor 4E-binding protein 1 requires multiple protein-protein interactions for substrate recognition. Cell. Signal. 2009, 21, 1073–1084. [Google Scholar]
  112. Wang, X.; Fonseca, B.D.; Tang, H.; Liu, R.; Elia, A.; Clemens, M.J.; Bommer, U.A.; Proud, C.G. Re-evaluating the roles of proposed modulators of mammalian target of rapamycin complex 1 (mTORC1) signaling. J. Biol. Chem. 2008, 283, 30482–30492. [Google Scholar]
  113. Maehama, T.; Tanaka, M.; Nishina, H.; Murakami, M.; Kanaho, Y.; Hanada, K. RalA functions as an indispensable signal mediator for the nutrient-sensing system. J. Biol. Chem. 2008, 283, 35053–35059. [Google Scholar]
  114. Sato, T.; Nakashima, A.; Guo, L.; Tamanoi, F. Specific activation of mTORC1 by Rheb G-protein in vitro involves enhanced recruitment of its substrate protein. J. Biol. Chem. 2009, 284, 12783–12791. [Google Scholar]
  115. Uhlenbrock, K.; Weiwad, M.; Wetzker, R.; Fischer, G.; Wittinghofer, A.; Rubio, I. Reassessment of the role of FKBP38 in the Rheb/mTORC1 pathway. FEBS Lett. 2009, 583, 965–970. [Google Scholar]

Share and Cite

MDPI and ACS Style

Zheng, X.; Liang, Y.; He, Q.; Yao, R.; Bao, W.; Bao, L.; Wang, Y.; Wang, Z. Current Models of Mammalian Target of Rapamycin Complex 1 (mTORC1) Activation by Growth Factors and Amino Acids. Int. J. Mol. Sci. 2014, 15, 20753-20769. https://doi.org/10.3390/ijms151120753

AMA Style

Zheng X, Liang Y, He Q, Yao R, Bao W, Bao L, Wang Y, Wang Z. Current Models of Mammalian Target of Rapamycin Complex 1 (mTORC1) Activation by Growth Factors and Amino Acids. International Journal of Molecular Sciences. 2014; 15(11):20753-20769. https://doi.org/10.3390/ijms151120753

Chicago/Turabian Style

Zheng, Xu, Yan Liang, Qiburi He, Ruiyuan Yao, Wenlei Bao, Lili Bao, Yanfeng Wang, and Zhigang Wang. 2014. "Current Models of Mammalian Target of Rapamycin Complex 1 (mTORC1) Activation by Growth Factors and Amino Acids" International Journal of Molecular Sciences 15, no. 11: 20753-20769. https://doi.org/10.3390/ijms151120753

Article Metrics

Back to TopTop