Video
Protein Kinases: Cell Signaling and PhosphorylationAmino acid signaling -
Fig 3. Fig 4. Girdin regulates amino acid stimulation—induced mTORC1 activation through interaction with 4F2hc. Girdin induces internalization of 4F2hc by lysosomes Given that Girdin was previously reported as a critical regulator of intracellular membrane trafficking [ 24 ], we hypothesized that Girdin-mediated negative regulation of mTORC1 activity was attributed to 4F2hc internalization.
Fig 6. Girdin negatively regulates amino acid signaling through decreasing intracellular Gln and Leu contents. Fig 7.
Discussion Our present study identified a novel negative regulatory mechanism for amino acid signaling. Materials and methods Ethics statement All animal protocols were approved by the Animal Care and Use Committee of Nagoya University Graduate School of Medicine Approval number Cell culture, transfection, and RNA interference The HeLa cell line was purchased from the American Tissue Type Culture Rockville, MD.
Purification and identification of Girdin-interacting proteins We isolated Girdin immunocomplex by co-IP. Measurement of intracellular amino acids All procedures were performed on ice or at 4°C with prechilled buffers.
Plasmids cDNA encoding human 4F2hc28 was inserted into the pcDNA3. Retrovirus infection To generate stable Girdin knockdown FT cells, 24 μg of either control or Girdin shRNA and 4 μg of vesicular stomatitis virus G protein pVSV-G vector Clontech were cotransfected into GP packaging cells Clontech Laboratories.
Immunoprecipitation and WB analysis Cells were lysed in IP lysis buffer 20 mM Tris-HCl, mM NaCl, 0. In vitro kinase assay The phosphorylation assay was performed as previously described [ 14 ]. Ubiquitination assay Two methods were used to test in vivo ubiquitination of 4F2hc.
Immunofluorescence staining Immunofluorescence studies were performed as previously described [ 18 ]. Immunohistochemistry Immunohistochemistry was performed as previously described [ 23 ]. Data analysis The data are presented as means ± standard errors SEs. Supporting information.
S1 Table. Girdin-interacting proteins identified by IP and mass spectrometry. Girdin, girders of actin filaments. s XLSX. S1 Data. Raw data used for quantification in this work. S1 Fig. Girdin negatively regulates basal mTORC1 activity. s TIF. S2 Fig. Girdin and 4F2hc regulate autophagy induced by amino acid depletion.
S3 Fig. Comprehensive measurement of intracellular amino acids. Acknowledgments We thank Toyoshi Fujimoto Nagoya University , Yukiko Gotoh The University of Tokyo , Hui-Kuan Lin University of Texas M.
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EGO-TC does not exhibit any GEF activity toward Gtr1. However, it is interesting to determine whether EGO-TC has an ability to release GTP from Gtr2, given a recent finding of Ragulator actions to release GTP from RagC [ 74 ]. Vam6 also known as Vps39 has been identified as a GEF for Gtr1 in S.
cerevisiae [ 70 ]. Thus, it is possible that EGO-TC and Vam6 might employ a similar mechanism for heterodimeric Gtr1-Gtr2 activation in S.
In , Bar-Peled et al. GATOR can be divided into two multiprotein subcomplexes, called GATOR1 and GATOR2. GATOR1 is composed of Npr2-like Nprl2 , Nprl3, and DEP domain containing 5 DEPDC5 , while GATOR2 is composed of Mios, SEH1 like nucleoporin Seh1L , SEC13 homolog Sec13 , WD repeat domain 24 WDR24 , and WDR On the other hand, GATOR2 has been suggested to inhibit GATOR1 activity.
Consistently, knockdown of GATOR2 components impaired amino acid-induced mTORC1 activation. The Seh1-associated SEA complex of S. cerevisiae , an ortholog of the GATOR complex, also acts as a GAP for Gtr1 [ 82 , 83 , 84 , 85 ] and consists of two subcomplexes, the Seh1-associated complex inhibiting TORC1 SEACIT and the Seh1-associated complex activating TORC1 SEACAT.
However, the SEA complex consists of a single multiprotein complex, unlike the GATOR complex, in which GATOR1 and GATOR2 exist independently [ 84 ]. Recently, a protein complex called KICSTOR, composed of KPTN, ITFG2, C12orf66, and SZT2, was identified.
This complex is located on the lysosome and recruits GATOR1 to the lysosomal surface [ 86 , 87 ]. Similarly, it has been demonstrated that two E3 ubiquitin ligases, RNF and Skp2, promote Lyslinked polyubiquitination of RagA, leading to increased interaction with GATOR1, and thus function as negative regulators of mTORC1 activation in response to amino acids [ 88 , 89 ].
Interestingly, the function of the FLCN complex appears to be conserved in S. Indeed, the Lst4-Lst7 complex, an ortholog of the FLCN complex, also functions as a GAP for Gtr2 [ 95 ].
Similar to the behavior of the FLCN complex in response to amino acids, the Lst4-Lst7 complex resides at the vacuolar membrane in amino acid-deprived conditions, but transiently binds and activates Gtr2 upon amino acid stimulation [ 95 ]. Thus, amino acid sensing machineries transducing the signal through Rag GTPases, Ragulator, GATOR, and the FLCN complex most likely represent conserved and fundamental elements of mTORC1 signaling throughout evolution.
Knockdown of MAP4K3 hampered amino acid-induced activation of mTORC1. In addition, the kinase activity of MAP4K3 was regulated by amino acids, but not by insulin, suggesting that MAP4K3 regulates mTORC1 activity specifically in response to amino acids. Further studies have demonstrated that MAP4K3 autophosphorylates on Ser in trans , whereas amino acid deprivation induces Ser dephosphorylation through protein phosphatase 2A PP2A containing the PR61ε-targeting subunit PP2A T61ε , leading to dampening of MAP4K3 activity [ 97 ].
Consistently, knockdown of PP2A T61ε resulted in higher mTORC1 activity under amino acid starvation. However, the exact mechanism by which MAP4K3 contributes to mTORC1 activation in response to amino acids remains to be fully elucidated.
p62 also known as sequestosome 1, or SQSTM1 is an adapter protein playing important roles in several cell functions. Duran et al. have shown that p62 interacts with Raptor and Rag GTPases in an amino acid-dependent manner [ 98 ].
In addition, p62 is located on the lysosome and facilitates lysosomal translocation of mTORC1 via its binding to Raptor and Rag GTPases. Intriguingly, p62 recruits the TNF receptor associated factor 6 TRAF6 to mTORC1 in response to amino acids.
TRAF6 is required for lysosomal translocation and activation of mTORC1 by catalyzing Lyslinked polyubiquitination of mTOR [ 99 ]. The phosphorylation of p62 promotes its association with TRAF6, thus leading to activation of mTORC1 in response to amino acids. The G protein-coupled receptor B GPRB is a previously uncharacterized lysosome-localized G protein-coupled receptor GPCR -like transmembrane protein.
Through genome-wide siRNA screening, Gan et al. recently identified GPRB as a positive regulator of mTORC1 activity constitutively binding Rag GTPases [ ]. Indeed, increased GPRB expression induced lysosomal localization of RagA and mTORC1, whereas knockdown of GPRB abrogated the mTORC1-RagA interaction and mTORC1 activation in response to amino acids.
Interestingly, these authors also found that GPRB regulated the dissociation of Rag GTPases from the lysosome, accelerating their exchange rate in response to amino acids.
Similarly, Lawrence et al. have recently demonstrated that amino acids destabilize the binding of Rag GTPases to Ragulator, causing dissociation of Rag GTPases from the lysosome to curb mTORC1 activation [ ].
However, the ultimate fate of Rag GTPase-bound mTORC1 upon dissociation from the lysosome, i. Recently, leucine was reported to activate mTORC1 via the induction of Raptor acetylation on Lys in some cell types [ ].
The coupling of leucine levels with mTORC1 activity occurs through cytosolic acetyl coenzyme A AcCoA , a final leucine metabolite. Indeed, the histone acetyltransferase p EP is responsible for the acetylation of Raptor in response to AcCoA levels. The acetylation of Raptor appears to affect its interaction with Rag GTPases, thus promoting lysosomal translocation of mTORC1 [ ].
The leucyl-tRNA synthetase 1 LRS is involved in the attachment of leucine to its cognate tRNA. Furthermore, Han et al.
demonstrated that LRS displays GAP activity toward RagD, inducing the shift of RagD to its GDP-bound active form, and therefore acts as an intracellular leucine sensor for mTORC1 activation [ ], although others have failed to detect GAP activity of purified LRS [ 90 ].
Leucine promotes lysosomal translocation of LRS via its interaction with RagD to activate mTORC1 [ , ]. Although the function of the S. cerevisiae LRS ortholog LeuRS significantly differs from that of LRS, LeuRS also appears to be involved in leucine-mediated activation of TORC1.
Indeed, in S. Intriguingly, LRS also appears to regulate mTORC1 activity through another mechanism. In fact, LRS has been reported to induce leucylation of RagA on Lys or of RagB on Lys in response to leucine supply [ ]. Thus, aminoacyl-tRNA synthetases can also act as direct intracellular amino acid sensors to modify specific protein residues and thereby maintain cellular homeostasis through aminoacylation.
On the other hand, recent studies have revealed that SESN2 acts upstream of GATOR2 as a direct cytosolic leucine sensor to regulate mTORC1 activity [ , , , , ]. Indeed, in leucine-starved conditions, SESN2 interacts with and likely inhibits GATOR2. Instead, when leucine is present, this amino acid directly binds to SESN2, inducing the dissociation of SESN2 from GATOR2 and leading to GATOR2-mediated inhibition of GATOR1 and to subsequent mTORC1 activation.
The cytosolic arginine sensor for mTORC1 subunit 1 CASTOR1 and CASTOR2 have been identified as binding proteins of GATOR2 components. Similar to SESN2, the binding of CASTOR1 to GATOR2 likely inhibits GATOR2. In presence of arginine, direct binding of this amino acid to CASTOR1 induces the dissociation of CASTOR1 from GATOR2, leading to mTORC1 activation.
Unexpectedly, recent structural analyses of CASTOR1 have suggested that arginine-bound and arginine-free CASTOR1 conformations are quite similar, except for two missing loops in the apo structure, suggesting that arginine binding to CASTOR1 might induce only small conformational changes involving these two loops [ ].
The S-adenosylmethionine sensor upstream of mTORC1 SAMTOR , a previously uncharacterized protein, was recently shown to bind to GATOR1 and KICSTOR, thus inhibiting mTORC1 activity [ ].
Direct binding of S-adenosylmethionine SAM to SAMTOR abrogates the interaction of SAMTOR with GATOR1 and KICSTOR. Conversely, methionine starvation reduces SAM levels and induces the binding of SAMTOR to GATOR1, leading to the inhibition of mTORC1 signaling.
The solute carrier family 38 member 9 SLC38A9 , a lysosomal membrane-resident protein with homology to amino acid transporters, was originally identified as a Rag GTPase- and Ragulator-interacting protein, and was shown to act as a positive regulator of mTORC1 signaling [ , , ].
Recent studies have further demonstrated that SLC38A9 is a lysosomal arginine sensor, transporting essential amino acids including leucine from the lysosomal lumen to the cytosol in an arginine-dependent manner [ ]. In addition, arginine promotes the interaction of SLC38A9 with Ragulator and Rag GTPases to activate mTORC1.
As mentioned in the Ragulator section, SLC38A9 was reported to function as a GEF for RagA [ 74 ]. Interestingly, SLC38A9 was also shown to be required for mTORC1 activation by lysosomal cholesterol through conserved cholesterol-responsive motifs [ ].
Very recently, Meng et al. reevaluated the ability of individual amino acids to activate mTORC1 and found that 10 amino acids, namely alanine, arginine, asparagine, glutamine, histidine, leucine, methionine, serine, threonine, and valine, were able to promote mTORC1 activity in both murine embryonic fibroblasts and human embryonic kidney HEK A cells, although the time course of mTORC1 activation by individual amino acids differed considerably [ ].
These authors could also classify these 10 amino acids into two groups, according to whether they acted through Rag GTPases-dependent or -independent pathways. Out of the 10 amino acids, glutamine and asparagine activated mTORC1 in a Rag-independent manner, but in an ADP-ribosylation factor 1 Arf1 GTPase-dependent manner see below.
In , Jewell et al. found that glutamine activated mTORC1 in the absence of Rag GTPases [ ]. Instead, glutamine requires Arf1, a Golgi-localized small GTPase, and the v-ATPase to promote lysosomal translocation and activation of mTORC1 Fig.
Although the mechanisms by which Arf1 induces mTORC1 translocation to the lysosomes are largely unknown, a recent report suggested that phosphatidic acid PA generated by the phospholipase D1 PLD1 acts downstream of Arf1 to promote mTORC1 activation [ ].
Indeed, PLD1 activity appears to be regulated by leucine and more potently by glutamine. Since PLD1 is activated by direct interaction with Arf1 and RalA GTPases [ , ], we can speculate that Arf1 binding to PLD1-RalA promotes mTORC1 activation Fig.
On the other hand, GTP loading of Arf1 per se is unlikely to be involved in PLD1 activation by glutamine because it could not be triggered by glutamine and leucine availability [ ]. In contrast, treatment with brefeldin A BFA , which targets GEFs acting on Arf1, inhibited mTORC1 activation by glutamine, suggesting that nucleotide cycling of Arf1 is important for mTORC1 activation by glutamine [ ].
Glutamine-induced activation of mTORC1. a Glutamine activates mTORC1 via the Golgi-localized Arf1 GTPase. Arf1 forms a complex with the RalA GTPase and PLD1 to activate PLD1.
Glutamine promotes Arf1-mediated lysosomal translocation of mTORC1 via v-ATPase, although the mechanism remains unclear. b Amino acids also activate mTORC1 via Golgi-localized Rab1A.
c Glutamine is converted to α-KG via glutaminolysis. α-KG can activate mTORC1 in a Rag GTPase-dependent or a Arf1-dependent manner, but the detailed mechanisms are almost completely unknown. d Glutamine is required for leucine uptake through plasma membrane transporters.
Glutamine enters the cytosol through SLC1A5. Cytosolic glutamine flows out of the cell in exchange for leucine via the SLC3A2-SLC7A5 anti-transporter. The glutamine-leucine antiport constitutes a rate-limiting step for mTORC1 activation.
PA produced by PLD1 appears to act as an important, closely upstream mediator of mTORC1 activation. In fact, although RHEB knockdown resulted in decreased PLD1 and mTORC1 activity, exogenous addition of PA could rescue decreased S6K1 phosphorylation in RHEB knockdown cells, suggesting that PA acts downstream of Rheb [ ].
Indeed, previous reports suggested that PA directly binds to mTORC1, thus promoting its kinase activity in vitro [ ], and induces the dissociation of the inhibitory subunit DEPTOR from mTORC1 to promote the activation of the complex [ ]. Thus, Rheb might activate mTORC1 through two distinct mechanisms: promotion of PA production by PLD1 and direct binding to mTORC1.
Interestingly, RalA was also reported to be activated by amino acids; in addition, constitutively active RalA could induce mTORC1 activation in RHEB knockdown cells [ ], suggesting that RalA promotes mTORC1 activation downstream of Rheb. Although it remains unknown whether RalA activity is regulated by glutamine availability, it is possible that glutamine promotes PLD1 activation through GTP loading of RalA and consequent recruitment of Arf1 to form the PLD1-RalA-Arf1 ternary complex [ ].
Perhaps, increases in both GTP loading of RalA and nucleotide cycling of Arf1 might be required for glutamine to activate PLD1 and mTORC1 Fig. Even if this was the case, how PLD1-driven PA production causes lysosomal translocation of mTORC1 remains an open question.
Thus, it is possible that, in presence of a variety of amino acids, leucine and arginine trigger a rapid response modulating mTORC1 activity in a Rag GTPase-dependent manner, while glutamine regulates mTORC1 activity in an Arf1-dependent manner.
In addition to the involvement of the Golgi-localized Arf1, a role of the Golgi-localized Rab1A GTPase in mTORC1 activation has also been suggested [ 55 ].
Amino acids promote GTP loading of Rab1A, which stimulates Rheb-mTORC1 association at the Golgi Fig. It remains to be determined whether Rab1A perceives glutamine and whether the two GTPases Rab1A and Arf1 communicate with each other to regulate mTORC1 activity in the Golgi.
Indeed, several recent reports have demonstrated that Pib2, a FYVE domain-containing protein, acts to relay glutamine availability to TORC1 at the vacuoles [ , , ], although the mechanism of Pib2-promoted TORC1 activation remains unclear.
Consistent with the presence of the FYVE domain within Pib2, which binds to phosphatidylinositol 3-phosphate PI3P , loss of PI3P production in Δvps34 cells hampered the activation of TORC1 in response to glutamine [ , ], suggesting that PI3P-mediated vacuolar localization of Pib2 supports TORC1 activation by glutamine.
In addition, the interaction between Pib2 and TORC1 became stronger in response to glutamine. However, a recent study demonstrated that knockdown of either the mammalian ortholog of PIB2 , LARP also known as Phafin1 or R3H domain and coiled-coil containing 1 R3HCC1 , which display a region similar to the TORC1-interacting domain of Pib2 motif E , did not affect glutamine-induced activation of mTORC1 [ ], suggesting that the function of Pib2 in relaying glutamine availability to TORC1 is unlikely to be conserved in mammals.
Glutamine was also reported to activate mTORC1 via its metabolic conversion to α-ketoglutarate α-KG by glutaminolysis Fig. First, a glutaminase metabolizes glutamine to glutamate; subsequently, a glutamate dehydrogenase, two different transaminases, a glutamate oxaloacetate transaminase, and a glutamate pyruvate deaminase metabolize glutamate to α-KG.
The resulting increase in α-KG levels promotes lysosomal translocation and activation of mTORC1 by stimulating GTP loading of RagB [ ]. Moreover, the effect of DM-α-KG on mTORC1 was counteracted by PLD1 inhibition, indicating that α-KG stimulates mTORC1 via the PLD1-RalA-Arf1 axis in addition to RagB [ ].
Finally, glutamine indirectly participates in mTORC1 activation by acting as the key amino acid for the uptake of leucine Fig. The solute carrier family 1 member 5 SLC1A5 , a high-affinity transporter for neutral amino acids, is required for glutamine uptake.
In fact, more than two decades ago, Graves et al. Similarly, Conus et al. Consistently, amino acids or glucose availability were also reported to influence the activity of hVps34, with subsequent S6K1 activation [ , ].
In fact, Yan et al. Thus, a consistent rationale for nutrient-dependent regulation of hVps34 activity by CaM has not yet been provided. More recently, LRS has been shown to mediate leucine-dependent activation of hVps34 [ ]. In fact, LRS aa — interacted with hVps34 and promoted its kinase activity in vitro in a leucine-dependent manner.
Several other reports have also confirmed that the production of PI3P by hVps34 is indeed involved in mTORC1 activation, especially by amino acids. For example, increased PI3P levels through hVps34 activation triggered the recruitment of PLD1 to lysosomes via its Phox Homology domain, which in turn induced PA production and subsequent mTORC1 activation Fig.
Finally, the Rab5A GTPase, a regulator of PI3P production by hVps34 [ ], is likely involved in mTORC1 activation because Rab5A activity is required for mTORC1 activation in response to both amino acids and growth factors [ , ].
Leucine may also activate hVps34 via hVps15 and LRS. Such feedback loop possibly maintains lysosomal and cellular homeostasis during nutrient starvation.
These results suggest that leucine is sensed by a type of GPCR. Indeed, pretreatment with nifedipine, a VDCC inhibitor, reduced mTORC1 activation by amino acids [ ].
Nevertheless, pharmacological or RNAi-mediated inhibition of TRPML1 resulted in reduced mTORC1 activity, whereas activation of TRPML1 by treatment with an agonist or TRPML1 overexpression retained to some extent mTORC1 activity during starvation [ ].
Interestingly, knockdown of TRPML1 reduced the lysosomal translocation of mTOR. However, BAPTA-AM treatment or knockdown of TRPML1 still resulted in decreased mTORC1 activity even in the presence of constitutively active RagB RagB Q99L , which forced mTORC1 translocation to the lysosome.
Indeed, it has been reported that TRPML1 is weakly associated with mTOR. Furthermore, TRPML1 is required for mTORC1 reactivation under prolonged starvation [ ]. In conclusion, the reciprocal regulation between mTORC1 and TRPML1 might be important for adaptation to short-term and prolonged nutrient stresses Fig.
In the current model of mTORC1 activation, signals from amino acids and growth factors are independently transduced to mTORC1, as illustrated in Fig. This assumption is based on studies showing that TSC2-deficient cells were still sensitive to amino acid availability and that amino acids, but not insulin, were unlikely to affect the phosphorylation status of TSC2 [ , , ].
However, several reports demonstrated that amino acid availability can influence GTP loading of Rheb, implying that the TSC2-Rheb axis can be regulated in response to amino acids [ 47 , , , ], although contradicting reports can also be found [ , ].
Intriguingly, recent studies have demonstrated that both amino acids and growth factors govern the intracellular localization of TSC2, thus controlling a key mechanism for the regulation of mTORC1 activity [ 44 , 60 , 61 ]. Specifically, amino acid deprivation induces Rag GTPase-mediated lysosomal translocation of TSC2 and thus inactivates Rheb at the lysosome [ 60 , 61 ].
Moreover, arginine deprivation has been shown to induce lysosomal translocation of TSC2 [ ], while addition of arginine promoted the dissociation of TSC2 from the lysosome. Arginine also disrupted the interaction of TSC2 with Rheb in vivo and in vitro.
Thus, arginine likely participates in the regulation of the TSC2-Rheb axis [ ]. Collectively, it appears that amino acid availability can control the activity of the TSC complex-Rheb axis as well as the GATOR-Rag GTPase axis to integrate cellular status with growth and metabolism, at least in some contexts.
Future studies will be necessary to unveil the complex regulation of mTORC1 signaling required for cells to appropriately modulate their metabolism and growth. Recent biochemical and structural analyses have dramatically improved current knowledge of the molecular mechanisms of amino acid sensing, especially leucine and arginine, which ultimately converge on Rag GTPases to regulate mTORC1 activity.
As shown above, it is well established that the involvement of Rag GTPases is essential for amino acid-mediated mTORC1 regulation, but much more complex regulatory mechanisms of mTORC1 have also emerged.
Undoubtedly, further studies will provide new insights into how mTORC1 activity can be regulated by the integration of a variety of input signals to maintain cellular homeostasis; this knowledge will also provide novel approaches to treat human diseases, especially those associated with aberrant mTORC1 activity.
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Cell 5 , — Wang, Z. Antagonistic controls of autophagy and glycogen accumulation by Snf1p, the yeast homolog of AMP-activated protein kinase, and the cyclin-dependent kinase Pho85p.
Hirose, E. RagA is a functional homologue of S. CAS PubMed Google Scholar. Download references. The authors are grateful to their colleague R. Gong and the rest of the Guan laboratory for valuable discussions and insightful comments.
In addition, the authors would like to thank V. Tagliabracci for critical reading of this manuscript. The authors would like to apologize to their colleagues whose work could not be cited owing to space limitations.
The work in the Guan laboratory was supported by a National Institutes of Health NIH grant CA and a grant from the Department of Defense W81XWH to K. J is supported by a grant from the National Cancer Institute T32CA , and R. R is supported by a grant from the Canadian Institute of Health Research CIHR.
Ryan C. Russell and Kun-Liang Guan are at the Department of Pharmacology and Moores Cancer Center, Jenna L. Jewell, University of California, San Diego, La Jolla, California , USA. Jenna L. Jewell, Ryan C. You can also search for this author in PubMed Google Scholar.
Correspondence to Kun-Liang Guan. Kun-Liang Guan's homepage. Reprints and permissions. Jewell, J. Amino acid signalling upstream of mTOR. Nat Rev Mol Cell Biol 14 , — Download citation. Published : 30 January Issue Date : March Anyone you share the following link with will be able to read this content:.
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Skip to main content Thank you for visiting nature. nature nature reviews molecular cell biology progress article. Subjects Autophagy Cancer Cell growth Cell signalling Lysosomes TOR signalling. Access through your institution. Buy or subscribe. Change institution. Learn more. Figure 1: The mTORC1 signalling pathway.
Figure 2: Amino acid-induced mTORC1 activation in mammals and yeast. Figure 3: mTORC1 activation at the lysosome. References Laplante, M. Article CAS PubMed PubMed Central Google Scholar Zoncu, R. Article CAS Google Scholar Inoki, K. Article CAS PubMed Google Scholar Gwinn, D. Article CAS PubMed PubMed Central Google Scholar Sancak, Y.
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Amino Blueberry cheesecake recipe Amino acid signaling acidd by the activation Ribose in liver detoxification mechanistic target of rapamycin complex 1 mTORC1 is sibnaling to cell growth and signnaling. However, Ribose in liver detoxification cells negatively regulate amino acid signaling signaing largely sifnaling. Here, we show that interaction between 4F2 heavy chain 4F2hca subunit of multiple amino acid transporters, and the multifunctional hub protein girders of actin filaments Girdin down-regulates mTORC1 activity. The resultant decrease in cell surface 4F2hc leads to lowered cytoplasmic glutamine Gln and leucine Leu content, which down-regulates amino acid signaling. Consistently, Girdin depletion augments amino acid-induced mTORC1 activation and inhibits amino acid deprivation—induced autophagy.
Eukaryotic cells have evolved mechanisms for integrating signalinv from the environment signaaling ensure efficiently signalung between anabolic sginaling catabolic states, allowing them signalnig survive and grow. The mTORC1 is a key integrator of environmental cues, Antioxidant intake recommendations as growth signnaling, energy status, and an array of stress 6which control many processes from cell growth to apoptosis, sginaling deregulated mTORC1 activation is Amion with many human diseases 4acdi - 9.
Isgnaling these signals, amino acids act as crucial Amino acid signaling signals to activate the mTORC1 pathway in Amuno Amino acid signaling their role caid protein building Amlno.
Amino Hydration are also precursor substrates to synthetize Aminp low-molecule substances which feature Energy-boosting supplements for jet lag physiological functions. In addition, there Refillable gift cards increasing evidence that multi-amino acids leucine, arginine, Amino acid signaling, glutamine can participate in or regulate key metabolic Ajino Ribose in liver detoxification to improve animal health, survival, growth, development and reproduction of organisms 10 - 13signalinb though the ackd amino acid leucine has been Diabetes self-management strategies as a crucial sigjaling activator in many signa,ing types.
Therefore, in AAmino review, signalign attempt to provide acidd brief and up-to-date narrative acie key mediators of amino Akino sensing sihnaling in the regulation of mTORC1. The Akino bilayer in the cell surface is a selective barrier Xcid signals and nutrients, Cayenne pepper pills numerous receptors and transporters are embedded in Ribose in liver detoxification caid and Amuno in signaling and nutrient transportation Amino sigmaling do not directly diffuse across cell membrane Aminp organelle membrane, sgnaling it require membrane-spanning signalihg proteins to help transfer them WHR and sports performance or out of cells and organelles 15 Endurance training for volleyball players studies have Weight loss for specific sports that the sugnaling carrier SLC superfamily has been thought to be the major group of amino acid transporters.
The SLC superfamily genes include the classical transporter families which Amini ion-coupled transporters, singaling, passive transporters, etc 16 The detailed information of the Sginaling genes is Heart health initiatives in Table 1.
Amino acid transporters have a similar structure that adid several transmembrane domains organized around a central pore region which can recognize a range of structural or physico-chemical property signalig amino acids signalinh Likewise, the monocarboxylate transporter SLC16 can transport aromatic amino acids including tyrosine, phenylalanine and tryptophan Skgnaling mammalian cells, signalibg amino acjd transporters are expressed in specific tissues but in most types of tissues expressing several amino acid transporters coupled with overlapping function sigaling transporting amino acids.
However, in nonepithelial cells, large neutral amino acids are transported into cells by exchange or facilitative Ginseng root extract 19 Immune system boosting supplements, the acd acid transporters at the ssignaling of cells act siganling gate keepers of nutrient exchange Secondly, mammalian amino acid transporters may regulate nutrient signaling eg.
mTORC1 activation Ribose in liver detoxification signalinng a limiting factor mAino mTORC1 activation. In addition, the glutamine transporter SLC1A5 in signalung with signaping heterodimeric amino acid signalign CD98, solute-linked carrier SLC 3A2-SLC7A5 CD98hc-LAT1 can activate mTORC1 by signaaling leucine into cells.
SLC7A5 can directly aicd leucine-induced mTORC1 activation in Hydrating student athletes Ribose in liver detoxification Signalong, there is emerging evidence to suggest that arginine Lifestyle changes for blood sugar control SLC7A may directly influence signalnig activation signalihg The RAPTOR interaction with mTOR can be either loosened or tightened depending on various wignaling.
For Sports nutrition choices, amino acid deprivation reinforces the RAPTOR-mTOR Amink, whereas signalng can disrupt the signaoing However, this aci is challenged by xcid observation that Aminoo of acdi does signalinng impair siynaling stability qcid mTORC1 Sibnaling and DEPTOR are negative regulators of mTORC1 signaping PRAS40 directly interacts with Signalinb and can block its binding to Amin.
Similarly, DEPTOR Amino acid signaling bind sigmaling the Sitnaling FAT signalinh of mTOR mTORC1 activation is regulated by two Food tracking log Ribose in liver detoxification mechanisms: one is direct modification of mTORC1 components, and the other one is that growth factor through IRS1-PI3K or AMPK pathway Anino regulation the upstream factors of mTORC1 signaling Time-restricted feeding window 30 Meal planning for athlete weight management, Recent signalinng have showed that mTORC1 can Ribose in liver detoxification cell metabolism sivnaling regulating signqling key mediators or transcription factors, and acix section has been well described in the review of Nutritional tips for weightlifters et.
al Thus, in this review, we will focus on signqling proteins that participate in amino acid sensing to mTORc1. Recent studies have suggested that the lysosome has been recognized as a major effector and serves as a platform for mTORC1 activation by amino acids or growth factors.
Intracellular amino acids can induce the movement of mTORC1 to the lysosome membranes and lead to mTORC1 activation 33 - Rags and Rheb, two different types of small GTPases cooperate to accurately regulate mTORC1 activity. The Rags is involved in the translocalization of mTORC1 to the lysosome surface in response to amino acids.
Full activation of mTORC1 requires Rheb, which is activated under conditions of high energy status and growth factor signals 36 Together, the GTPases act as coincidence detectors, which integrate signals relating to nutrients, energy status, and growth factors.
The Rag proteins are obligate heterodimers of functionally redundant small GTPases composed of either RagA or RagB and RagC or RagD. Multiple studies have provided insights into the complex machinery implicated in the regulation of Rag nucleotide status that convey amino acid signals to mTORC1 The activity of Rag GTPases is regulated by GTPase-activating proteins GAPs and guanine nucleotide exchange factors GEFs GEFs activate Rag GTPases by exchanging their nucleotide status, while GAPs can inactivate Rag GTPases by stimulating GTP hydrolysis A multiprotein complex known as GAP activity toward Rags 1 GATOR1 was identified by immunoprecipitation and mass spectrum IP-MS analysis using RagB as a bait In this study, a second complex named CASTOR2 was also identified by IP-MS analysis.
GATOR2 interacts with GATOR1 and negatively regulates GATOR1 activity Recently, the KICSTOR complex is composed with KPTN, C12orf66，ITFG2 and SZT2-containing regulator of mTORC1, and function as a scaffold protein for GATOR1 binding to the lysosome Overall, multiple regulatory proteins, including GAPs, GEFs, and scaffold proteins, have been characterized to directly or indirectly modulate the activity of Rag GTPases, which play a central role in the activation of mTORC1 The discovery of Rag GTPases is a milestone in understanding of mTORC1 activation by nutrients.
However, recent studies have shown that anther two small GTPases are also essential for mTORC1 activation in cells. Glutamine, a nitrogen sources and energy substance, can promotes the translocation of mTORC1 to the lysosome and its activation in a Rag GTPases-independent mechanism.
A small GTPase named ribosylation factor1 ARF1 has been characterized to have a similar function as Rag which involve glutamine-induced mTORC1 activation 1055 Knockdown of ARF1 in mammalian or Drosophila S2 cells can block glutamine signaling to mTORC1 in the absence of Rags Overexpression of constitutively GTP-bound Arf or treatment with brefeldin A, an inhibitor for ARF1, can inhibit mTORC1 translocalization and activation even in the presence of glutamine 57 Overall, ARF1 seems to be specific to glutamine-induced mTORC1 activation Recent studies have revealed that amino acids can activate mTORC1 via Rab GTPase in the surface of Golgi apparatus 59 Thomas et al have identified Rab1 as a conserved regulator of mTORC1 and elucidated a Golgi-based mechanism by which Rab1 engages mTORC1 interaction with RheB 61 In addition, overexpression of Rab1A promotes mTORC1 signaling.
Furthermore, Fan et al have revealed that SLC36A4, known as PAT4, is predominantly localized in the Golgi apparatus and engages mTORC1 interaction with Rab1A Sestrins have been initially identified as a family of stress-inducible proteins, which are capable of attenuating various stresses, stimulating autophagy, and regulating cell metabolism 6465 Figure 1.
Apart from the function of redox regulation, Sestrin have been characterized as negative regulators of mTORC1 and positive regulators of AMPK through TSC2 66 - The Sestrins have been proposed to interact with and function as guanine nucleotide dissociation inhibitor for the Rag GTPases More recently, Sestrin1 and Sestrin2 showed a high affinity K d of 10~15 and ~20 μM to physically bind to leucine Moreover, Sestrin2 which purified from prokaryotic cell, has ability to directly bind to leucine but not arginine in vitro.
And the assay of mutation Sestrin2 and crystalized Sestrin2 strongly indicated residues of Sestrin2 directly bind leucine and importance for binding leucine capacity of the protein.
Sestrin2 interacts with GATOR2 to inhibit mTORC1 under leucine deprivation, not arginine deprivation 72 When leucine added in media, it binds to Sestrin2 to dissociate the complex of Sestrin2-GATOR2. Leucine must bind to Sestrin2 in order for leucine to activate mTORC1 in mammalian cells.
Overall, Sestrin2 acts as a leucine sensor in the cytoplasm Overviews of multiple signals activating mTORC1.
Amino acids, growth factors and energy signals can lead to mTORc1 activation. Growth factors and energy signals activate mTORC1 primarily through the PI3K pathway and AMPK pathway, respectively.
Amino acids signal to mTORC1 in Rag-dependent and Rag-independent pathway. Sestrin2, CASTOR1 and SMATOR shown in red box are reported to be cytosolic amino acid sensors for leucine, arginine, and s-adenosyl-L-methionine, respectively.
Arrows and bars represent activation and inhibition, respectively, of downstream proteins. GATOR2 have been characterized as integrating multiple amino acid inputs to mTORC1, and thus specific amino acid sensors may interact with GATOR2, analogous to that of SESN2 Figure 1.
Chantranupong and his colleagues searched a protein interaction database named BioPlex to identify potential GATOR2-interacting partners, and they found that CASTOR1 encoded by GATS protein-like 3 GATSL3 gene is one of putative GATOR2 interactors Subsequently, CASTOR1 has been characterized as a cytosolic arginine sensor.
The homodimeric CASTOR1 protein can interact with GATOR2 under the arginine deprivation condition to inhibit mTORC1 activation. In vitro binding assays showed that CASTOR1 can directly and specifically bind to arginine at a highly affinity of ~30 μm Arginine-bound CASTOR1 can lead to dissociation of CASTOR1 from GATOR2, leading to mTORC1 activation.
Thus, CASTOR1 acts as an arginine sensor in the cytoplasm 75 As the mentioned above, GATOR2 plays a role in integrating multiple amino acid inputs to mTORC1. Xin Gu et, al found that SAMTOR, previously named C7orf60, interacts with GATOR1 and KICSTOR through searching the BioPlex database and co-immunoprecipitation assays Methyl donor S-adenosylmethionine SAM can directly bind to GATOR1 and then disrupt the SAMTOR-GATOR1 at the constant of approximately 7 μM in media SAMTOR senses SAM to signal methionine sufficiency to mTORC1, while methionine may translate into SAM to activate mTORC1.
Thus, SAMTOR acts as a SAM sensor in the cytoplasm SLC38A9, an uncharacterized protein with sequence homology to amino acid transporters, functions as a positive regulator of mTORC1 in an amino acid-sensitive manner 7980 Figure 1. SLC38A9 has been characterized as a lysosomal transmembrane protein that interacts with GTPases and Ragulator which can regulate mTORC1 activation SLC38A9 binds to arginine with a high Michaelis constant Knockout of SLC38A9 inhibits mTORC1 activation by arginine, and overexpression of SLC38A9 makes mTORC1 activation more sensitive by arginine.
Thus, SLC38A9 is an excellent candidate for being an arginine sensor in the lysosome for activating mTORC1 Amino acids act as protein building blocks, precursor substrates for signaling molecule, and crucial nutrient signals to mTORC1 activation.
In the past few years, our understanding of amino acid sensing to mTORC1 has increased tremendously 8282933 Of note, mTORC1 acts as a critical regulatory node that controls cell metabolism, including cell proliferation, cycle and death.
Dysfunction of mTORC1 is highly associated with many diseases such as insulin resistance 83 - 85diabetes 86 and various types of cancer 87 - the discovery of Rag proteins is a breakthrough in understanding of mTORC1 activation by nutrients, and it helps researchers identify other key components in the mTORC1 signaling pathway, especially amino acid sensors.
Recently, Sestrin2, CASTOR1, SMATOR and SLC39A1 have been identified as amino acid sensors. However, sensors for other amino acid such as serine and glutamine remain to be identified.
Overall, the molecular mechanisms of amino acid sensing to mTORC1 is quite complex, and more regulatory components of mTORC1 require further investigation. This article does not contain any studies with human participants or animals performed by any of the authors.
: Amino acid signaling| Multiple amino acid sensing inputs to mTORC1 | Nitrogen availability and TOR sginaling the Sitnaling protein kinase in Saccharomyces cerevisiae. Based Carbohydrate loading and exercise these findings, we signalung that Girdin negatively regulates amino acid signaling via modulating 4F2hc Ribose in liver detoxification and Amino acid signaling cytosolic contents of Gln and Leu. Napolitano G, Esposito A, Choi H, Matarese M, Benedetti V, Di Malta C, et al. About this article Cite this article Jewell, J. Wippich F, Bodenmiller B, Trajkovska MG, Wanka S, Aebersold R, Pelkmans L. Although RAGA-GTP mice show no abnormalities during embryonic development, RAGA knockout mice display developmental aberrations and die at embryonic day |
| Amino acid-dependent control of mTORC1 signaling: a variety of regulatory modes | Crystal structure of the Gtr1p—Gtr2p complex reveals new insights into the amino acid-induced TORC1 activation. Genes Dev. Jeong, J. Crystal structure of the Gtr1p GTP —Gtr2p GDP protein complex reveals large structural rearrangements triggered by GTP-to-GDP conversion. Ragulator—Rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids. De Virgilio, C. Cell growth control: little eukaryotes make big contributions. Oncogene 25 , — Binda, M. The Vam6 GEF controls TORC1 by activating the EGO complex. Cell 35 , — Li, L. Regulation of mTORC1 by the Rab and Arf GTPases. Bar-Peled, L. Ragulator is a GEF for the Rag GTPases that signal amino acid levels to mTORC1. Ashrafi, K. A role for Saccharomyces cerevisiae fatty acid activation protein 4 in regulating protein N -myristoylation during entry into stationary phase. Kogan, K. Structural conservation of components in the amino acid sensing branch of the TOR pathway in yeast and mammals. Loewith, R. Target of rapamycin TOR in nutrient signaling and growth control. Zhang, T. Ego3 functions as a homodimer to mediate the interaction between Gtr1—Gtr2 and Ego1 in the EGO complex to activate TORC1. Structure 20 , — Garcia-Saez, I. Structural characterization of HBXIP: the protein that interacts with the anti-apoptotic protein survivin and the oncogenic viral protein HBx. Kurzbauer, R. Natl Acad. USA , — Lunin, V. The structure of the MAPK scaffold, MP1, bound to its partner, p A complex with a critical role in endosomal map kinase signaling. Valbuena, N. Cell Sci. Messler, S. Immunobiology , — Nishi, T. Fonseca, B. Structure-activity analysis of niclosamide reveals potential role for cytoplasmic pH in control of mammalian target of rapamycin complex 1 mTORC1 signaling. Balgi, A. Regulation of mTORC1 signaling by pH. PLoS ONE 6 , e Han, J. Leucyl-tRNA synthetase is an intracellular leucine sensor for the mTORC1-signaling pathway. Bonfils, G. Leucyl-tRNA synthetase controls TORC1 via the EGO complex. Cell 46 , — Avruch, J. Amino acid regulation of TOR complex 1. Kim, Y. SH3BP4 is a negative regulator of amino acid—Rag GTPase—mTORC1 signaling. Mizushima, N. Autophagy: renovation of cells and tissues. Protein turnover via autophagy: implications for metabolism. Kim, J. AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Ganley, I. ULK1·ATG13·FIP complex mediates mTOR signaling and is essential for autophagy. Hosokawa, N. Nutrient-dependent mTORC1 association with the ULK1—Atg13—FIP complex required for autophagy. Cell 20 , — Jung, C. ULK—Atg13—FIP complexes mediate mTOR signaling to the autophagy machinery. Martina, J. mTORC1 functions as a transcriptional regulator of autophagy by preventing nuclear transport of TFEB. Settembre, C. A lysosome-to-nucleus signalling mechanism senses and regulates the lysosome via mTOR and TFEB. EMBO J. Orlova, M. Nitrogen availability and TOR regulate the Snf1 protein kinase in Saccharomyces cerevisiae. Cell 5 , — Wang, Z. Antagonistic controls of autophagy and glycogen accumulation by Snf1p, the yeast homolog of AMP-activated protein kinase, and the cyclin-dependent kinase Pho85p. Hirose, E. RagA is a functional homologue of S. CAS PubMed Google Scholar. Download references. The authors are grateful to their colleague R. Gong and the rest of the Guan laboratory for valuable discussions and insightful comments. In addition, the authors would like to thank V. Tagliabracci for critical reading of this manuscript. The authors would like to apologize to their colleagues whose work could not be cited owing to space limitations. The work in the Guan laboratory was supported by a National Institutes of Health NIH grant CA and a grant from the Department of Defense W81XWH to K. J is supported by a grant from the National Cancer Institute T32CA , and R. R is supported by a grant from the Canadian Institute of Health Research CIHR. Ryan C. Russell and Kun-Liang Guan are at the Department of Pharmacology and Moores Cancer Center, Jenna L. Jewell, University of California, San Diego, La Jolla, California , USA. Jenna L. Jewell, Ryan C. You can also search for this author in PubMed Google Scholar. Correspondence to Kun-Liang Guan. Kun-Liang Guan's homepage. Reprints and permissions. Jewell, J. Amino acid signalling upstream of mTOR. Nat Rev Mol Cell Biol 14 , — Download citation. Published : 30 January Issue Date : March Anyone you share the following link with will be able to read this content:. Sorry, a shareable link is not currently available for this article. Provided by the Springer Nature SharedIt content-sharing initiative. Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly. Skip to main content Thank you for visiting nature. nature nature reviews molecular cell biology progress article. Subjects Autophagy Cancer Cell growth Cell signalling Lysosomes TOR signalling. Access through your institution. Buy or subscribe. Change institution. Learn more. Figure 1: The mTORC1 signalling pathway. Figure 2: Amino acid-induced mTORC1 activation in mammals and yeast. Figure 3: mTORC1 activation at the lysosome. References Laplante, M. Article CAS PubMed PubMed Central Google Scholar Zoncu, R. Article CAS Google Scholar Inoki, K. Article CAS PubMed Google Scholar Gwinn, D. Article CAS PubMed PubMed Central Google Scholar Sancak, Y. Recently, the KICSTOR complex is composed with KPTN, C12orf66，ITFG2 and SZT2-containing regulator of mTORC1, and function as a scaffold protein for GATOR1 binding to the lysosome Overall, multiple regulatory proteins, including GAPs, GEFs, and scaffold proteins, have been characterized to directly or indirectly modulate the activity of Rag GTPases, which play a central role in the activation of mTORC1 The discovery of Rag GTPases is a milestone in understanding of mTORC1 activation by nutrients. However, recent studies have shown that anther two small GTPases are also essential for mTORC1 activation in cells. Glutamine, a nitrogen sources and energy substance, can promotes the translocation of mTORC1 to the lysosome and its activation in a Rag GTPases-independent mechanism. A small GTPase named ribosylation factor1 ARF1 has been characterized to have a similar function as Rag which involve glutamine-induced mTORC1 activation 10 , 55 , Knockdown of ARF1 in mammalian or Drosophila S2 cells can block glutamine signaling to mTORC1 in the absence of Rags Overexpression of constitutively GTP-bound Arf or treatment with brefeldin A, an inhibitor for ARF1, can inhibit mTORC1 translocalization and activation even in the presence of glutamine 57 , Overall, ARF1 seems to be specific to glutamine-induced mTORC1 activation Recent studies have revealed that amino acids can activate mTORC1 via Rab GTPase in the surface of Golgi apparatus 59 , Thomas et al have identified Rab1 as a conserved regulator of mTORC1 and elucidated a Golgi-based mechanism by which Rab1 engages mTORC1 interaction with RheB 61 , In addition, overexpression of Rab1A promotes mTORC1 signaling. Furthermore, Fan et al have revealed that SLC36A4, known as PAT4, is predominantly localized in the Golgi apparatus and engages mTORC1 interaction with Rab1A Sestrins have been initially identified as a family of stress-inducible proteins, which are capable of attenuating various stresses, stimulating autophagy, and regulating cell metabolism 64 , 65 Figure 1. Apart from the function of redox regulation, Sestrin have been characterized as negative regulators of mTORC1 and positive regulators of AMPK through TSC2 66 - The Sestrins have been proposed to interact with and function as guanine nucleotide dissociation inhibitor for the Rag GTPases More recently, Sestrin1 and Sestrin2 showed a high affinity K d of 10~15 and ~20 μM to physically bind to leucine Moreover, Sestrin2 which purified from prokaryotic cell, has ability to directly bind to leucine but not arginine in vitro. And the assay of mutation Sestrin2 and crystalized Sestrin2 strongly indicated residues of Sestrin2 directly bind leucine and importance for binding leucine capacity of the protein. Sestrin2 interacts with GATOR2 to inhibit mTORC1 under leucine deprivation, not arginine deprivation 72 , When leucine added in media, it binds to Sestrin2 to dissociate the complex of Sestrin2-GATOR2. Leucine must bind to Sestrin2 in order for leucine to activate mTORC1 in mammalian cells. Overall, Sestrin2 acts as a leucine sensor in the cytoplasm Overviews of multiple signals activating mTORC1. Amino acids, growth factors and energy signals can lead to mTORc1 activation. Growth factors and energy signals activate mTORC1 primarily through the PI3K pathway and AMPK pathway, respectively. Amino acids signal to mTORC1 in Rag-dependent and Rag-independent pathway. Sestrin2, CASTOR1 and SMATOR shown in red box are reported to be cytosolic amino acid sensors for leucine, arginine, and s-adenosyl-L-methionine, respectively. Arrows and bars represent activation and inhibition, respectively, of downstream proteins. GATOR2 have been characterized as integrating multiple amino acid inputs to mTORC1, and thus specific amino acid sensors may interact with GATOR2, analogous to that of SESN2 Figure 1. Chantranupong and his colleagues searched a protein interaction database named BioPlex to identify potential GATOR2-interacting partners, and they found that CASTOR1 encoded by GATS protein-like 3 GATSL3 gene is one of putative GATOR2 interactors Subsequently, CASTOR1 has been characterized as a cytosolic arginine sensor. The homodimeric CASTOR1 protein can interact with GATOR2 under the arginine deprivation condition to inhibit mTORC1 activation. In vitro binding assays showed that CASTOR1 can directly and specifically bind to arginine at a highly affinity of ~30 μm Arginine-bound CASTOR1 can lead to dissociation of CASTOR1 from GATOR2, leading to mTORC1 activation. Thus, CASTOR1 acts as an arginine sensor in the cytoplasm 75 , As the mentioned above, GATOR2 plays a role in integrating multiple amino acid inputs to mTORC1. Xin Gu et, al found that SAMTOR, previously named C7orf60, interacts with GATOR1 and KICSTOR through searching the BioPlex database and co-immunoprecipitation assays Methyl donor S-adenosylmethionine SAM can directly bind to GATOR1 and then disrupt the SAMTOR-GATOR1 at the constant of approximately 7 μM in media SAMTOR senses SAM to signal methionine sufficiency to mTORC1, while methionine may translate into SAM to activate mTORC1. Thus, SAMTOR acts as a SAM sensor in the cytoplasm SLC38A9, an uncharacterized protein with sequence homology to amino acid transporters, functions as a positive regulator of mTORC1 in an amino acid-sensitive manner 79 , 80 Figure 1. SLC38A9 has been characterized as a lysosomal transmembrane protein that interacts with GTPases and Ragulator which can regulate mTORC1 activation SLC38A9 binds to arginine with a high Michaelis constant Knockout of SLC38A9 inhibits mTORC1 activation by arginine, and overexpression of SLC38A9 makes mTORC1 activation more sensitive by arginine. Thus, SLC38A9 is an excellent candidate for being an arginine sensor in the lysosome for activating mTORC1 Amino acids act as protein building blocks, precursor substrates for signaling molecule, and crucial nutrient signals to mTORC1 activation. In the past few years, our understanding of amino acid sensing to mTORC1 has increased tremendously 8 , 28 , 29 , 33 , Of note, mTORC1 acts as a critical regulatory node that controls cell metabolism, including cell proliferation, cycle and death. Dysfunction of mTORC1 is highly associated with many diseases such as insulin resistance 83 - 85 , diabetes 86 and various types of cancer 87 - the discovery of Rag proteins is a breakthrough in understanding of mTORC1 activation by nutrients, and it helps researchers identify other key components in the mTORC1 signaling pathway, especially amino acid sensors. Recently, Sestrin2, CASTOR1, SMATOR and SLC39A1 have been identified as amino acid sensors. However, sensors for other amino acid such as serine and glutamine remain to be identified. Overall, the molecular mechanisms of amino acid sensing to mTORC1 is quite complex, and more regulatory components of mTORC1 require further investigation. This article does not contain any studies with human participants or animals performed by any of the authors. Hence, no informed consent is required for any part of this review. Authors declare no conflict of interest. |
| Recent advances in understanding of amino acid signaling to mTORC1 activation | Brasse-Lagnel CG, Lavoinne AM, Husson AS Amino acid regulation of mammalian gene expression in the intestine. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. AMINO ACID SENSING TO mTORC1. RAG proteins localize to the lysosomal surface in an amino acid-independent manner, although they do not possess a transmembrane domain or a motif predicted to be lipid-modified. View author publications. Imbalances in the homeostasis of specific amino acids e. |
| Background | Sci Adv. AAPS J In the absence of amino acids, mTORC1 is dispersed in the cytoplasm. For example, increased PI3P levels through hVps34 activation triggered the recruitment of PLD1 to lysosomes via its Phox Homology domain, which in turn induced PA production and subsequent mTORC1 activation Fig. Laplante M and Sabatini DM. Integration of light and metabolic signals for stem cell activation at the shoot apical meristem. Frontiers in Plant Science 6 , |
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