氨基酸调控哺乳动物细胞mTORC1上游通路研究进展

doi:10.3864/j.issn.0578-1752.2015.S.008

Abstract

Abstract: In mammalian cells, the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway is one of the main signaling pathways that regulate life activities, such as cell proliferation, growth, protein synthesis and cell autophagy and so on, in response to the change of nutrients (such as amino acids), hormones (such as growth factors) and energy. Amino acid is one of the most important regulatory factors in nutrients factors that regulate mTORC1 signaling pathways in cells. In mammalian cells, mTORC1 is phosphorylated and activated by amino acid, and then phosphorylated mTORC1 participates in the translation process of protein and promotes the protein synthesis by activating two downstream molecules, ribosomal protein S6 kinase 1 (S6K1) and eukaryotic translation initiation factor 4E binding protein 1 (4EBP1). But about the regulatory pathways and molecular mechanism of amino acids-mediated-mTORC1 upstream pathway is still poorly understood. Studies have shown that, the regulation of amino acid on the mTORC1 upstream pathways may have several different models: (1): “inside-out” model, in this model, amino acid is transported into lysosome, and then the amino acid recruits mTORC1 to the lysosomal surface and activates mTORC1 by activating SLC38A9, v-ATPase, Ragulator and Rag GTPase, and amino acid activates these proteins in lysosome; (2): GATOR - Rag GTPase model, in this model, amino acid activates mTORC1 by activating or inhibiting Sestrins, GATOR2, GATOR1, Skp2 and Rag GTPase, and amino acid activates or inhibits these proteins in cytoplasm; (3): Leucine regulatory model, Leucine activates mTORC1 by leucyl-tRNA synthetase and Rag GTPase; (4): Glutamine regulatory model, glutamine activates mTORC1 by Glutamine metabolic enzymes, Alpha ketone glutaric acid and small GTPase ADP ribose base factor 1 (Arf1); (5): Other regulatory factors, besides above models, there are also some signaling molecules playing important role in the regulation of amino acids-mediated-mTORC1 upstream pathway, but not belonging to the above models, such as MAP4K3, B/PR61 epsilon, p62, T1R1 / T1R3, TRAF6 and SH3BP4, etc. This review summarized the regulation and the possible pathways of amino acids-mediated-mTORC1 upstream pathway in mammalian cells.

Key words: mTORC1, Rag GTPase, amino acid, Ragulator, GATOR

LUO Chao-chao, ZHENG Nan, ZHAO Sheng-guo, LI Song-li, WEN Fang, WANG Jia-qi, ZHANG Yang-dong. Advances of the Regulation of Amino Acids-Mediated-mTORC1 Upstream Pathway in Mammalian Cells[J].Scientia Agricultura Sinica, 2015, 48(S): 67-74.

0
/ / Recommend

Add to citation manager EndNote|Reference Manager|ProCite|BibTeX|RefWorks

URL: https://www.chinaagrisci.com/EN/10.3864/j.issn.0578-1752.2015.S.008

https://www.chinaagrisci.com/EN/Y2015/V48/IS/67

References

[1] Wang X, Proud C G. Nutrient control of TORC1, a cell-cycle regulator. Trends in Cell Biology, 2009, 19(6): 260-267.

[2] Howell J J, Ricoult S J H, Ben-Sahra I, Manning B D. A growing role for mTOR in promoting anabolic metabolism. Biochemical Society Transactions, 2013, 41(4): 906-912.

[3] Dunlop E A, Tee A R. Mammalian target of rapamycin complex 1: signalling inputs, substrates and feedback mechanisms. Cell Signalling, 2009, 21(6): 827-835.

[4] Kim D H, Sarbassov D D, Ali S M, Latek R R, Guntur K V, Erdjument-Bromage H, Tempst P, Sabatini D M. GbetaL, a positive regulator of the rapamycin sensitive pathway required for the nutrient-sensitive interaction between raptor and mTOR. Molecular Cell, 2003, 11(4): 895-904.

[5] 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 nutrientsensitive complex that signals to the cell growth machinery. Cell, 2002, 110(2): 163-175.

[6] 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(5): 873-886.

[7] Huang J, Manning B D. A complex interplay between Akt, TSC2 and the two mTOR complexes. Biochemical Society Transactions, 2009, 37(Pt 1): 217-222.

[8] Dibble C C, Manning B D. Signal integration by mTORC1 coordinates nutrient input with biosynthetic output. Nature Cell Biology, 2013, 15(6): 555-564.

[9] Chantranupong L, Wolfson R L, Sabatini D M. Nutrient-sensing mechanisms across evolution. Cell, 2015, 161(1): 67-83.

[10] Wellen K E, Thompson C B. Cellular metabolic stress: considering how cells respond to nutrient excess. Molecular Cell, 2010, 40(2): 323-332.

[11] Yuan H X, Xiong Y, Guan K L. Nutrient sensing, metabolism, and cell growth control. Molecular Cell, 2013, 49(3): 379-387.

[12] 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(4): 771-785.

[13] Kim S G, Buel G R, Blenis J. Nutrient regulation of the mTOR complex 1 signaling pathway. Moleculars and Cells, 2013, 35(6): 463-473.

[14] Huang K, Fingar D C. Growing knowledge of the mTOR signaling network. Seminars in Cell & Developmental Biology, 2014, 36(12): 79-90.

[15] Sengupta S, Peterson T R, Sabatini D M. Regulation of the mTOR complex 1 pathway by nutrients, growth factors, and stress. Molecular Cell, 2010, 40(2): 310-322.

[16] Tan J. Amino Acid Intricacy. Cell, 2015, 160(4): 575.

[17] Wang X, Proud C G. mTORC1 signaling: what we still don't know. Journal of Molecular Cell Biology, 2011, 3(4): 206-220.

[18] Proud C G. A new link in the chain from amino acids to mTORC1 activation. Molecular Cell, 2011, 44(1): 7-8.

[19] Avruch J, Long X, Ortiz-Vega S, Rapley J, Papageorgiou A, Dai N. Amino acid regulation of TOR complex 1. American Journal of Physiology-Endocrinology and Metabolism, 2009, 296(4): E592-602.

[20] Zhou H Y, Huang S L. The complexes of mammalian target of rapamycin. Current Protein & Peptide Science, 2010, 11(6): 409–424.

[21] Jewell J L, Russell R C, Guan K L. Amino acid signaling upstream of mTOR. Nature Reviews Molecular Cell Biology, 2013, 14(3): 133-139.

[22] Kim J, Guan K L. Amino acid signaling in TOR activation. Annual Review of Biochemistry, 2011, 80: 1001-1032.

[23] Laplante M, Sabatini D M. mTOR signaling in growth control and disease. Cell, 2012, 149(2): 274-293.

[24] Goberdhan D C, Ogmundsdóttir M H, Kazi S. Amino acid sensing and mTOR regulation: inside or out? Biochemical Society Transactions, 2009, 37(Pt 1): 248-252.

[25] Abraham R T. Making sense of amino acid sensing. Science, 2015, 347(6218): 128-129.

[26] Kim E, Goraksha-Hicks P, Li L. Regulation of TORC1 by Rag GTPases in nutrient response. Nature Cell Biology, 2008, 10(8): 935-945.

[27] Sancak Y, Peterson T R, Shaul Y D. The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1. Science, 2008, 320(5882): 1496-1501.

[28] Sancak Y, Sabatini D M. Rag proteins regulate amino-acid-induced mTORC1 signalling. Biochemical Society Transactions, 2009, 37(Pt 1): 289-290.

[29] Groenewoud M J, Zwartkruis F J. Rheb and Rags come together at the lysosome to activate mTORC1. Biochemical Society Transactions, 2013, 41(4): 951-955.

[30] Suzuki T, Inoki K. Spatial regulation of the mTORC1 system in amino acids sensing pathway. Acta Biochim Biophys Sin (Shanghai), 2011, 43(9): 671-679.

[31] 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(5): e36616.

[32] Tsun Z Y, Bar-Peled L, Chantranupong L, Zoncu R, Wang T, Kim C, Spooner E, Sabatini D M. The folliculin tumor suppressor is a GAP for the RagC/D GTPases that signal amino acid levels to mTORC1. Molecular Cell, 2013, 52(4): 495-505.

[33] Demetriades C, Doumpas N, Teleman A A. Regulation of TORC1 in response to amino acid starvation via lysosomal recruitment of TSC2. Cell, 2014, 156(4): 786-799.

[34] 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(2): 290-303.

[35] Jin G, Lee S W, Zhang X, Cai Z, Gao Y, Chou P C, Rezaeian A H, Han F, Wang C Y, Yao J C, Gong Z, Chan C H, Huang C Y, Tsai F J, Tsai C H, Tu S H, Wu C H, Sarbassov dos D, Ho Y S, Lin H K. Skp2-Mediated RagA Ubiquitination Elicits a Negative Feedback to Prevent Amino-Acid-Dependent mTORC1 Hyperactivation by Recruiting GATOR1. Molecular Cell, 2015, 58(6): 989-1000.

[36] Deng L, Jiang C, Chen L, Jin J, Wei J, Zhao L, Chen M, Pan W, Xu Y, Chu H, Wang X, Ge X, Li D, Liao L, Liu M, Li L, Wang P. The ubiquitination of rag A GTPase by RNF152 negatively regulates mTORC1 activation. Molecular Cell, 2015, 58(5): 804-818.

[37] Jewell J L, Kim Y C, Russell R C, Yu F X, Park H W, Plouffe S W, Tagliabracci V S, Guan K L. Differential regulation of mTORC1 by leucine and glutamine. Science, 2015, 347(6218): 194-198.

[38] 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(6): 1196-1208.

[39] Bar-Peled L, Sabatini D M. Regulation of mTORC1 by amino acids. Trends in Cell Biology, 2014, 24(7): 400-406.

[40] 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(6056): 678-683.

[41] Xie X S, Padron D, Liao X, Wang J, Roth M G, De Brabander J K. Salicylihalamide A inhibits the V0 sector of the V-ATPase through a mechanism distinct from bafilomycin A1. Journal of Biological Chemistry, 2004, 279(19): 19755-19763.

[42] Wang S, Tsun Z Y, Wolfson R L, Shen K, Wyant G A, Plovanich M E, Yuan E D, Jones T D, Chantranupong L, Comb W, Wang T, Bar-Peled L, Zoncu R, Straub C, Kim C, Park J, Sabatini B L, Sabatini D M. Lysosomal amino acid transporter SLC38A9 signals arginine sufficiency to mTORC1. Science, 2015, 347(6218): 188-194.

[43] Rebsamen M, Pochini L, Stasyk T, de Araújo M E, Galluccio M, Kandasamy R K, Snijder B, Fauster A, Rudashevskaya E L, Bruckner M, Scorzoni S, Filipek P A, Huber K V, Bigenzahn J W, Heinz L X, Kraft C, Bennett K L, Indiveri C, Huber L A, Superti-Furga G. SLC38A9 is a component of the lysosomal amino acid sensing machinery that controls mTORC1. Nature, 2015, 519(7544): 477-481.

[44] Fingar D C. Rag Ubiquitination Recruits a GATOR1: Attenuation of Amino Acid-Induced mTORC1 Signaling. Molecular Cell, 2015, 58(5): 713-715.

[45] Parmigiani A, Nourbakhsh A, Ding B, Wang W, Kim Y C, Akopiants K, Guan K L, Karin M, Budanov A V. Sestrins inhibit mTORC1 kinase activation through the GATOR complex. Cell Reports, 2014, 9(4): 1281-1291.

[46] Chantranupong L, Wolfson R L, Orozco J M, Saxton R A, Scaria S M, Bar-Peled L, Spooner E, Isasa M, Gygi S P, Sabatini D M. The Sestrins interact with GATOR2 to negatively regulate the amino-acid-sensing pathway upstream of mTORC1. Cell Reports, 2014, 9(1): 1-8.

[47] 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(2): 410-424.

[48] Averous J, Lambert-Langlais S, Carraro V, Gourbeyre O, Parry L, B'Chir W, Muranishi Y, Jousse C, Bruhat A, Maurin A C, Proud C G, Fafournoux P. Requirement for lysosomal localization of mTOR for its activation differs between leucine and other amino acids. Cell Signalling, 2014, 26(9): 1918-1927.

[49] Laufenberg L J, Pruznak A M, Navaratnarajah M, Lang C H. Sepsis-induced changes in amino acid transporters and leucine signaling via mTOR in skeletal muscle. Amino Acids, 2014, 46(12): 2787-2798.

[50] Durán R V, Oppliger W, Robitaille A M, Heiserich L, Skendaj R, Gottlieb E, Hall M N. Glutaminolysis activates Rag-mTORC1 signaling. Molecular Cell, 2012, 47(3): 349-358.

[51] Yan L, Mieulet V, Burgess D, Findlay G M, Sully K, Procter J, Goris J, Janssens V, Morrice N A, Lamb R F. PP2A T61 epsilon is an inhibitor of MAP4K3 in nutrient signaling to mTOR. Molecular Cell, 2010, 37(5): 633-642.

[52] 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. Molecular Cell, 2011, 44(1): 134-146.

[53] Moscat J, Diaz-Meco M T. p62 at the crossroads of autophagy, apoptosis, and cancer. Cell, 2009, 137(6): 1001-1004.

[54] Wauson E M, Zaganjor E, Lee A Y, Guerra M L, Ghosh A B, Bookout A L, Chambers C P, Jivan A, McGlynn K, Hutchison M R, Deberardinis R J, Cobb M H. The G protein-coupled taste receptor T1R1/T1R3 regulates mTORC1 and autophagy. Molecular Cell, 2012, 47(6): 851-862.

[55] Linares J F, Duran A, Yajima T, Pasparakis M, Moscat J, Diaz-Meco M T. K63 polyubiquitination and activation of mTOR by the p62-TRAF6 complex in nutrient-activated cells. Molecular Cell, 2013, 51(3): 283-296.

[56] Kim Y M, Kim D H. dRAGging amino acid-mTORC1 signaling by SH3BP4. Molecules and Cells, 2013, 35(1): 1-6.

[57] Schweitzer L D, Comb W C, Bar-Peled L, Sabatini D M. Disruption of the Rag-Ragulator Complex by c17orf59 Inhibits mTORC1. Cell Reports, 2015, 12(9): 1445-1455.

Related Articles 15

[1]	YU QiLong,HAN YingYan,HAO JingHong,QIN XiaoXiao,LIU ChaoJie,FAN ShuangXi. Effect of Exogenous Spermidine on Nitrogen Metabolism of Lettuce Under High-Temperature Stress [J]. Scientia Agricultura Sinica, 2022, 55(7): 1399-1410.
[2]	YANG ShiMan, XU ChengZhi, XU BangFeng, WU YunPu, JIA YunHui, QIAO ChuanLing, CHEN HuaLan. Amino Acid of 225 in the HA Protein Affects the Pathogenicities of H1N1 Subtype Swine Influenza Viruses [J]. Scientia Agricultura Sinica, 2022, 55(4): 816-824.
[3]	YAN TongJing,ZHANG DeQuan,LI Xin,LIU Huan,FANG Fei,LIU ShanShan,WANG Su,HOU ChengLi. Effects of Very Fast Chilling on Flavor Quality in Chilled Lamb [J]. Scientia Agricultura Sinica, 2022, 55(15): 3029-3041.
[4]	ZHU Yin,ZHANG Yue,YAN Han,LÜ HaiPeng,LIN Zhi. Enantiomeric Analysis of Free Amino Acids in Different Teas [J]. Scientia Agricultura Sinica, 2021, 54(4): 804-819.
[5]	HOU ChengLi,HUANG CaiYan,ZHENG XiaoChun,LIU WeiHua,YANG Qi,ZHANG DeQuan. Changes of Antioxidant Activity and Its Possible Mechanism in Tan Sheep Meat in Different Postmortem Time [J]. Scientia Agricultura Sinica, 2021, 54(23): 5110-5124.
[6]	PAN ZhengYan,LIU Bo,JIANG HongBo,YAO JiPan,BAI YuanJun,XU ZhengJin. Effect of Panicle Neck Blast on Grain Yield and Stem Node Metabolites at the Rice Filling Stage [J]. Scientia Agricultura Sinica, 2020, 53(20): 4177-4188.
[7]	ZHU ZiJian,CHEN SiYu,SU Jun,TAO YongSheng. Correlation Analysis Between Amino Acids and Fruity Esters During Spine Grape Fermentation [J]. Scientia Agricultura Sinica, 2020, 53(11): 2272-2284.
[8]	ZHANG WenQiang,CHEN QingJun,ZHANG GuoQing,SHI ShiDa,CAO Na,ABLAT· Tohtirjap,GUO YuXin,LIN WenCai. Effects of Protein Supplements on Agronomic Characters and Quality of the Mushroom Agaricus bisporus [J]. Scientia Agricultura Sinica, 2020, 53(10): 2091-2100.
[9]	Wei ZHANG,JinJun DAI,XueHai YANG,JinTao WEI,MingXin CHEN,JunPeng HU,ShaoWen HUANG. Evaluation of Apparent Metabolic Energy, Nitrogen Corrected Metabolic Energy, Biological Value of Protein and Ileal Digestibility of Amino Acid of Yeast Hydrolysate for Broilers [J]. Scientia Agricultura Sinica, 2019, 52(20): 3685-3694.
[10]	SUN JuanJuan, A LaMuSi, ZHAO JinMei, XUE YanLin, YU LinQing, YU Zhu, ZHANG YingJun. Analysis of Amino Acid Composition and Six Native Alfalfa Cultivars [J]. Scientia Agricultura Sinica, 2019, 52(13): 2359-2367.
[11]	HAN YaFei, WANG XueDe, ZHENG YongZhan, MEI HongXian, WEI AnChi, LIU YanYang. Study on Changes of Sesame Protein Content and Its Components of Yuzhi 11 Sesame Seed During Growth Period [J]. Scientia Agricultura Sinica, 2018, 51(4): 652-661.
[12]	YuLing YANG, Lei ZHOU, Yuan YOU, XiaoZhi TANG, SuMeng WEI. The Effects of Oxidation on Textural Properties and Water Holding Capacity of Heat-Induced Myofibrillar Protein Gel [J]. Scientia Agricultura Sinica, 2018, 51(18): 3570-3581.
[13]	ZHANG Hui, WU ShengYong, WANG XiaoQing, LEI ZhongRen. Changes in the Contents of Proteins and Free Amino Acid in haemolymph of Delia antique Adult Infected by Beauveria bassiana [J]. Scientia Agricultura Sinica, 2017, 50(3): 591-598.
[14]	ZHANG QingAn, ZHANG XinYun, FENG YuLin, SHI FangFang. Compositions and Physicochemical Properties of Sweet Almond Isolate Proteins [J]. Scientia Agricultura Sinica, 2017, 50(13): 2564-2575.
[15]	BO Xiao-pei1, WANG Meng-xin1, CUI Lin1, WANG Jin-he2, HAN Bao-yu1. Evaluation on Correlations of Three Kinds of Osmoregulation Substances in Tea Fresh Leaves with Low Temperature During Winter and Spring Respectively and Their Difference Among Cultivars [J]. Scientia Agricultura Sinica, 2016, 49(19): 3807-3817.

Metrics

Viewed

Full text

Abstract

Cited

Shared

Discussed

Comments

Recommended 0

No Suggested Reading articles found!

Advances of the Regulation of Amino Acids-Mediated-mTORC1 Upstream Pathway in Mammalian Cells

RichHTML

PDF