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

摘要/Abstract

摘要： 在哺乳动物细胞中，雷帕霉素靶蛋白复合体1（mTORC1）信号通路是细胞感应内外营养素（如氨基酸）、激素（如生长因子）和能量等因素的变化，调节细胞的增殖、生长、蛋白合成和自噬等生命活动的主要信号通路之一。在营养素对细胞中mTORC1信号通路的调控中，氨基酸是重要的调控因子之一。在哺乳动物细胞中，mTORC1被氨基酸磷酸化激活后，通过核糖体蛋白S6激酶1（S6K1）和真核翻译起始因子4E结合蛋白1（4EBP1）两个下游分子参与蛋白质翻译过程，促进蛋白质的合成，但在氨基酸如何调控细胞中mTORC1上游通路方面，还知之甚少。目前研究表明，氨基酸对细胞中mTORC1上游通路的调控可能有如下几个模式：（1）“inside-out”模式，即氨基酸先进入溶酶体内，然后在溶酶体内部通过激活SLC38A9、v-ATPase、Ragulator和Rag GTPase等信号分子募集mTORC1至溶酶体表面并将其激活；（2）GATOR-Rag GTPase模式，即氨基酸进入细胞后在胞浆中通过激活或抑制Sestrins、GATOR2、GATOR1、Skp2和Rag GTPase等信号分子激活mTORC1；（3）亮氨酸调控模式，即亮氨酸通过亮氨酰-tRNA合成酶和Rag GTPase等信号分子激活mTORC1；（4）谷氨酰胺调控模式，即谷氨酰胺通过谷氨酰胺代谢酶、谷氨酰胺产物α-酮戊二酸和小GTP酶ADP核糖基化因子1（Arf1）等信号分子激活mTORC1；（5）其他调控因子。除了上述4种模式外，还有一些在氨基酸调控mTORC1过程中起重要调控作用，但又不归属于上述任何一种调控通路的调控因子。如MAP4K3、B/PR61ε、p62、T1R1/T1R3、TRAF6 和SH3BP4等。文章综合近几年的研究，对氨基酸对哺乳动物中mTORC1上游的调控及其可能的通路做一综述。

关键词: mTORC1, Rag GTPase, 氨基酸, Ragulator, GATOR

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

骆超超，郑楠，赵圣国，李松励，文芳，王加启，张养东. 氨基酸调控哺乳动物细胞mTORC1上游通路研究进展[J]. 中国农业科学, 2015, 48(S): 67-74.

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
/ / 推荐

导出引用管理器 EndNote|Reference Manager|ProCite|BibTeX|RefWorks

链接本文: https://www.chinaagrisci.com/CN/10.3864/j.issn.0578-1752.2015.S.008

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

参考文献

[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.