Full Text:   <577>

Summary:  <429>

CLC number: Q291

On-line Access: 2019-08-05

Received: 2019-04-03

Revision Accepted: 2019-05-26

Crosschecked: 2019-07-09

Cited: 0

Clicked: 1947

Citations:  Bibtex RefMan EndNote GB/T7714

-   Go to

Article info.
Open peer comments

Journal of Zhejiang University SCIENCE B 2019 Vol.20 No.9 P.699-712


Sensors for the mTORC1 pathway regulated by amino acids

Author(s):  Xiu-Zhi Li, Xiang-Hua Yan

Affiliation(s):  State Key Laboratory of Agricultural Microbiology, College of Animal Sciences and Technology, Huazhong Agricultural University, Wuhan 430070, China; more

Corresponding email(s):   xhyan@mail.hzau.edu.cn

Key Words:  Mechanistic target of rapamycin complex 1 (mTORC1), Amino acid, Sensor, Lysosome, Rag GTPases

Share this article to: More |Next Article >>>

Xiu-Zhi Li, Xiang-Hua Yan. Sensors for the mTORC1 pathway regulated by amino acids[J]. Journal of Zhejiang University Science B, 2019, 20(1): 699-712.

@article{title="Sensors for the mTORC1 pathway regulated by amino acids",
author="Xiu-Zhi Li, Xiang-Hua Yan",
journal="Journal of Zhejiang University Science B",
publisher="Zhejiang University Press & Springer",

%0 Journal Article
%T Sensors for the mTORC1 pathway regulated by amino acids
%A Xiu-Zhi Li
%A Xiang-Hua Yan
%J Journal of Zhejiang University SCIENCE B
%V 20
%N 9
%P 699-712
%@ 1673-1581
%D 2019
%I Zhejiang University Press & Springer

T1 - Sensors for the mTORC1 pathway regulated by amino acids
A1 - Xiu-Zhi Li
A1 - Xiang-Hua Yan
J0 - Journal of Zhejiang University Science B
VL - 20
IS - 9
SP - 699
EP - 712
%@ 1673-1581
Y1 - 2019
PB - Zhejiang University Press & Springer
ER -

The mechanistic target of rapamycin complex 1 (mTORC1) controls cell growth and metabolism in response to various environmental inputs, especially amino acids. In fact, the activity of mTORC1 is highly sensitive to changes in amino acid levels. Over past decades, a variety of proteins have been identified as participating in the mTORC1 pathway regulated by amino acids. Classically, the Rag guanosine triphosphatases (GTPases), which reside on the lysosome, transmit amino acid availability to the mTORC1 pathway and recruit mTORC1 to the lysosome upon amino acid sufficiency. Recently, several sensors of leucine, arginine, and S-adenosylmethionine for the amino acid-stimulated mTORC1 pathway have been coming to light. Characterization of these sensors is requisite for understanding how cells adjust amino acid sensing pathways to their different needs. In this review, we summarize recent advances in amino acid sensing mechanisms that regulate mTORC1 activity and highlight these identified sensors that accurately transmit specific amino acid signals to the mTORC1 pathway.


概要:哺乳动物雷帕霉素靶蛋白复合物1(mTORC1)能够感受一系列细胞内外的环境因素(如氨基酸),从而控制细胞生长和代谢.在过去的几十年里,众多蛋白被发现能够参与受氨基酸调控的mTORC1信号通路中.Rag GTPases能够将氨基酸的信号传递给mTORC1并招募mTORC1到溶酶体表面.近年来,参与mTORC1信号通路的蛋氨酸代谢物、亮氨酸以及精氨酸的感受体逐渐被发现.感受体的鉴定有助于理解细胞是如何通过调整内部氨基酸感应通路来满足自身需求.本文综述了氨基酸调控mTORC1信号通路的分子机制,并探讨了感受体如何将特定氨基酸信号精确传递给mTORC1信号通路.

关键词:哺乳动物雷帕霉素靶蛋白复合物1(mTORC1);氨基酸;感受体;溶酶体;Rag GTPases

Darkslateblue:Affiliate; Royal Blue:Author; Turquoise:Article


[1]Abu-Remaileh M, Wyant GA, Kim C, et al., 2017. Lysosomal metabolomics reveals V-ATPase- and mTOR-dependent regulation of amino acid efflux from lysosomes. Science, 358(6364):807-813.

[2]Aylett CHS, Sauer E, Imseng S, et al., 2016. Architecture of human mTOR complex 1. Science, 351(6268):48-52.

[3]Baba M, Hong SB, Sharma N, et al., 2006. Folliculin encoded by the BHD gene interacts with a binding protein, FNIP1, and AMPK, and is involved in AMPK and mTOR signaling. Proc Natl Acad Sci USA, 103(42):15552-15557.

[4]Bar-Peled L, Schweitzer LD, Zoncu R, et al., 2012. Ragulator is a GEF for the rag GTPases that signal amino acid levels to mTORC1. Cell, 150(6):1196-1208.

[5]Bar-Peled L, Chantranupong L, Cherniack AD, et al., 2013. A tumor suppressor complex with GAP activity for the Rag GTPases that signal amino acid sufficiency to mTORC1. Science, 340(6136):1100-1106.

[6]Bonfils G, Jaquenoud M, Bontron S, et al., 2012. Leucyl-tRNA synthetase controls TORC1 via the EGO complex. Mol Cell, 46(1):105-110.

[7]Brown EJ, Albers MW, Shin TB, et al., 1994. A mammalian protein targeted by G1-arresting rapamycin-receptor complex. Nature, 369(6483):756-758.

[8]Buckbinder L, Talbott R, Seizinger BR, et al., 1994. Gene regulation by temperature-sensitive p53 mutants: identification of p53 response genes. Proc Natl Acad Sci USA, 91(22):10640-10644.

[9]Budanov AV, Karin M, 2008. p53 target genes Sestrin1 and Sestrin2 connect genotoxic stress and mTOR signaling. Cell, 134(3):451-460.

[10]Budanov AV, Shoshani T, Faerman A, et al., 2002. Identification of a novel stress-responsive gene Hi95 involved in regulation of cell viability. Oncogene, 21(39):6017-6031.

[11]Buerger C, DeVries B, Stambolic V, 2006. Localization of Rheb to the endomembrane is critical for its signaling function. Biochem Biophys Res Commun, 344(3):869-880.

[12]Burnett PE, Barrow RK, Cohen NA, et al., 1998. RAFT1 phosphorylation of the translational regulators p70 S6 kinase and 4E-BP1. Proc Natl Acad Sci USA, 95(4):1432-1437.

[13]Carroll B, Maetzel D, Maddocks OD, et al., 2016. Control of TSC2-Rheb signaling axis by arginine regulates mTORC1 activity. eLife, 5:e11058.

[14]Castellano BM, Thelen AM, Moldavski O, et al., 2017. Lysosomal cholesterol activates mTORC1 via an SLC38A9-Niemann-Pick C1 signaling complex. Science, 355(6331):1306-1311.

[15]Chantranupong L, Wolfson RL, Orozco JM, et al., 2014. The Sestrins interact with GATOR2 to negatively regulate the amino-acid-sensing pathway upstream of mTORC1. Cell Rep, 9(1):1-8.

[16]Chantranupong L, Wolfson RL, Sabatini DM, 2015. Nutrient-sensing mechanisms across evolution. Cell, 161(1):67-83.

[17]Chantranupong L, Scaria SM, Saxton RA, et al., 2016. The CASTOR proteins are arginine sensors for the mTORC1 pathway. Cell, 165(1):153-164.

[18]Chen J, Ou YH, Yang YY, et al., 2018. KLHL22 activates amino-acid-dependent mTORC1 signalling to promote tumorigenesis and ageing. Nature, 557(7706):585-589.

[19]Chen X, Ma JJ, Tan M, et al., 2011. Modular pathways for editing non-cognate amino acids by human cytoplasmic leucyl-tRNA synthetase. Nucleic Acids Res, 39(1):235-247.

[20]Chiu MI, Katz H, Berlin V, 1994. RAPT1, a mammalian homolog of yeast Tor, interacts with the FKBP12/rapamycin complex. Proc Natl Acad Sci USA, 91(26):12574-12578.

[21]de Araujo MEG, Naschberger A, Fürnrohr BG, et al., 2017. Crystal structure of the human lysosomal mTORC1 scaffold complex and its impact on signaling. Science, 358(6361):377-381.

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

[23]Deng L, Jiang C, Chen L, et al., 2015. The ubiquitination of RagA GTPase by RNF152 negatively regulates mTORC1 activation. Mol Cell, 58(5):804-818.

[24]Dibble CC, Elis W, Menon S, et al., 2012. TBC1D7 is a third subunit of the TSC1-TSC2 complex upstream of mTORC1. Mol Cell, 47(4):535-546.

[25]Durán RV, Oppliger W, Robitaille AM, et al., 2012. Glutaminolysis activates Rag-mTORC1 signaling. Mol Cell, 47(3):349-358.

[26]Efeyan A, Zoncu R, Chang S, et al., 2013. Regulation of mTORC1 by the Rag GTPases is necessary for neonatal autophagy and survival. Nature, 493(7434):679-683.

[27]Fan SJ, Snell C, Turley H, et al., 2016. PAT4 levels control amino-acid sensitivity of rapamycin-resistant mTORC1 from the Golgi and affect clinical outcome in colorectal cancer. Oncogene, 35(23):3004-3015.

[28]Gai ZC, Wang Q, Yang C, et al., 2016. Structural mechanism for the arginine sensing and regulation of CASTOR1 in the mTORC1 signaling pathway. Cell Discov, 2:16051.

[29]Gao HN, Hu H, Zheng N, et al., 2015. Leucine and histidine independently regulate milk protein synthesis in bovine mammary epithelial cells via mTOR signaling pathway. J Zhejiang Univ-Sci B (Biomed & Biotechnol), 16(6):560-572.

[30]Grant GA, 2006. The ACT domain: a small molecule binding domain and its role as a common regulatory element. J Biol Chem, 281(45):33825-33829.

[31]Grinde B, Seglen PO, 1981. Leucine inhibition of autophagic vacuole formation in isolated rat hepatocytes. Exp Cell Res, 134(1):33-39.

[32]Gu X, Orozco JM, Saxton RA, et al., 2017. SAMTOR is an S-adenosylmethionine sensor for the mTORC1 pathway. Science, 358(6364):813-818.

[33]Han JM, Jeong SJ, Park MC, et al., 2012. Leucyl-tRNA synthetase is an intracellular leucine sensor for the mTORC1-signaling pathway. Cell, 149(2):410-424.

[34]Hara K, Yonezawa K, Weng QP, et al., 1998. Amino acid sufficiency and mTOR regulate p70 S6 kinase and eIF-4E BP1 through a common effector mechanism. J Biol Chem, 273(23):14484-14494.

[35]Hara K, Maruki Y, Long XM, et al., 2002. Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action. Cell, 110(2):177-189.

[36]Hasumi H, Baba M, Hong SB, et al., 2008. Identification and characterization of a novel folliculin-interacting protein FNIP2. Gene, 415(1-2):60-67.

[37]He XD, Gong W, Zhang JN, et al., 2018. Sensing and transmitting intracellular amino acid signals through reversible lysine aminoacylations. Cell Metab, 27(1):151-166.e6.

[38]Heitman J, Movva NR, Hall MN, 1991. Targets for cell cycle arrest by the immunosuppressant rapamycin in yeast. Science, 253(5022):905-909.

[39]Hirose E, Nakashima N, Sekiguchi T, et al., 1998. RagA is a functional homologue of S. cerevisiae Gtr1p involved in the Ran/Gsp1-GTPase pathway. J Cell Sci, 111(Pt 1):11-21.

[40]Ho A, Cho CS, Namkoong S, et al., 2016. Biochemical basis of Sestrin physiological activities. Trends Biochem Sci, 41(7):621-632.

[41]Huttlin EL, Ting L, Bruckner RJ, et al., 2015. The BioPlex network: a systematic exploration of the human interactome. Cell, 162(2):425-440.

[42]Inoki K, Li Y, Zhu TQ, et al., 2002. TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat Cell Biol, 4(9):648-657.

[43]Inoki K, Zhu TQ, Guan KL, 2003. TSC2 mediates cellular energy response to control cell growth and survival. Cell, 115(5):577-590.

[44]Jewell JL, Russell RC, Guan KL, 2013. Amino acid signalling upstream of mTOR. Nat Rev Mol Cell Biol, 14(3):133-139.

[45]Jewell JL, Kim YC, Russell RC, et al., 2015. Differential regulation of mTORC1 by leucine and glutamine. Science, 347(6218):194-198.

[46]Jin GX, Lee SW, Zhang X, et al., 2015. Skp2-mediated RagA ubiquitination elicits a negative feedback to prevent amino-acid-dependent mTORC1 hyperactivation by recruiting GATOR1. Mol Cell, 58(6):989-1000.

[47]Jung J, Genau HM, Behrends C, 2015. Amino acid-dependent mTORC1 regulation by the lysosomal membrane protein SLC38A9. Mol Cell Biol, 35(14):2479-2494.

[48]Jung JW, Macalino SJY, Cui MH, et al., 2019. Transmembrane 4 L six family member 5 senses arginine for mTORC1 signaling. Cell Metab, 29(6):1306-1319.e7.

[49]Kim DH, Sarbassov DD, Ali SM, et al., 2002. mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell, 110(2):163-175.

[50]Kim DH, Sarbassov DD, Ali SM, et al., 2003. GβL, a positive regulator of the rapamycin-sensitive pathway required for the nutrient-sensitive interaction between raptor and mTOR. Mol Cell, 11(4):895-904.

[51]Kim E, Goraksha-Hicks P, Li L, et al., 2008. Regulation of TORC1 by Rag GTPases in nutrient response. Nat Cell Biol, 10(8):935-945.

[52]Kim H, An S, Ro SH, et al., 2015. Janus-faced Sestrin2 controls ROS and mTOR signalling through two separate functional domains. Nat Commun, 6:10025.

[53]Koltin Y, Faucette L, Bergsma DJ, et al., 1991. Rapamycin sensitivity in Saccharomyces cerevisiae is mediated by a peptidyl-prolyl cis-trans isomerase related to human FK506-binding protein. Mol Cell Biol, 11(3):1718-1723.

[54]Lawrence RE, Cho KF, Rappold R, et al., 2018. A nutrient-induced affinity switch controls mTORC1 activation by its Rag GTPase-Ragulator lysosomal scaffold. Nat Cell Biol, 20(9):1052-1063.

[55]Layman DK, Anthony TG, Rasmussen BB, et al., 2015. Defining meal requirements for protein to optimize metabolic roles of amino acids. Am J Clin Nutr, 101(6):1330S-1338S.

[56]Lee JH, Budanov AV, Park EJ, et al., 2010. Sestrin as a feedback inhibitor of TOR that prevents age-related pathologies. Science, 327(5970):1223-1228.

[57]Lee JH, Cho US, Karin M, 2016. Sestrin regulation of TORC1: is Sestrin a leucine sensor? Sci Signal, 9(431):re5.

[58]Lee M, Kim JH, Yoon I, et al., 2018. Coordination of the leucine-sensing Rag GTPase cycle by leucyl-tRNA synthetase in the mTORC1 signaling pathway. Proc Natl Acad Sci USA, 115(23):E5279-E5288.

[59]Liu B, Du HW, Rutkowski R, et al., 2012. LAAT-1 is the lysosomal lysine/arginine transporter that maintains amino acid homeostasis. Science, 337(6092):351-354.

[60]Long XM, Lin Y, Ortiz-Vega S, et al., 2005. Rheb binds and regulates the mTOR kinase. Curr Biol, 15(8):702-713.

[61]Manning BD, Tee AR, Logsdon MN, et al., 2002. Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/Akt pathway. Mol Cell, 10(1):151-162.

[62]Menon S, Dibble CC, Talbott G, et al., 2014. Spatial control of the TSC complex integrates insulin and nutrient regulation of mTORC1 at the lysosome. Cell, 156(4):771-785.

[63]Nada S, Hondo A, Kasai A, et al., 2009. The novel lipid raft adaptor p18 controls endosome dynamics by anchoring the MEK-ERK pathway to late endosomes. EMBO J, 28(5):477-489.

[64]Nakashima N, Noguchi E, Nishimoto T, 1999. Saccharomyces cerevisiae putative G protein, Gtr1p, which forms complexes with itself and a novel protein designated as Gtr2p, negatively regulates the Ran/Gsp1p G protein cycle through Gtr2p. Genetics, 152(3):853-867.

[65]Nguyen TP, Frank AR, Jewell JL, 2017. Amino acid and small GTPase regulation of mTORC1. Cell Logist, 7(4):e1378794.

[66]Nicklin P, Bergman P, Zhang BL, et al., 2009. Bidirectional transport of amino acids regulates mTOR and autophagy. Cell, 136(3):521-534.

[67]Oshiro N, Takahashi R, Yoshino KI, et al., 2007. The proline-rich Akt substrate of 40 kDa (PRAS40) is a physiological substrate of mammalian target of rapamycin complex 1. J Biol Chem, 282(28):20329-20339.

[68]Pal R, Palmieri M, Chaudhury A, et al., 2018. Src regulates amino acid-mediated mTORC1 activation by disrupting GATOR1-Rag GTPase interaction. Nat Commun, 9(1):4351.

[69]Park SG, Ewalt KL, Kim S, 2005. Functional expansion of aminoacyl-tRNA synthetases and their interacting factors: new perspectives on housekeepers. Trends Biochem Sci, 30(10):569-574.

[70]Parmigiani A, Nourbakhsh A, Ding BX, et al., 2014. Sestrins inhibit mTORC1 kinase activation through the GATOR complex. Cell Rep, 9(4):1281-1291.

[71]Peng M, Yin N, Li MO, 2014. Sestrins function as guanine nucleotide dissociation inhibitors for Rag GTPases to control mTORC1 signaling. Cell, 159(1):122-133.

[72]Peng M, Yin N, Li MO, 2017. SZT2 dictates GATOR control of mTORC1 signalling. Nature, 543(7645):433-437.

[73]Perera RM, Zoncu R, 2016. The lysosome as a regulatory hub. Annu Rev Cell Dev Biol, 32:223-253.

[74]Peterson TR, Laplante M, Thoreen CC, et al., 2009. DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival. Cell, 137(5):873-886.

[75]Petit CS, Roczniak-Ferguson A, Ferguson SM, 2013. Recruitment of folliculin to lysosomes supports the amino acid-dependent activation of Rag GTPases. J Cell Biol, 202(7):1107-1122.

[76]Potter CJ, Pedraza LG, Xu T, 2002. Akt regulates growth by directly phosphorylating Tsc2. Nat Cell Biol, 4(9):658-665.

[77]Quinlan CL, Kaiser SE, Bolaños B, et al., 2017. Targeting S-adenosylmethionine biosynthesis with a novel allosteric inhibitor of Mat2A. Nat Chem Biol, 13(7):785-792.

[78]Rebsamen M, Pochini L, Stasyk T, et al., 2015. SLC38A9 is a component of the lysosomal amino acid sensing machinery that controls mTORC1. Nature, 519(7544):477-481.

[79]Sabatini DM, Erdjument-Bromage H, Lui M, et al., 1994. RAFT1: a mammalian protein that binds to FKBP12 in a rapamycin-dependent fashion and is homologous to yeast TORs. Cell, 78(1):35-43.

[80]Sabers CJ, Martin MM, Brunn GJ, et al., 1995. Isolation of a protein target of the FKBP12-rapamycin complex in mammalian cells. J Biol Chem, 270(2):815-822.

[81]Saier MH Jr, Reddy VS, Tsu BV, et al., 2016. The Transporter Classification Database (TCDB):recent advances. Nucleic Acids Res, 44(D1):D372-D379.

[82]Saito K, Araki Y, Kontani K, et al., 2005. Novel role of the small GTPase Rheb: its implication in endocytic pathway independent of the activation of mammalian target of rapamycin. J Biochem, 137(3):423-430.

[83]Sancak Y, Thoreen CC, Peterson TR, et al., 2007. PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinase. Mol Cell, 25(6):903-915.

[84]Sancak Y, Peterson TR, Shaul YD, et al., 2008. The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1. Science, 320(5882):1496-1501.

[85]Sancak Y, Bar-Peled L, Zoncu R, et al., 2010. Ragulator-Rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids. Cell, 141(2):290-303.

[86]Saxton RA, Sabatini DM, 2017. mTOR signaling in growth, metabolism, and disease. Cell, 168(6):960-976.

[87]Saxton RA, Knockenhauer KE, Schwartz TU, et al., 2016a. The apo-structure of the leucine sensor Sestrin2 is still elusive. Sci Signal, 9(446):ra92.

[88]Saxton RA, Chantranupong L, Knockenhauer KE, et al., 2016b. Mechanism of arginine sensing by CASTOR1 upstream of mTORC1. Nature, 536(7615):229-233.

[89]Saxton RA, Knockenhauer KE, Wolfson RL, et al., 2016c. Structural basis for leucine sensing by the Sestrin2-mTORC1 pathway. Science, 351(6268):53-58.

[90]Schürmann A, Brauers A, Maßmann S, et al., 1995. Cloning of a novel family of mammalian GTP-binding proteins (RagA, RagBs, RagB1) with remote similarity to the Ras-related GTPases. J Biol Chem, 270(48):28982-28988.

[91]Sekiguchi T, Hirose E, Nakashima N, et al., 2001. Novel G proteins, Rag C and Rag D, interact with GTP-binding proteins, Rag A and Rag B. J Biol Chem, 276(10):7246-7257.

[92]Shen K, Sabatini DM, 2018. Ragulator and SLC38A9 activate the Rag GTPases through noncanonical GEF mechanisms. Proc Natl Acad Sci USA, 115(38):9545-9550.

[93]Shen K, Choe A, Sabatini DM, 2017. Intersubunit crosstalk in the Rag GTPase heterodimer enables mTORC1 to respond rapidly to amino acid availability. Mol Cell, 68(3):552-565.e8.

[94]Shen K, Huang RK, Brignole EJ, et al., 2018. Architecture of the human GATOR1 and GATOR1-Rag GTPases complexes. Nature, 556(7699):64-69.

[95]Shimobayashi M, Hall MN, 2016. Multiple amino acid sensing inputs to mTORC1. Cell Res, 26(1):7-20.

[96]Son SM, Park SJ, Lee H, et al., 2019. Leucine signals to mTORC1 via its metabolite acetyl-coenzyme A. Cell Metab, 29(1):192-201.e7.

[97]Stracka D, Jozefczuk S, Rudroff F, et al., 2014. Nitrogen source activates TOR (target of rapamycin) complex 1 via glutamine and independently of Gtr/Rag proteins. J Biol Chem, 289(36):25010-25020.

[98]Su MY, Morris KL, Kim DJ, et al., 2017. Hybrid structure of the RagA/C-ragulator mTORC1 activation complex. Mol Cell, 68(5):835-846.e3.

[99]Sutter BM, Wu X, Laxman S, et al., 2013. Methionine inhibits autophagy and promotes growth by inducing the SAM-responsive methylation of PP2A. Cell, 154(2):403-415.

[100]Takagi Y, Kobayashi T, Shiono M, et al., 2008. Interaction of folliculin (Birt-Hogg-Dubé gene product) with a novel Fnip1-like (FnipL/Fnip2) protein. Oncogene, 27(40):5339-5347.

[101]Taylor PM, 2014. Role of amino acid transporters in amino acid sensing. Am J Clin Nutr, 99(1):223S-230S.

[102]Tee AR, Manning BD, Roux PP, et al., 2003. Tuberous sclerosis complex gene products, Tuberin and Hamartin, control mTOR signaling by acting as a GTPase-activating protein complex toward Rheb. Curr Biol, 13(15):1259-1268.

[103]Thomas JD, Zhang YJ, Wei YH, et al., 2014. Rab1A is an mTORC1 activator and a colorectal oncogene. Cancer Cell, 26(5):754-769.

[104]Tsun ZY, Bar-Peled L, Chantranupong L, et al., 2013. The folliculin tumor suppressor is a GAP for the RagC/D GTPases that signal amino acid levels to mTORC1. Mol Cell, 52(4):495-505.

[105]Vander Haar E, Lee SI, Bandhakavi S, et al., 2007. Insulin signalling to mTOR mediated by the Akt/PKB substrate PRAS40. Nat Cell Biol, 9(3):316-323.

[106]Velasco-Miguel S, Buckbinder L, Jean P, et al., 1999. PA26, a novel target of the p53 tumor suppressor and member of the GADD family of DNA damage and growth arrest inducible genes. Oncogene, 18(1):127-137.

[107]Wang LF, Harris TE, Roth RA, et al., 2007. PRAS40 regulates mTORC1 kinase activity by functioning as a direct inhibitor of substrate binding. J Biol Chem, 282(27):20036-20044.

[108]Wang SY, Tsun ZY, Wolfson RL, et al., 2015. Lysosomal amino acid transporter SLC38A9 signals arginine sufficiency to mTORC1. Science, 347(6218):188-194.

[109]Wolfson RL, Chantranupong L, Saxton RA, et al., 2016. Sestrin2 is a leucine sensor for the mTORC1 pathway. Science, 351(6268):43-48.

[110]Wolfson RL, Chantranupong L, Wyant GA, et al., 2017. KICSTOR recruits GATOR1 to the lysosome and is necessary for nutrients to regulate mTORC1. Nature, 543(7645):438-442.

[111]Wright MD, Rudy GB, Ni J, 2000. The L6 membrane proteins—a new four-transmembrane superfamily. Protein Sci, 9(8):1594-1600.

[112]Wu H, Wang FL, Hu SL, et al., 2012. MiR-20a and miR-106b negatively regulate autophagy induced by leucine deprivation via suppression of ULK1 expression in C2C12 myoblasts. Cell Signal, 24(11):2179-2186.

[113]Wyant GA, Abu-Remaileh M, Wolfson RL, et al., 2017. mTORC1 activator SLC38A9 is required to efflux essential amino acids from lysosomes and use protein as a nutrient. Cell, 171(3):642-654.e12.

[114]Xia J, Wang R, Zhang TL, et al., 2016. Structural insight into the arginine-binding specificity of CASTOR1 in amino acid-dependent mTORC1 signaling. Cell Discov, 2:16035.

[115]Yan XH, Sun QM, Ji J, et al., 2012. Reconstitution of leucine-mediated autophagy via the mTORC1-Barkor pathway in vitro. Autophagy, 8(2):213-221.

[116]Yang HJ, Jiang XL, Li BR, et al., 2017. Mechanisms of mTORC1 activation by RHEB and inhibition by PRAS40. Nature, 552(7685):368-373.

[117]Yang HR, Wang J, Liu MJ, et al., 2016. 4.4 Å resolution Cryo-EM structure of human mTOR complex 1. Protein Cell, 7(12):878-887.

[118]Yonehara R, Nada S, Nakai T, et al., 2017. Structural basis for the assembly of the Ragulator-Rag GTPase complex. Nat Commun, 8(1):1625.

[119]Zhang TL, Wang R, Wang ZJ, et al., 2017. Structural basis for Ragulator functioning as a scaffold in membrane-anchoring of Rag GTPases and mTORC1. Nat Commun, 8(1):1394.

[120]Zoncu R, Bar-Peled L, Efeyan A, et al., 2011. mTORC1 senses lysosomal amino acids through an inside-out mechanism that requires the vacuolar H+-ATPase. Science, 334(6056):678-683.

Open peer comments: Debate/Discuss/Question/Opinion


Please provide your name, email address and a comment

Journal of Zhejiang University-SCIENCE, 38 Zheda Road, Hangzhou 310027, China
Tel: +86-571-87952783; E-mail: cjzhang@zju.edu.cn
Copyright © 2000 - Journal of Zhejiang University-SCIENCE