Amino acids regulate mTORC1

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Homo sapiens
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The mTORC1 complex acts as an integrator that regulates translation, lipid synthesis, autophagy, and cell growth in response to multiple inputs, notably glucose, oxygen, amino acids, and growth factors such as insulin (reviewed in Sabatini 2017, Meng et al. 2018, Kim and Guan 2019).
MTOR, the kinase subunit of mTORC1, is activated by interaction with RHEB:GTP at the cytosolic face of lysosomal membrane (Long et al. 2005, Tee et al. 2005, Long et al. 2007, Yang et al. 2017). Recruitment of mTORC1 to the lysosomal membrane is intricate and incompletely understood. At the center of the system is a complex of two small GTPases, the Rag heterodimer (RRAGA or RRAGB bound to RRAGC or RRAGD). The Rag heterodimer is tethered to the membrane by the Ragulator complex, which also binds the v-ATPase complex. The Rag heterodimer acts as a cross-regulating switch, with the binding of GTP by one subunit inhibiting the exchange of GDP for GTP by the other subunit (Shen et al. 2017). The active conformation of the Rag heterodimer that recruits mTORC1 to the lysosomal membrane is RRAGA,B:GTP:RRAGC,D:GDP while the inactive conformation, RRAGA,B:GDP:RRAGC,D:GTP, releases mTORC1 (Sancak et al. 2008, Kim et al. 2008, Sancak et al. 2010, Lawrence et al. 2018). GTPase activating proteins (GAPs) and guanyl nucleotide exchange factors (GEFs) acting upon the Rag heterodimer thereby regulate recruitment of mTORC1. RHEB:GTP at the lysosomal membrane also binds mTORC1 and directly activates mTORC1. During inactivation of mTORC1 in response to removal of amino acids, the TSC complex, a GAP for RHEB, is required in addition to the inactive Rag complex to release mTORC1 from RHEB and hence fully release mTORC1 from the lysosomal membrane (Demetriades et al. 2014).
Amino acids regulate recruitment of mTORC1 to the lysosomal membrane by at least 4 mechanisms (reviewed in Zhuang et al. 2019, Wolfson and Sabatini 2017, Yao et al. 2017). 1) Sestrin1 (SESN1) or Sestrin2 (SESN2) binds leucine and the Sestrin1,2:leucine complex is then released from the GATOR2 complex, allowing GATOR2 to positively regulate mTORC1 activation (Chantranupong et al. 2014, Parmigiani et al. 2014, Kim et al. 2015, Wolfson et al. 2016, Saxton et al. 2016). 2) CASTOR1 in a homodimer or a heterodimer with CASTOR2 binds arginine and the CASTOR1:arginine complex is likewise released from GATOR2, allowing GATOR2 to activate mTORC1 (Chantranupong et al. 2016, Saxton et al. 2016, Gai et al. 2016, Xia et al. 2016). 3) BMT2 (SAMTOR), a negative regulator of mTORC1 activation, binds S-adenosylmethionine (SAM), a derivative of methionine (Gu et al. 2017). The binding of SAM causes BMT2 to dissociate from GATOR1, allowing the activation of mTORC1. 4) The amino acid transporter SLC38A9 binds arginine and SLC38A9 then acts as a GEF to convert RRAGA,B:GDP to the active form, RRAGA,B:GTP (Rebsamen et al. 2015, Wang et al. 2015, Wyant et al. 2017, Shen and Sabatini 2018). Amino acid starvation also regulates the assembly of the V0 and V1 subunits of v-ATPase by an uncharacterized mechanism (Stransky and Forgac 2015) and v-ATPase is required for activation of mTORC1 by amino acids (Zoncu et al. 2011). Glutamine activates mTORC1 by a mechanism that is independent of the Rag GTPases, requires ARF1, but is not yet fully elucidated (Jewell et al. 2015).

Literature References
PubMed ID Title Journal Year
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Proud, CG, Blenis, J, Tee, AR

FEBS Lett. 2005
29053970 mTORC1 Activator SLC38A9 Is Required to Efflux Essential Amino Acids from Lysosomes and Use Protein as a Nutrient

Chen, WW, Sabatini, DM, Danai, LV, Abu-Remaileh, M, Wyant, GA, Vander Heiden, MG, Freinkman, E, Wolfson, RL

Cell 2017
25561175 SLC38A9 is a component of the lysosomal amino acid sensing machinery that controls mTORC1

Bigenzahn, JW, Huber, KV, Indiveri, C, Bennett, KL, Rebsamen, M, Superti-Furga, G, Kandasamy, RK, Rudashevskaya, EL, Snijder, B, Galluccio, M, Huber, LA, Heinz, LX, de Ara├║jo, ME, Pochini, L, Fauster, A, Filipek, PA, Bruckner, M, Scorzoni, S, Kraft, C, Stasyk, T

Nature 2015
30844724 Recent advances in understanding of amino acid signaling to mTORC1 activation

Wang, XX, Zhuang, Y, Yin, Y, He, J, He, S

Front Biosci (Landmark Ed) 2019
26378229 Amino Acid Availability Modulates Vacuolar H+-ATPase Assembly

Forgac, M, Stransky, LA

J. Biol. Chem. 2015
29123071 SAMTOR is an S-adenosylmethionine sensor for the mTORC1 pathway

Sabatini, DM, Scaria, SM, Gu, X, Saxton, RA, Gygi, SP, Liu, GY, Harper, JW, Condon, KJ, Krawczyk, PA, Orozco, JM

Science 2017
25567906 Metabolism. Lysosomal amino acid transporter SLC38A9 signals arginine sufficiency to mTORC1

Sabatini, DM, Wang, T, Zoncu, R, Jones, TD, Comb, W, Park, J, Straub, C, Wang, S, Shen, K, Tsun, ZY, Bar-Peled, L, Plovanich, ME, Chantranupong, L, Sabatini, BL, Kim, C, Yuan, ED, Wyant, GA, Wolfson, RL

Science 2015
25567907 Metabolism. Differential regulation of mTORC1 by leucine and glutamine

Park, HW, Russell, RC, Guan, KL, Yu, FX, Tagliabracci, VS, Kim, YC, Plouffe, SW, Jewell, JL

Science 2015
30181260 Ragulator and SLC38A9 activate the Rag GTPases through noncanonical GEF mechanisms

Sabatini, DM, Shen, K

Proc. Natl. Acad. Sci. U.S.A. 2018
20381137 Ragulator-Rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids

Sabatini, DM, Zoncu, R, Sancak, Y, Bar-Peled, L, Nada, S, Markhard, AL

Cell 2010
27487210 Mechanism of arginine sensing by CASTOR1 upstream of mTORC1

Sabatini, DM, Schwartz, TU, Saxton, RA, Chantranupong, L, Knockenhauer, KE

Nature 2016
28066558 Structural mechanism for the arginine sensing and regulation of CASTOR1 in the mTORC1 signaling pathway

Yang, C, Wang, Q, Gai, Z, Deng, W, Wang, L, Wu, G

Cell Discov 2016
25457612 Sestrins inhibit mTORC1 kinase activation through the GATOR complex

Budanov, AV, Nourbakhsh, A, Ding, B, Guan, KL, Kim, YC, Akopiants, K, Wang, W, Karin, M, Parmigiani, A

Cell Rep 2014
25263562 The Sestrins interact with GATOR2 to negatively regulate the amino-acid-sensing pathway upstream of mTORC1

Sabatini, DM, Scaria, SM, Spooner, E, Saxton, RA, Gygi, SP, Bar-Peled, L, Chantranupong, L, Isasa, M, Orozco, JM, Wolfson, RL

Cell Rep 2014
27648300 Structural insight into the arginine-binding specificity of CASTOR1 in amino acid-dependent mTORC1 signaling

Ding, J, Wang, R, Zhang, T, Xia, J

Cell Discov 2016
26972053 The CASTOR Proteins Are Arginine Sensors for the mTORC1 Pathway

Sabatini, DM, Wang, T, Scaria, SM, Saxton, RA, Gygi, SP, Gygi, MP, Chantranupong, L, Harper, JW, Wyant, GA, Shen, K

Cell 2016
29236692 Mechanisms of mTORC1 activation by RHEB and inhibition by PRAS40

Yang, A, Yang, HJ, Jiang, X, Li, B, Pavletich, NP, Yang, H, Dhar, A, Miller, M

Nature 2017
17470430 The Rheb switch 2 segment is critical for signaling to target of rapamycin complex 1

Busch, S, Lin, Y, Long, X, Avruch, J, Ortiz-Vega, S

J. Biol. Chem. 2007
26449471 Sestrin2 is a leucine sensor for the mTORC1 pathway

Sabatini, DM, Scaria, SM, Saxton, RA, Chantranupong, L, Cantor, JR, Shen, K, Wolfson, RL

Science 2016
15854902 Rheb binds and regulates the mTOR kinase

Yonezawa, K, Ortiz-Vega, S, Avruch, J, Lin, Y, Long, X

Curr Biol 2005
26586190 Structural basis for leucine sensing by the Sestrin2-mTORC1 pathway

Sabatini, DM, Schwartz, TU, Wang, T, Pacold, ME, Saxton, RA, Chantranupong, L, Knockenhauer, KE, Wolfson, RL

Science 2016
28199306 KICSTOR recruits GATOR1 to the lysosome and is necessary for nutrients to regulate mTORC1

Sabatini, DM, Petri, S, Condon, KJ, Shen, K, Orozco, JM, Scaria, SM, Gu, X, Frankel, WN, Chantranupong, L, Kedir, J, Abu-Remaileh, M, Wyant, GA, Wolfson, RL

Nature 2017
18497260 The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1

Thoreen, CC, Shaul, YD, Sabatini, DM, Sancak, Y, Bar-Peled, L, Lindquist, RA, Peterson, TR

Science 2008
15878852 Rheb binding to mammalian target of rapamycin (mTOR) is regulated by amino acid sufficiency

Lin, Y, Long, X, Avruch, J, Ortiz-Vega, S

J. Biol. Chem. 2005
30061680 A nutrient-induced affinity switch controls mTORC1 activation by its Rag GTPase-Ragulator lysosomal scaffold

Rappold, R, Zoncu, R, Cho, KF, Kim, DJ, Hurley, JH, Moldavski, O, Tofaute, M, Lawrence, RE, Thrun, A

Nat. Cell Biol. 2018
29056322 Intersubunit Crosstalk in the Rag GTPase Heterodimer Enables mTORC1 to Respond Rapidly to Amino Acid Availability

Sabatini, DM, Choe, A, Shen, K

Mol. Cell 2017
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Guan, KL, Kim, J

Nat. Cell Biol. 2019
28686218 Lysosomal Regulation of mTORC1 by Amino Acids in Mammalian Cells

Inoki, K, Yao, Y, Jones, E

Biomolecules 2017
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Guan, KL, Neufeld, TP, Kim, E, Goraksha-Hicks, P, Li, L

Nat. Cell Biol. 2008
29311260 mTOR signaling in stem and progenitor cells

Frank, AR, Meng, D, Jewell, JL

Development 2018
22053050 mTORC1 senses lysosomal amino acids through an inside-out mechanism that requires the vacuolar H(+)-ATPase

Sabatini, DM, Sancak, Y, Zoncu, R, Bar-Peled, L, Efeyan, A, Wang, S

Science 2011
28768171 The Dawn of the Age of Amino Acid Sensors for the mTORC1 Pathway

Sabatini, DM, Wolfson, RL

Cell Metab. 2017
29078414 Twenty-five years of mTOR: Uncovering the link from nutrients to growth

Sabatini, DM

Proc. Natl. Acad. Sci. U.S.A. 2017
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Demetriades, C, Teleman, AA, Doumpas, N

Cell 2014
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