Prolonged deprivation of arginine or leucine induces PI3K/Akt-dependent reactivation of mTORC1

Abstract

The mechanistic target of rapamycin complex 1 (mTORC1) is a serine/threonine kinase complex that promotes anabolic processes including protein, lipid, and nucleotide synthesis, while suppressing catabolic processes such as macroautophagy. mTORC1 activity is regulated by growth factors and amino acids, which signal through distinct but integrated molecular pathways: growth factors largely signal through the PI3K/Akt-dependent pathway, whereas the availabilities of amino acids leucine and arginine are communicated to mTORC1 by the Rag-GTPase pathway. While it is relatively well described how acute changes in leucine and arginine levels affect mTORC1 signaling, the effects of prolonged amino acid deprivation remain less well understood. Here, we demonstrate that prolonged deprivation of arginine and/or leucine leads to reactivation of mTORC1 activity, which reaches activation levels similar to those observed in nutrient-rich conditions. Surprisingly, we find that this reactivation is independent of the regeneration of amino acids by canonical autophagy or proteasomal degradation but is dependent on PI3K/Akt signaling. Together, our data identify a novel crosstalk between the amino acid and PI3K/Akt signaling pathways upstream of mTORC1. These observations extend our understanding of the role of mTORC1 in growth-related diseases and indicate that dietary intervention by removal of leucine and/or arginine may be an ineffective therapeutic approach. The mechanistic target of rapamycin complex 1 (mTORC1) is a serine/threonine kinase complex that promotes anabolic processes including protein, lipid, and nucleotide synthesis, while suppressing catabolic processes such as macroautophagy. mTORC1 activity is regulated by growth factors and amino acids, which signal through distinct but integrated molecular pathways: growth factors largely signal through the PI3K/Akt-dependent pathway, whereas the availabilities of amino acids leucine and arginine are communicated to mTORC1 by the Rag-GTPase pathway. While it is relatively well described how acute changes in leucine and arginine levels affect mTORC1 signaling, the effects of prolonged amino acid deprivation remain less well understood. Here, we demonstrate that prolonged deprivation of arginine and/or leucine leads to reactivation of mTORC1 activity, which reaches activation levels similar to those observed in nutrient-rich conditions. Surprisingly, we find that this reactivation is independent of the regeneration of amino acids by canonical autophagy or proteasomal degradation but is dependent on PI3K/Akt signaling. Together, our data identify a novel crosstalk between the amino acid and PI3K/Akt signaling pathways upstream of mTORC1. These observations extend our understanding of the role of mTORC1 in growth-related diseases and indicate that dietary intervention by removal of leucine and/or arginine may be an ineffective therapeutic approach. In order for cells to maintain homeostasis in an ever-changing environment, cells need to carefully balance anabolic reactions with catabolic reactions. This is largely orchestrated by the mechanistic target of rapamycin complex 1 (mTORC1), a highly evolutionarily conserved serine/threonine kinase complex that promotes growth-favoring processes, including protein translation, lipid synthesis, and nucleotide biosynthesis, under conditions of nutrient sufficiency (1Kim J. Guan K.-L. mTOR as a central hub of nutrient signalling and cell growth.Nat. Cell Biol. 2019; 21: 63-71Crossref PubMed Scopus (591) Google Scholar, 2Liu G.Y. Sabatini D.M. mTOR at the nexus of nutrition, growth, ageing and disease.Nat. Rev. Mol. Cell Biol. 2020; 21: 183-203Crossref PubMed Scopus (1203) Google Scholar, 3González A. Hall M.N. Nutrient sensing and TOR signaling in yeast and mammals.EMBO J. 2017; 36: 397-408Crossref PubMed Scopus (453) Google Scholar, 4Ben-Sahra I. Manning B.D. mTORC1 signaling and the metabolic control of cell growth.Curr. Opin. Cell Biol. 2017; 45: 72-82Crossref PubMed Scopus (391) Google Scholar, 5Melick C.H. Jewell J.L. Regulation of mTORC1 by upstream stimuli.Genes (Basel). 2020; 11: 989Crossref PubMed Scopus (51) Google Scholar). Among the upstream cues that regulate mTORC1 activity, growth factors and amino acids have long been known to be crucial for mTORC1 activity (6Kim S.G. Buel G.R. Blenis J. Nutrient regulation of the mTOR complex 1 signaling pathway.Mol. Cells. 2013; 35: 463-473Crossref PubMed Scopus (199) Google Scholar, 7Yao Y. Jones E. Inoki K. Lysosomal regulation of mTORC1 by amino acids in mammalian cells.Biomolecules. 2017; 7: 51Crossref PubMed Scopus (47) Google Scholar). Growth factor stimulation leads to activation of PI3K/Akt signaling, which inactivates the tuberous sclerosis complex (TSC) component TSC2, leading to activation of the small GTPase Rheb, a key regulator of mTORC1 (8Long X. Lin Y. Ortiz-Vega S. Yonezawa K. Avruch J. Rheb binds and regulates the mTOR kinase.Curr. Biol. 2005; 15: 702-713Abstract Full Text Full Text PDF PubMed Scopus (788) Google Scholar, 9Manning B.D. Tee A.R. Logsdon M.N. Blenis J. Cantley L.C. Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/Akt pathway.Mol. Cell. 2002; 10: 151-162Abstract Full Text Full Text PDF PubMed Scopus (1310) Google Scholar, 10Tee A.R. Manning B.D. Roux P.P. Cantley L.C. Blenis J. Tuberous sclerosis complex gene products, tuberin and hamartin, control mTOR signaling by acting as a GTPase-activating protein complex toward Rheb.Curr. Biol. 2003; 13: 1259-1268Abstract Full Text Full Text PDF PubMed Scopus (983) Google Scholar). In contrast, amino acids have been shown to communicate through a TSC2/Rheb-independent mechanism, reliant on the family of Rag small GTPases, which exists as heterodimers of RagA or RagB and RagC or RagD (2Liu G.Y. Sabatini D.M. mTOR at the nexus of nutrition, growth, ageing and disease.Nat. Rev. Mol. Cell Biol. 2020; 21: 183-203Crossref PubMed Scopus (1203) Google Scholar, 11Nakashima N. Noguchi E. Nishimoto T. 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. 1999; 152: 853-867Crossref PubMed Google Scholar, 12Sekiguchi T. Hirose E. Nakashima N. Ii M. Nishimoto T. Novel G proteins, Rag C and Rag D, interact with GTP-binding proteins, Rag A and Rag B.J. Biol. Chem. 2001; 276: 7246-7257Abstract Full Text Full Text PDF PubMed Scopus (188) Google Scholar). When the Rag-GTPases are active, they recruit mTORC1 to lysosomes, where association with Rheb leads to mTORC1 activation when growth factors are present (13Sancak Y. Peterson T.R. Shaul Y.D. Lindquist R.A. Thoreen C.C. Bar-Peled L. et al.The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1.Science. 2008; 320: 1496-1501Crossref PubMed Scopus (2063) Google Scholar, 14Mutvei A.P. Nagiec M.J. Hamann J.C. Kim S.G. Vincent C.T. Blenis J. Rap1-GTPases control mTORC1 activity by coordinating lysosome organization with amino acid availability.Nat. Commun. 2020; 11: 1416Crossref PubMed Scopus (40) Google Scholar, 15Kim E. Goraksha-Hicks P. Li L. Neufeld T.P. Guan K.-L. Regulation of TORC1 by Rag GTPases in nutrient response.Nat. Cell Biol. 2008; 10: 935-945Crossref PubMed Scopus (1044) Google Scholar). Among the 20 proteinogenic amino acids, arginine and leucine are known to be key regulators of mTORC1 activity, as deprivation of these amino acids leads to rapid inhibition of mTORC1 activity (16Hara K. Yonezawa K. Weng Q. Kozlowski M.T. Belham C. Avruch J. Amino acid sufficiency and mTOR regulate p70 S6 kinase and eIF-4E BP1 through a common effector mechanism.J. Biol. Chem. 1998; 273: 14484-14494Abstract Full Text Full Text PDF PubMed Scopus (1150) Google Scholar). Recently, it was shown that cytosolic leucine and arginine are communicated to the Rag-GTPases by the Sestrin and Castor proteins, respectively, through the Gator1 and Gator2 complexes (2Liu G.Y. Sabatini D.M. mTOR at the nexus of nutrition, growth, ageing and disease.Nat. Rev. Mol. Cell Biol. 2020; 21: 183-203Crossref PubMed Scopus (1203) Google Scholar, 3González A. Hall M.N. Nutrient sensing and TOR signaling in yeast and mammals.EMBO J. 2017; 36: 397-408Crossref PubMed Scopus (453) Google Scholar). While these recent advancements have increased our understanding of how mTORC1 activity is regulated during acute changes in leucine or arginine levels (2Liu G.Y. Sabatini D.M. mTOR at the nexus of nutrition, growth, ageing and disease.Nat. Rev. Mol. Cell Biol. 2020; 21: 183-203Crossref PubMed Scopus (1203) Google Scholar, 13Sancak Y. Peterson T.R. Shaul Y.D. Lindquist R.A. Thoreen C.C. Bar-Peled L. et al.The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1.Science. 2008; 320: 1496-1501Crossref PubMed Scopus (2063) Google Scholar, 15Kim E. Goraksha-Hicks P. Li L. Neufeld T.P. Guan K.-L. Regulation of TORC1 by Rag GTPases in nutrient response.Nat. Cell Biol. 2008; 10: 935-945Crossref PubMed Scopus (1044) Google Scholar, 16Hara K. Yonezawa K. Weng Q. Kozlowski M.T. Belham C. Avruch J. Amino acid sufficiency and mTOR regulate p70 S6 kinase and eIF-4E BP1 through a common effector mechanism.J. Biol. Chem. 1998; 273: 14484-14494Abstract Full Text Full Text PDF PubMed Scopus (1150) Google Scholar), the effects of prolonged amino acid deprivation remain less characterized. Curiously, a few studies have observed what appears to be a reactivation of mTORC1 activity upon prolonged deprivation of individual amino acids, including histidine, glutamine, and leucine (17Iiboshi Y. Papst P.J. Kawasome H. Hosoi H. Abraham R.T. Houghton P.J. et al.Amino acid-dependent control of p70 s6k.J. Biol. Chem. 1999; 274: 1092-1099Abstract Full Text Full Text PDF PubMed Scopus (185) Google Scholar, 18Yu L. McPhee C.K. Zheng L. Mardones G.A. Rong Y. Peng J. et al.Termination of autophagy and reformation of lysosomes regulated by mTOR.Nature. 2010; 465: 942-946Crossref PubMed Scopus (1188) Google Scholar, 19Chen R. Zou Y. Mao D. Sun D. Gao G. Shi J. et al.The general amino acid control pathway regulates mTOR and autophagy during serum/glutamine starvation.J. Cell Biol. 2014; 206: 173-182Crossref PubMed Scopus (139) Google Scholar, 20Ye J. Palm W. Peng M. King B. Lindsten T. Li M.O. et al.GCN2 sustains mTORC1 suppression upon amino acid deprivation by inducing Sestrin2.Genes Dev. 2015; 29: 2331-2336Crossref PubMed Scopus (193) Google Scholar), but the molecular details and extent of this reactivation remain poorly understood. Since amino acid levels may drop in an organism for more extended periods of time (21Efeyan A. Zoncu R. Chang S. Gumper I. Snitkin H. Wolfson R.L. et al.Regulation of mTORC1 by the Rag GTPases is necessary for neonatal autophagy and survival.Nature. 2013; 493: 679-683Crossref PubMed Scopus (345) Google Scholar), we chose to address how prolonged arginine or leucine deprivation affects mTORC1 activity (prolonged starvation is defined in this work as 1.5–24 h and acute starvation less than an hour). Here, we demonstrate that acute leucine or arginine deprivation leads to rapid inactivation of mTORC1 but that prolonged starvation leads to potent reactivation of mTORC1 activity. Importantly, we find that this reactivation is independent of regeneration of amino acids by canonical macroautophagy, the lysosome, or the the reactivation is by increased signaling, which is necessary for the reactivation of mTORC1 activity to that a crosstalk exists between the growth factor and amino acid of mTORC1 and indicate that PI3K/Akt-dependent signaling may for a in amino acid signaling. mTORC1 activation leucine and arginine (16Hara K. Yonezawa K. Weng Q. Kozlowski M.T. Belham C. Avruch J. Amino acid sufficiency and mTOR regulate p70 S6 kinase and eIF-4E BP1 through a common effector mechanism.J. Biol. Chem. 1998; 273: 14484-14494Abstract Full Text Full Text PDF PubMed Scopus (1150) Google Scholar), but how prolonged deprivation of these amino acids affects mTORC1 activity less characterized. address we of leucine and or amino acids, and the of mTORC1 activity at time to of by the of the mTORC1 S6 kinase 1 and protein 1 (6Kim S.G. Buel G.R. Blenis J. Nutrient regulation of the mTOR complex 1 signaling pathway.Mol. Cells. 2013; 35: 463-473Crossref PubMed Scopus (199) Google Scholar). starvation conditions a rapid suppression of mTORC1 activity in with studies (16Hara K. Yonezawa K. Weng Q. Kozlowski M.T. Belham C. Avruch J. Amino acid sufficiency and mTOR regulate p70 S6 kinase and eIF-4E BP1 through a common effector mechanism.J. Biol. Chem. 1998; 273: 14484-14494Abstract Full Text Full Text PDF PubMed Scopus (1150) Google Scholar). whereas mTORC1 in cells of amino acids, a reactivation was observed in and mTORC1 signaling levels similar to those observed under amino acid conditions this reactivation was by deprivation of arginine or leucine and cells of of these amino acids, the of mTORC1 and at time between and h that the of mTORC1 inactivation and reactivation was similar between and cells and that the is to of the amino mTORC1 at levels to that during amino levels for to h leucine or arginine deprivation mTORC1 reactivation was observed when the of mTORC1 and the and of between leucine and arginine starvation In contrast, mTORC1 reactivation was observed during a h time of amino acid deprivation and C and the mTORC1 reactivation in cell the cell and the cell and In and prolonged arginine and leucine deprivation to a reactivation of to our in A and in where the mTORC1 pathway is regulated by or Y. Thoreen C.C. Peterson T.R. Lindquist R.A. E. et is an of the mTORC1 protein Cell. Full Text Full Text PDF PubMed Scopus Google Scholar), reactivation was that the mTORC1 reactivation is observed in cell our data that prolonged leucine or arginine deprivation leads to reactivation of mTORC1 activity in cell When are cells by inducing to as to and cytosolic I. and of mammalian Rev. Mol. Cell Biol. PubMed Scopus Google Scholar). The of amino acids canonical autophagy been to mTORC1 reactivation under conditions L. McPhee C.K. Zheng L. Mardones G.A. Rong Y. Peng J. et al.Termination of autophagy and reformation of lysosomes regulated by mTOR.Nature. 2010; 465: 942-946Crossref PubMed Scopus (1188) Google Scholar), but it mTORC1 reactivation in a that is independent of we mTORC1 was in that which is for canonical N. A. M. Y. Y. K. et of Cell Biol. 2001; 152: PubMed Scopus Google Scholar). a mTORC1 reactivation was observed in during prolonged arginine or leucine deprivation that this of canonical the reactivation was by a regeneration of amino acids through or proteasomal degradation of proteins, we cells with the or the proteasomal for h in with arginine mTORC1 was by these inhibition of the lysosome or the the reactivation and that mTORC1 reactivation the regeneration of amino acids through these protein degradation the that regeneration of arginine was the reactivation of in arginine levels was observed during the time of mTORC1 as by In these data that the mTORC1 reactivation the regeneration of amino that mTORC1 reactivation was to be independent of regeneration of amino acids, we signaling that are in mTORC1 to role in the In to amino acids, mTORC1 activation is by growth factor signaling through the (6Kim S.G. Buel G.R. Blenis J. Nutrient regulation of the mTOR complex 1 signaling pathway.Mol. Cells. 2013; 35: 463-473Crossref PubMed Scopus (199) Google Scholar). when signaling was by during prolonged arginine mTORC1 reactivation was that the pathway is for reactivation to signaling was for mTORC1 we cells with of the or the with inhibition of mTORC1 reactivation and a role for PI3K/Akt signaling in the mTORC1 reactivation we in to cells in of and these cells of cells inhibition of PI3K/Akt signaling, as these cells a mTORC1 reactivation these data demonstrate that PI3K/Akt signaling is for mTORC1 reactivation to Since of PI3K/Akt signaling mTORC1 we activation levels during the time of mTORC1 reactivation by the of at and M. B. P. N. P. et of activation of protein kinase by and J. 15: PubMed Scopus Google Scholar). activation was increased upon prolonged arginine or leucine deprivation in cells and that prolonged deprivation of arginine or leucine signaling. signaling was increased in cells where we reactivation of mTORC1 the in signaling was to a in growth factor signaling in we that been of arginine or leucine with an the of growth factor signaling is through T. M. S. D.M. by Growth and Growth in a Biol. PubMed Scopus Google Scholar). we find of a general in growth factor signaling activity, as levels during the arginine or leucine deprivation time that arginine and leucine deprivation have a more on signaling. of mTORC1 signaling through a of T. T. J. A. K. et pathway signaling and proteasomal degradation of PubMed Scopus Google Scholar, C.C. Manning B.D. of regulation of mTOR complex by Cell. Biol. 29: PubMed Scopus Google Scholar, Y. G. Q. J. et as an mTORC1 that negatively regulates PubMed Scopus Google Scholar, P.P. J. Y. D. et al.The a of inhibition of growth factor PubMed Scopus Google Scholar). the in signaling was by of mTORC1 activity by arginine or leucine this was in cells where mTORC1 signaling been for h with rapamycin to a h time of leucine and arginine during which cells with mTORC1 inhibition signaling during the starvation that the of mTORC1 activity is a of this the reactivation was by a of which is known to signaling Kim S. M. et to levels to the Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). changes in levels during leucine or arginine starvation cells with of for a of h during the of arginine starvation mTORC1 or signaling, which increased at the and starvation time that a in is the Since arginine and leucine signal to mTORC1 through the we the reactivation was dependent on this pathway. mTORC1 in Rag cells to leucine or arginine starvation with the role of this pathway in leucine and arginine signaling to mTORC1 (2Liu G.Y. Sabatini D.M. mTOR at the nexus of nutrition, growth, ageing and disease.Nat. Rev. Mol. Cell Biol. 2020; 21: 183-203Crossref PubMed Scopus (1203) Google Scholar, J.L. Kim et regulation of mTORC1 by leucine and 2015; PubMed Scopus Google Scholar). Rag cells to control cells in with observations A. Chang S. et but is for and Cell. 2014; 29: Full Text Full Text PDF PubMed Scopus Google Scholar). Together, these indicate that suppression of amino acid signaling may to of signaling in signaling and mTORC1 signaling periods of arginine and leucine we the levels of and at and for to h of and to to h of starvation A and this drop in levels and h of starvation with a in mTORC1 signaling A and our data that arginine or leucine deprivation leads to a of signaling through an mechanism, which is in mTORC1 reactivation mTORC1 a of and including amino acid and growth factor to growth C.H. Jewell J.L. Regulation of mTORC1 by upstream stimuli.Genes (Basel). 2020; 11: 989Crossref PubMed Scopus (51) Google Scholar). studies have that growth factors and amino acids are communicated to mTORC1 through distinct molecular pathways A.R. Manning B.D. Roux P.P. Cantley L.C. Blenis J. Tuberous sclerosis complex gene products, tuberin and hamartin, control mTOR signaling by acting as a GTPase-activating protein complex toward Rheb.Curr. 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Sabatini D.M. mTOR at the nexus of nutrition, growth, ageing and disease.Nat. Rev. Mol. Cell Biol. 2020; 21: 183-203Crossref PubMed Scopus (1203) Google Scholar, 13Sancak Y. Peterson T.R. Shaul Y.D. Lindquist R.A. Thoreen C.C. Bar-Peled L. et al.The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1.Science. 2008; 320: 1496-1501Crossref PubMed Scopus (2063) Google Scholar, S. Wolfson R.L. K. G.A. M. et amino acid arginine sufficiency to mTORC1.Science. 2015; PubMed Scopus Google Scholar, L. R.A. K. G.A. et al.The are arginine for the mTORC1 Full Text Full Text PDF PubMed Scopus Google Scholar). these studies have on acute amino acid during which mTORC1 is and as a the effects of prolonged amino acid deprivation remain less understood. find to acute prolonged leucine or arginine deprivation leads to a potent mTORC1 this is on we have a understanding of what role this mTORC1 reactivation that this be a of an which cells to maintain during forms of amino acid in the that levels of amino acid be in the These that the leucine or arginine signaling pathways Chang Chang et deprivation as a for and PubMed Scopus Google Scholar, of amino acids for 2020; PubMed Scopus Google may to reactivation of the mTORC1 pathway. deprivation of amino acids histidine, and been shown to to reactivation of mTORC1 (17Iiboshi Y. Papst P.J. Kawasome H. Hosoi H. Abraham R.T. Houghton P.J. et al.Amino acid-dependent control of p70 s6k.J. Biol. Chem. 1999; 274: 1092-1099Abstract Full Text Full Text PDF PubMed Scopus (185) Google Scholar, 18Yu L. McPhee C.K. Zheng L. Mardones G.A. Rong Y. Peng J. et al.Termination of autophagy and reformation of lysosomes regulated by mTOR.Nature. 2010; 465: 942-946Crossref PubMed Scopus (1188) Google Scholar, 19Chen R. Zou Y. Mao D. Sun D. Gao G. Shi J. et al.The general amino acid control pathway regulates mTOR and autophagy during serum/glutamine starvation.J. Cell Biol. 2014; 206: 173-182Crossref PubMed Scopus (139) Google Scholar, 20Ye J. Palm W. Peng M. King B. Lindsten T. Li M.O. et al.GCN2 sustains mTORC1 suppression upon amino acid deprivation by inducing Sestrin2.Genes Dev. 2015; 29: 2331-2336Crossref PubMed Scopus (193) Google Scholar, Kim S. M. et to levels to the Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). extend these observations to prolonged arginine it been that mTORC1 reactivation to regeneration of amino acids through canonical autophagy L. McPhee C.K. Zheng L. Mardones G.A. Rong Y. Peng J. et al.Termination of autophagy and reformation of lysosomes regulated by mTOR.Nature. 2010; 465: 942-946Crossref PubMed Scopus (1188) Google Scholar). find that mTORC1 reactivation upon prolonged arginine and leucine deprivation of or autophagy or proteasomal we that amino acids are through less forms of protein such as of our metabolic of arginine during the time of Together, these data that mTORC1 reactivation upon prolonged arginine or leucine deprivation of the regeneration of these amino Importantly, our data demonstrate that deprivation of arginine or leucine leads to an in signaling, which is for the mTORC1 reactivation to we have the that the growth factor signaling we find that the is by mTORC1 inactivation by leucine or arginine which PI3K/Akt signaling through for by of of an of signaling Y. G. Q. J. et as an mTORC1 that negatively regulates PubMed Scopus Google Scholar, P.P. J. Y. D. et al.The a of inhibition of growth factor PubMed Scopus Google Scholar). our data a where signaling may be to for the of amino acid to mTORC1. In of this we increased signaling in which the to signal leucine and arginine to mTORC1 J.L. Kim et regulation of mTORC1 by leucine and 2015; PubMed Scopus Google Scholar). or starvation was to signaling levels by activity Kim S. M. et to levels to the Cell. Full Text Full Text PDF PubMed Scopus Google Scholar, D. B. C. D. X. et to cell during acute 2019; PubMed Scopus Google Scholar). we find of that prolonged arginine or leucine deprivation the role of in this is to be work be necessary to the complex between the amino acid and growth upstream of mTORC1 and the that they In we that prolonged arginine or leucine deprivation leads to a PI3K/Akt-dependent reactivation of mTORC1. This novel between the mTORC1 amino acid and growth a of to mTORC1 which may be of for therapeutic those amino acid such as been for Chang Chang et deprivation as a for and PubMed Scopus Google Scholar, of amino acids for 2020; PubMed Scopus Google Scholar, L. M. M.T. M. S. et deprivation as a for 2008; PubMed Scopus Google Scholar, J. G. growth of small cell of J. PubMed Scopus Google Scholar). cell in with at with a and and by N. N. A. M. Y. Y. K. et of Cell Biol. 2001; 152: PubMed Scopus Google The and a M. RagA and RagB cells and control cells by Jewell and Guan J.L. Kim et regulation of mTORC1 by leucine and 2015; PubMed Scopus Google Scholar). and and with for amino acid as the amino acids, or to be as control amino acid was the or on the by Amino or control with to amino acids to the the cell during 20 in was to the for 1 h to cell or at in for to h at cells with for the amino the cells with and with the amino acid as a control or the individual amino for the time described in The as to cells in amino acid for the time of the The Cell mTOR and to and The was was and at a of and was and was and Cell was on a with The 1 1 and or with and on and to at for at h or on and to the was with in with or in with or of the including and or and to be on to in in at for with an In and an of arginine or leucine for the time as described conditions with at time with on in and on at of was to and cells at for 1 for cell and at The was and the in 20 of and a to a with in for of the for integrated data the of this are the upon This The that they have of with the of this of the Blenis J. and for of the Vincent and for G. R. J. M. and A. P. M. G. R. H. Q. J. M. J. and A. P. M. G. R. H. Q. and A. P. M. G. R. H. Q. J. M. J. and A. P. M. G. R. J. M. and H. Q. D. G. R. J. and A. P. M. G. R. H. Q. J. M. J. and A. P. M. G. R. H. Q. and A. P. M. J. B. and A. P. M. G. R. J. and A. P. M. J. B. and A. P. This work was by The The 20 and to A. P. of to G. R. and of to J. B. The is the of the and the of the of

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