{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T18:26:45Z","timestamp":1793039205933,"version":"4.5.0"},"reference-count":49,"publisher":"Elsevier BV","issue":"43","license":[{"start":{"date-parts":[[2016,10,1]],"date-time":"2016-10-01T00:00:00Z","timestamp":1475280000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2020,10,8]],"date-time":"2020-10-08T00:00:00Z","timestamp":1602115200000},"content-version":"vor","delay-in-days":1468,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01GM030355"],"award-info":[{"award-number":["R01GM030355"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01DK034128"],"award-info":[{"award-number":["R01DK034128"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100004917","name":"Cancer Prevention and Research Institute of Texas","doi-asserted-by":"publisher","award":["RP120695"],"award-info":[{"award-number":["RP120695"]}],"id":[{"id":"10.13039\/100004917","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["jbc.org","elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["Journal of Biological Chemistry"],"published-print":{"date-parts":[[2016,10]]},"DOI":"10.1074\/jbc.m116.732511","type":"journal-article","created":{"date-parts":[[2016,9,2]],"date-time":"2016-09-02T02:45:45Z","timestamp":1472784345000},"page":"22414-22426","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":82,"title":["Amino Acids Regulate mTORC1 by an Obligate Two-step Mechanism"],"prefix":"10.1016","volume":"291","author":[{"given":"Julia","family":"Dyachok","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Svetlana","family":"Earnest","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erica N.","family":"Iturraran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melanie H.","family":"Cobb","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elliott M.","family":"Ross","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"78","reference":[{"key":"10.1074\/jbc.M116.732511_bib1","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1016\/j.cell.2008.02.031","article-title":"SKAR links pre-mRNA splicing to mTOR\/S6K1-mediated enhanced translation efficiency of spliced mRNAs","volume":"133","author":"Ma","year":"2008","journal-title":"Cell"},{"key":"10.1074\/jbc.M116.732511_bib2","first-page":"169","article-title":"mTOR signaling to translation","volume":"279","author":"Gingras","year":"2004","journal-title":"Curr. Top. Microbiol. Immunol"},{"key":"10.1074\/jbc.M116.732511_bib3","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1038\/ncb2152","article-title":"AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1","volume":"13","author":"Kim","year":"2011","journal-title":"Nat. Cell Biol"},{"key":"10.1074\/jbc.M116.732511_bib4","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.ccr.2007.05.008","article-title":"Defining the role of mTOR in cancer","volume":"12","author":"Guertin","year":"2007","journal-title":"Cancer Cell"},{"key":"10.1074\/jbc.M116.732511_bib5","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1016\/j.molcel.2011.09.005","article-title":"mTOR generates an auto-amplification loop by triggering the \u03b2TrCP- and CK1\u03b1-dependent degradation of DEPTOR","volume":"44","author":"Duan","year":"2011","journal-title":"Mol. Cell"},{"key":"10.1074\/jbc.M116.732511_bib6","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1016\/j.molcel.2011.08.030","article-title":"mTOR drives its own activation via SCF(\u03b2TrCP)-dependent degradation of the mTOR inhibitor DEPTOR","volume":"44","author":"Gao","year":"2011","journal-title":"Mol. Cell"},{"key":"10.1074\/jbc.M116.732511_bib7","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1016\/j.cell.2009.03.046","article-title":"DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival","volume":"137","author":"Peterson","year":"2009","journal-title":"Cell"},{"key":"10.1074\/jbc.M116.732511_bib8","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1016\/j.molcel.2015.03.028","article-title":"Rapid mitogenic regulation of the mTORC1 inhibitor, DEPTOR, by phosphatidic acid","volume":"58","author":"Yoon","year":"2015","journal-title":"Mol. Cell"},{"key":"10.1074\/jbc.M116.732511_bib9","doi-asserted-by":"crossref","first-page":"1269","DOI":"10.1016\/j.cub.2008.07.078","article-title":"Oncogenic MAPK signaling stimulates mTORC1 activity by promoting RSK-mediated raptor phosphorylation","volume":"18","author":"Carri\u00e8re","year":"2008","journal-title":"Curr. Biol"},{"key":"10.1074\/jbc.M116.732511_bib10","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1038\/nrm2822","article-title":"The nuts and bolts of AGC protein kinases","volume":"11","author":"Pearce","year":"2010","journal-title":"Nat. Rev. Mol. Cell Biol"},{"key":"10.1074\/jbc.M116.732511_bib11","doi-asserted-by":"crossref","first-page":"702","DOI":"10.1016\/j.cub.2005.02.053","article-title":"Rheb binds and regulates the mTOR kinase","volume":"15","author":"Long","year":"2005","journal-title":"Curr. Biol"},{"key":"10.1074\/jbc.M116.732511_bib12","doi-asserted-by":"crossref","first-page":"1496","DOI":"10.1126\/science.1157535","article-title":"The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1","volume":"320","author":"Sancak","year":"2008","journal-title":"Science"},{"key":"10.1074\/jbc.M116.732511_bib13","doi-asserted-by":"crossref","first-page":"1829","DOI":"10.1101\/gad.1110003","article-title":"Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling","volume":"17","author":"Inoki","year":"2003","journal-title":"Genes Dev"},{"key":"10.1074\/jbc.M116.732511_bib14","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1038\/ncb2763","article-title":"Signal integration by mTORC1 coordinates nutrient input with biosynthetic output","volume":"15","author":"Dibble","year":"2013","journal-title":"Nat. Cell Biol"},{"key":"10.1074\/jbc.M116.732511_bib15","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1097\/MNH.0b013e3283520f38","article-title":"Mammalian target of rapamycin signaling in the podocyte","volume":"21","author":"Inoki","year":"2012","journal-title":"Curr. Opin. Nephrol. Hypertens"},{"key":"10.1074\/jbc.M116.732511_bib16","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1016\/S1097-2765(02)00568-3","article-title":"Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase\/akt pathway","volume":"10","author":"Manning","year":"2002","journal-title":"Mol. Cell"},{"key":"10.1074\/jbc.M116.732511_bib17","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1016\/j.cell.2013.11.049","article-title":"Spatial control of the TSC complex integrates insulin and nutrient regulation of mTORC1 at the lysosome","volume":"156","author":"Menon","year":"2014","journal-title":"Cell"},{"key":"10.1074\/jbc.M116.732511_bib18","doi-asserted-by":"crossref","first-page":"1100","DOI":"10.1126\/science.1232044","article-title":"A tumor suppressor complex with GAP activity for the Rag GTPases that signal amino acid sufficiency to mTORC1","volume":"340","author":"Bar-Peled","year":"2013","journal-title":"Science"},{"key":"10.1074\/jbc.M116.732511_bib19","doi-asserted-by":"crossref","first-page":"9502","DOI":"10.1038\/srep09502","article-title":"Sestrin2 inhibits mTORC1 through modulation of GATOR complexes","volume":"5","author":"Kim","year":"2015","journal-title":"Sci. Rep"},{"key":"10.1074\/jbc.M116.732511_bib20","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1016\/j.cell.2008.11.044","article-title":"Bidirectional transport of amino acids regulates mTOR and autophagy","volume":"136","author":"Nicklin","year":"2009","journal-title":"Cell"},{"key":"10.1074\/jbc.M116.732511_bib21","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1016\/j.cell.2014.08.038","article-title":"Sestrins function as guanine nucleotide dissociation inhibitors for Rag GTPases to control mTORC1 signaling","volume":"159","author":"Peng","year":"2014","journal-title":"Cell"},{"key":"10.1074\/jbc.M116.732511_bib22","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1038\/nature14107","article-title":"SLC38A9 is a component of the lysosomal amino acid sensing machinery that controls mTORC1","volume":"519","author":"Rebsamen","year":"2015","journal-title":"Nature"},{"key":"10.1074\/jbc.M116.732511_bib23","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1126\/science.1257132","article-title":"Metabolism. Lysosomal amino acid transporter SLC38A9 signals arginine sufficiency to mTORC1","volume":"347","author":"Wang","year":"2015","journal-title":"Science"},{"key":"10.1074\/jbc.M116.732511_bib24","doi-asserted-by":"crossref","first-page":"851","DOI":"10.1016\/j.molcel.2012.08.001","article-title":"The G protein-coupled taste receptor T1R1\/T1R3 regulates mTORC1 and autophagy","volume":"47","author":"Wauson","year":"2012","journal-title":"Mol. Cell"},{"key":"10.1074\/jbc.M116.732511_bib25","doi-asserted-by":"crossref","first-page":"678","DOI":"10.1126\/science.1207056","article-title":"mTORC1 senses lysosomal amino acids through an inside-out mechanism that requires the vacuolar H+-ATPase","volume":"334","author":"Zoncu","year":"2011","journal-title":"Science"},{"key":"10.1074\/jbc.M116.732511_bib26","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1126\/science.aab2674","article-title":"Sestrin2 is a leucine sensor for the mTORC1 pathway","volume":"351","author":"Wolfson","year":"2016","journal-title":"Science"},{"key":"10.1074\/jbc.M116.732511_bib27","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1126\/science.1259472","article-title":"Metabolism: differential regulation of mTORC1 by leucine and glutamine","volume":"347","author":"Jewell","year":"2015","journal-title":"Science"},{"key":"10.1074\/jbc.M116.732511_bib28","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1016\/j.molcel.2012.05.043","article-title":"Glutaminolysis activates Rag-mTORC1 signaling","volume":"47","author":"Dur\u00e1n","year":"2012","journal-title":"Mol. Cell"},{"key":"10.1074\/jbc.M116.732511_bib29","doi-asserted-by":"crossref","first-page":"14484","DOI":"10.1074\/jbc.273.23.14484","article-title":"Amino acid sufficiency and mTOR regulate p70 S6 kinase and eIF-4E BP1 through a common effector mechanism","volume":"273","author":"Hara","year":"1998","journal-title":"J. Biol. Chem"},{"key":"10.1074\/jbc.M116.732511_bib30","doi-asserted-by":"crossref","first-page":"754","DOI":"10.1016\/j.ccell.2014.09.008","article-title":"Rab1A is an mTORC1 activator and a colorectal oncogene","volume":"26","author":"Thomas","year":"2014","journal-title":"Cancer Cell"},{"key":"10.1074\/jbc.M116.732511_bib31","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1016\/S1535-6108(03)00187-9","article-title":"TSC2 regulates VEGF through mTOR-dependent and -independent pathways","volume":"4","author":"Brugarolas","year":"2003","journal-title":"Cancer Cell"},{"key":"10.1074\/jbc.M116.732511_bib32","doi-asserted-by":"crossref","first-page":"3993","DOI":"10.1529\/biophysj.103.038422","article-title":"Automatic and quantitative measurement of protein-protein colocalization in live cells","volume":"86","author":"Costes","year":"2004","journal-title":"Biophys. J"},{"key":"10.1074\/jbc.M116.732511_bib33","doi-asserted-by":"crossref","first-page":"14056","DOI":"10.1074\/jbc.M700906200","article-title":"RAS\/ERK signaling promotes site-specific ribosomal protein S6 phosphorylation via RSK and stimulates cap-dependent translation","volume":"282","author":"Roux","year":"2007","journal-title":"J. Biol. Chem"},{"key":"10.1074\/jbc.M116.732511_bib34","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1016\/j.cell.2010.02.024","article-title":"Ragulator-Rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids","volume":"141","author":"Sancak","year":"2010","journal-title":"Cell"},{"key":"10.1074\/jbc.M116.732511_bib35","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1038\/ncb2204","article-title":"Lysosomal positioning coordinates cellular nutrient responses","volume":"13","author":"Korolchuk","year":"2011","journal-title":"Nat. Cell Biol"},{"key":"10.1074\/jbc.M116.732511_bib36","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1172\/JCI7319","article-title":"Tsc2+\/\u2212 mice develop tumors in multiple sites that express gelsolin and are influenced by genetic background","volume":"104","author":"Onda","year":"1999","journal-title":"J. Clin. Invest"},{"key":"10.1074\/jbc.M116.732511_bib37","doi-asserted-by":"crossref","first-page":"e11058","DOI":"10.7554\/eLife.11058","article-title":"Control of TSC2-Rheb signaling axis by arginine regulates mTORC1 activity","volume":"5","author":"Carroll","year":"2016","journal-title":"eLife"},{"key":"10.1074\/jbc.M116.732511_bib38","doi-asserted-by":"crossref","first-page":"410","DOI":"10.1016\/j.cell.2012.02.044","article-title":"Leucyl-tRNA synthetase is an intracellular leucine sensor for the mTORC1-signaling pathway","volume":"149","author":"Han","year":"2012","journal-title":"Cell"},{"key":"10.1074\/jbc.M116.732511_bib39","first-page":"537","article-title":"Arginine and Leucine regulate p70 S6 kinase and 4E-BP1 in intestinal epithelial cells","volume":"13","author":"Ban","year":"2004","journal-title":"Int. J. Mol. Med"},{"key":"10.1074\/jbc.M116.732511_bib40","doi-asserted-by":"crossref","first-page":"867","DOI":"10.1093\/jn\/138.5.867","article-title":"Dietary arginine supplementation increases mTOR signaling activity in skeletal muscle of neonatal pigs","volume":"138","author":"Yao","year":"2008","journal-title":"J. Nutr"},{"key":"10.1074\/jbc.M116.732511_bib41","doi-asserted-by":"crossref","first-page":"6904","DOI":"10.1073\/pnas.1204176109","article-title":"Pyruvate kinase M2 promotes de novo serine synthesis to sustain mTORC1 activity and cell proliferation","volume":"109","author":"Ye","year":"2012","journal-title":"Proc. Natl. Acad. Sci. U.S.A"},{"key":"10.1074\/jbc.M116.732511_bib42","doi-asserted-by":"crossref","first-page":"2479","DOI":"10.1128\/MCB.00125-15","article-title":"Amino acid-dependent mTORC1 regulation by the lysosomal membrane protein SLC38A9","volume":"35","author":"Jung","year":"2015","journal-title":"Mol. Cell Biol"},{"key":"10.1074\/jbc.M116.732511_bib43","doi-asserted-by":"crossref","first-page":"7250","DOI":"10.1038\/ncomms8250","article-title":"LAPTM4b recruits the LAT1\u20134F2hc Leu transporter to lysosomes and promotes mTORC1 activation","volume":"6","author":"Milkereit","year":"2015","journal-title":"Nat. Commun"},{"key":"10.1074\/jbc.M116.732511_bib44","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1016\/j.cell.2012.03.017","article-title":"mTOR signaling in growth control and disease","volume":"149","author":"Laplante","year":"2012","journal-title":"Cell"},{"key":"10.1074\/jbc.M116.732511_bib45","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1111\/nyas.12756","article-title":"mTOR activation is a biomarker and a central pathway to autoimmune disorders, cancer, obesity, and aging","volume":"1346","author":"Perl","year":"2015","journal-title":"Ann. N.Y. Acad. Sci"},{"key":"10.1074\/jbc.M116.732511_bib46","first-page":"2541","article-title":"Human tumor growth in nude mice is associated with decreased plasma cysteine and homocysteine","volume":"28","author":"Al-Awadi","year":"2008","journal-title":"Anticancer Res"},{"key":"10.1074\/jbc.M116.732511_bib47","doi-asserted-by":"crossref","first-page":"2397","DOI":"10.1158\/0008-5472.CAN-09-3648","article-title":"Plasma homocysteine and cysteine and risk of breast cancer in women","volume":"70","author":"Lin","year":"2010","journal-title":"Cancer Res"},{"key":"10.1074\/jbc.M116.732511_bib48","doi-asserted-by":"crossref","first-page":"618","DOI":"10.1136\/gut.2010.225854","article-title":"Prospective study of serum cysteine levels and oesophageal and gastric cancers in China","volume":"60","author":"Murphy","year":"2011","journal-title":"Gut"},{"key":"10.1074\/jbc.M116.732511_bib49","doi-asserted-by":"crossref","first-page":"12387","DOI":"10.1016\/S0021-9258(18)43284-X","article-title":"Mechanism of growth stimulation of L1210 cells by 2-mercaptoethanol in vitro. Role of the mixed disulfide of 2-mercaptoethanol and cysteine","volume":"256","author":"Ishii","year":"1981","journal-title":"J. Biol. Chem"}],"updated-by":[{"DOI":"10.1074\/jbc.aac120.014360","type":"erratum","label":"Erratum","source":"publisher","updated":{"date-parts":[[2020,6,26]],"date-time":"2020-06-26T00:00:00Z","timestamp":1593129600000}}],"container-title":["Journal of Biological Chemistry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0021925820357136?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0021925820357136?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1074\/jbc.M116.732511","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,1,4]],"date-time":"2022-01-04T07:23:29Z","timestamp":1641281009000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S0021925820357136"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,10]]},"references-count":49,"journal-issue":{"issue":"43","published-print":{"date-parts":[[2016,10]]}},"alternative-id":["S0021925820357136"],"URL":"https:\/\/doi.org\/10.1074\/jbc.m116.732511","relation":{"erratum":[{"id-type":"doi","id":"10.1074\/jbc.AAC120.014360","asserted-by":"object"}]},"ISSN":["0021-9258"],"issn-type":[{"value":"0021-9258","type":"print"}],"subject":[],"published":{"date-parts":[[2016,10]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"Amino Acids Regulate mTORC1 by an Obligate Two-step Mechanism","name":"articletitle","label":"Article Title"},{"value":"Journal of Biological Chemistry","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1074\/jbc.M116.732511","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"\u00a9 2016 ASBMB. Currently published by Elsevier Inc; originally published by American Society for Biochemistry and Molecular Biology.","name":"copyright","label":"Copyright"}]}}