{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T07:03:23Z","timestamp":1791356603653,"version":"4.3.1"},"reference-count":34,"publisher":"Portland Press Ltd.","issue":"1","content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2009,2,1]]},"abstract":"<jats:p>Akt\/PKB (protein kinase B) both regulates and is regulated by the TSC (tuberous sclerosis complex) 1\u2013TSC2 complex. Downstream of PI3K (phosphoinositide 3-kinase), Akt phosphorylates TSC2 directly on multiple sites. Although the molecular mechanism is not well understood, these phosphorylation events relieve the inhibitory effects of the TSC1\u2013TSC2 complex on Rheb and mTORC1 [mTOR (mammalian target of rapamycin) complex] 1, thereby activating mTORC1 in response to growth factors. Through negative-feedback mechanisms, mTORC1 activity inhibits growth factor stimulation of PI3K. This is particularly evident in cells and tumours lacking the TSC1\u2013TSC2 complex, where Akt signalling is severely attenuated due, at least in part, to constitutive activation of mTORC1. An additional level of complexity in the relationship between Akt and the TSC1\u2013TSC2 complex has recently been uncovered. The growth-factor-stimulated kinase activity of mTORC2 [also known as the mTOR\u2013rictor (rapamycin-insensitive companion of mTOR) complex], which normally enhances Akt signalling by phosphorylating its hydrophobic motif (Ser473), was found to be defective in cells lacking the TSC1\u2013TSC2 complex. This effect on mTORC2 can be separated from the inhibitory effects of the TSC1\u2013TSC2 complex on Rheb and mTORC1. The present review discusses our current understanding of the increasingly complex functional interactions between Akt, the TSC1\u2013TSC2 complex and mTOR, which are fundamentally important players in a large variety of human diseases.<\/jats:p>","DOI":"10.1042\/bst0370217","type":"journal-article","created":{"date-parts":[[2009,1,22]],"date-time":"2009-01-22T10:03:13Z","timestamp":1232618593000},"page":"217-222","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":639,"title":["A complex interplay between Akt, TSC2 and the two mTOR complexes"],"prefix":"10.1042","volume":"37","author":[{"given":"Jingxiang","family":"Huang","sequence":"first","affiliation":[{"name":"Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, MA 02115, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brendan\u00a0D.","family":"Manning","sequence":"additional","affiliation":[{"name":"Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, MA 02115, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2009,1,20]]},"reference":[{"key":"2021111720010109200_B1","doi-asserted-by":"crossref","first-page":"606","DOI":"10.1038\/nrg1879","article-title":"The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism","volume":"7","author":"Engelman","year":"2006","journal-title":"Nat. Rev. Genet."},{"key":"2021111720010109200_B2","doi-asserted-by":"crossref","first-page":"6541","DOI":"10.1002\/j.1460-2075.1996.tb01045.x","article-title":"Mechanism of activation of protein kinase B by insulin and IGF-1","volume":"15","author":"Alessi","year":"1996","journal-title":"EMBO J."},{"key":"2021111720010109200_B3","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1016\/S0960-9822(06)00122-9","article-title":"Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase B\u03b1","volume":"7","author":"Alessi","year":"1997","journal-title":"Curr. Biol."},{"key":"2021111720010109200_B4","doi-asserted-by":"crossref","first-page":"1261","DOI":"10.1016\/j.cell.2007.06.009","article-title":"Akt\/PKB signaling: navigating downstream","volume":"129","author":"Manning","year":"2007","journal-title":"Cell"},{"key":"2021111720010109200_B5","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1016\/j.cell.2006.01.016","article-title":"TOR signaling in growth and metabolism","volume":"124","author":"Wullschleger","year":"2006","journal-title":"Cell"},{"key":"2021111720010109200_B6","doi-asserted-by":"crossref","first-page":"3151","DOI":"10.1038\/sj.onc.1207542","article-title":"Target of rapamycin (TOR): an integrator of nutrient and growth factor signals and coordinator of cell growth and cell cycle progression","volume":"23","author":"Fingar","year":"2004","journal-title":"Oncogene"},{"key":"2021111720010109200_B7","doi-asserted-by":"crossref","first-page":"1926","DOI":"10.1101\/gad.1212704","article-title":"Upstream and downstream of mTOR","volume":"18","author":"Hay","year":"2004","journal-title":"Genes Dev."},{"key":"2021111720010109200_B8","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/j.molcel.2006.03.029","article-title":"Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt\/PKB","volume":"22","author":"Sarbassov","year":"2006","journal-title":"Mol. Cell"},{"key":"2021111720010109200_B9","doi-asserted-by":"crossref","first-page":"1098","DOI":"10.1126\/science.1106148","article-title":"Phosphorylation and regulation of Akt\/PKB by the rictor\u2013mTOR complex","volume":"307","author":"Sarbassov","year":"2005","journal-title":"Science"},{"key":"2021111720010109200_B10","doi-asserted-by":"crossref","first-page":"859","DOI":"10.1016\/j.devcel.2006.10.007","article-title":"Ablation in mice of the mTORC components raptor, rictor, or mLST8 reveals that mTORC2 is required for signaling to Akt-FOXO and PKC\u03b1, but not S6K1","volume":"11","author":"Guertin","year":"2006","journal-title":"Dev. Cell"},{"key":"2021111720010109200_B11","doi-asserted-by":"crossref","first-page":"1296","DOI":"10.1016\/j.cub.2004.06.054","article-title":"Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton","volume":"14","author":"Sarbassov","year":"2004","journal-title":"Curr. Biol."},{"key":"2021111720010109200_B12","doi-asserted-by":"crossref","first-page":"1932","DOI":"10.1038\/emboj.2008.120","article-title":"The mammalian target of rapamycin complex 2 controls folding and stability of Akt and protein kinase C","volume":"27","author":"Facchinetti","year":"2008","journal-title":"EMBO J."},{"key":"2021111720010109200_B13","doi-asserted-by":"crossref","first-page":"1919","DOI":"10.1038\/emboj.2008.119","article-title":"Essential function of TORC2 in PKC and Akt turn motif phosphorylation, maturation and signalling","volume":"27","author":"Ikenoue","year":"2008","journal-title":"EMBO J."},{"key":"2021111720010109200_B14","doi-asserted-by":"crossref","first-page":"1345","DOI":"10.1056\/NEJMra055323","article-title":"The tuberous sclerosis complex","volume":"355","author":"Crino","year":"2006","journal-title":"N. Engl. J. Med."},{"key":"2021111720010109200_B15","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1016\/j.tibs.2003.09.003","article-title":"Rheb fills a GAP between TSC and TOR","volume":"28","author":"Manning","year":"2003","journal-title":"Trends Biochem. Sci."},{"key":"2021111720010109200_B16","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1042\/BJ20080281","article-title":"The TSC1\u2013TSC2 complex: a molecular switchboard controlling cell growth","volume":"412","author":"Huang","year":"2008","journal-title":"Biochem. J."},{"key":"2021111720010109200_B17","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":"2021111720010109200_B18","doi-asserted-by":"crossref","first-page":"648","DOI":"10.1038\/ncb839","article-title":"TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling","volume":"4","author":"Inoki","year":"2002","journal-title":"Nat. Cell Biol."},{"key":"2021111720010109200_B19","doi-asserted-by":"crossref","first-page":"658","DOI":"10.1038\/ncb840","article-title":"Akt regulates growth by directly phosphorylating Tsc2","volume":"4","author":"Potter","year":"2002","journal-title":"Nat. Cell Biol."},{"key":"2021111720010109200_B20","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1083\/jcb.200507119","article-title":"Activity of TSC2 is inhibited by Akt-mediated phosphorylation and membrane partitioning","volume":"173","author":"Cai","year":"2006","journal-title":"J. Cell Biol."},{"key":"2021111720010109200_B21","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1101\/gad.1617608","article-title":"Hypoxia regulates TSC1\/2 mTOR signaling and tumor suppression through REDD1-mediated 14-3-3 shuttling","volume":"22","author":"Deyoung","year":"2008","journal-title":"Genes Dev."},{"key":"2021111720010109200_B22","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1083\/jcb.200408161","article-title":"Balancing Akt with S6K: implications for both metabolic diseases and tumorigenesis","volume":"167","author":"Manning","year":"2004","journal-title":"J. Cell Biol."},{"key":"2021111720010109200_B23","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.tibs.2004.11.003","article-title":"Restraining PI3K: mTOR signalling goes back to the membrane","volume":"30","author":"Harrington","year":"2005","journal-title":"Trends Biochem. Sci."},{"key":"2021111720010109200_B24","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1083\/jcb.200403069","article-title":"The TSC1\u20132 tumor suppressor controls insulin\u2013PI3K signaling via regulation of IRS proteins","volume":"166","author":"Harrington","year":"2004","journal-title":"J. Cell Biol."},{"key":"2021111720010109200_B25","doi-asserted-by":"crossref","first-page":"1650","DOI":"10.1016\/j.cub.2004.08.026","article-title":"Inappropriate activation of the TSC\/Rheb\/mTOR\/S6K cassette induces IRS1\/2 depletion, insulin resistance, and cell survival deficiencies","volume":"14","author":"Shah","year":"2004","journal-title":"Curr. Biol."},{"key":"2021111720010109200_B26","doi-asserted-by":"crossref","first-page":"RE5","DOI":"10.1126\/stke.2003.172.re5","article-title":"The many forks in FOXO's road","volume":"2003","author":"Tran","year":"2003","journal-title":"Science STKE"},{"key":"2021111720010109200_B27","doi-asserted-by":"crossref","first-page":"1773","DOI":"10.1101\/gad.1314605","article-title":"Feedback inhibition of Akt signaling limits the growth of tumors lacking Tsc2","volume":"19","author":"Manning","year":"2005","journal-title":"Genes Dev."},{"key":"2021111720010109200_B28","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1016\/j.molcel.2006.09.019","article-title":"S6K1 regulates GSK3 under conditions of mTOR-dependent feedback inhibition of Akt","volume":"24","author":"Zhang","year":"2006","journal-title":"Mol. Cell"},{"key":"2021111720010109200_B29","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1083\/jcb.200710100","article-title":"FOXO-regulated transcription restricts overgrowth of Tsc mutant organs","volume":"180","author":"Harvey","year":"2008","journal-title":"J. Cell Biol."},{"key":"2021111720010109200_B30","doi-asserted-by":"crossref","first-page":"4104","DOI":"10.1128\/MCB.00289-08","article-title":"The TSC1\u2013TSC2 complex is required for proper activation of mTOR complex 2","volume":"28","author":"Huang","year":"2008","journal-title":"Mol. Cell. Biol."},{"key":"2021111720010109200_B31","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1093\/hmg\/11.5.525","article-title":"A mouse model of TSC1 reveals sex-dependent lethality from liver hemangiomas, and up-regulation of p70S6 kinase activity in Tsc1 null cells","volume":"11","author":"Kwiatkowski","year":"2002","journal-title":"Hum. Mol. Genet."},{"key":"2021111720010109200_B32","doi-asserted-by":"crossref","first-page":"8271","DOI":"10.1074\/jbc.275.12.8271","article-title":"Akt\/protein kinase B is regulated by autophosphorylation at the hypothetical PDK-2 site","volume":"275","author":"Toker","year":"2000","journal-title":"J. Biol. Chem."},{"key":"2021111720010109200_B33","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/j.molcel.2008.02.024","article-title":"PKB\u03b1\/Akt1 acts downstream of DNA-PK in the DNA double-strand break response and promotes survival","volume":"30","author":"Bozulic","year":"2008","journal-title":"Mol. Cell"},{"key":"2021111720010109200_B34","doi-asserted-by":"crossref","first-page":"1865","DOI":"10.1016\/j.cub.2006.08.001","article-title":"mSin1 is necessary for Akt\/PKB phosphorylation, and its isoforms define three distinct mTORC2s","volume":"16","author":"Frias","year":"2006","journal-title":"Curr. Biol."}],"container-title":["Biochemical Society Transactions"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/portlandpress.com\/biochemsoctrans\/article-pdf\/37\/1\/217\/545748\/bst0370217.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/portlandpress.com\/biochemsoctrans\/article-pdf\/37\/1\/217\/545748\/bst0370217.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,11,17]],"date-time":"2021-11-17T22:58:35Z","timestamp":1637189915000},"score":1,"resource":{"primary":{"URL":"https:\/\/portlandpress.com\/biochemsoctrans\/article\/37\/1\/217\/65628\/A-complex-interplay-between-Akt-TSC2-and-the-two"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2009,1,20]]},"references-count":34,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2009,1,20]]},"published-print":{"date-parts":[[2009,2,1]]}},"URL":"https:\/\/doi.org\/10.1042\/bst0370217","relation":{},"ISSN":["0300-5127","1470-8752"],"issn-type":[{"value":"0300-5127","type":"print"},{"value":"1470-8752","type":"electronic"}],"subject":[],"published":{"date-parts":[[2009,1,20]]}}}