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How the molecular mechanisms regulating mTORC1 signaling established through biochemical and cell biological studies function under physiological states in specific mammalian tissues are unknown. Here, we characterize a genetic mouse model lacking the 5 phosphorylation sites on the tuberous sclerosis complex 2 (TSC2) protein through which the growth factor-stimulated protein kinase AKT can active mTORC1 signaling in cell culture models. These phospho-mutant mice (TSC2-5A) are developmentally normal but exhibit reduced body weight and the weight of specific organs, such as brain and skeletal muscle, associated with cell intrinsic decreases in growth factor-stimulated mTORC1 signaling. The TSC2-5A mouse model demonstrates that TSC2 phosphorylation is a primary mechanism of mTORC1 activation in some, but not all, tissues and provides a genetic tool to facilitate studies on the physiological regulation of mTORC1.<\/jats:p>","DOI":"10.1101\/2024.09.23.614519","type":"posted-content","created":{"date-parts":[[2024,9,23]],"date-time":"2024-09-23T18:35:15Z","timestamp":1727116515000},"source":"Crossref","is-referenced-by-count":5,"title":["AKT-mediated phosphorylation of TSC2 controls stimulus- and tissue-specific mTORC1 signaling and organ growth"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4913-0327","authenticated-orcid":false,"given":"Yann","family":"Cormerais","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Samuel C.","family":"Lapp","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Krystle 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