AKT-mediated phosphorylation of TSC2 controls stimulus- and tissue-specific mTORC1 signaling and organ growth

doi:10.1016/j.devcel.2025.05.008

. 2025 May 30:S1534-5807(25)00319-3.

doi: 10.1016/j.devcel.2025.05.008. Online ahead of print.

AKT-mediated phosphorylation of TSC2 controls stimulus- and tissue-specific mTORC1 signaling and organ growth

Yann Cormerais¹, Samuel C Lapp¹, Krystle C Kalafut¹, Madi Y Cissé¹, Jong Shin¹, Benjamin Stefadu¹, Jean Personnaz², Sandra Schrötter², Jessica Freed², Angelica D'Amore³, Emma R Martin³, Catherine L Salussolia³, Mustafa Sahin³, Suchithra Menon², Vanessa Byles², Brendan D Manning⁴

Affiliations

¹ Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
² Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
³ Kirby Neurobiology Center, Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
⁴ Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: bmanning@hsph.harvard.edu.

PMID: 40480230
PMCID: PMC12258181 (available on 2026-05-30)
DOI: 10.1016/j.devcel.2025.05.008

AKT-mediated phosphorylation of TSC2 controls stimulus- and tissue-specific mTORC1 signaling and organ growth

Yann Cormerais et al. Dev Cell. 2025.

. 2025 May 30:S1534-5807(25)00319-3.

doi: 10.1016/j.devcel.2025.05.008. Online ahead of print.

Authors

Affiliations

¹ Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
² Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
³ Kirby Neurobiology Center, Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
⁴ Department of Molecular Metabolism, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: bmanning@hsph.harvard.edu.

PMID: 40480230
PMCID: PMC12258181 (available on 2026-05-30)
DOI: 10.1016/j.devcel.2025.05.008

Abstract

Mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) integrates diverse growth signals to regulate cell and tissue growth. How the molecular mechanisms regulating mTORC1 signaling-established through biochemical and cell biological studies-function under physiological states in specific mammalian tissues is undefined. Here, we characterize a genetic mouse model lacking the five phosphorylation sites on the tuberous sclerosis complex 2 (TSC2) protein through which the growth factor-stimulated protein kinase AKT can activate 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 the brain and skeletal muscle, associated with cell-intrinsic decreases in growth factor-stimulated mTORC1 signaling. The TSC2-5A mice demonstrate that TSC2 phosphorylation is a primary mechanism of mTORC1 regulation in response to exogenous signals in some, but not all, tissues and provide a genetic tool to study the physiological regulation of mTORC1.

Keywords: PI3K; RHEB; feeding; insulin; lean mass; lysosome; microcephaly; myotubes; neurons; phosphoinositide 3-kinase.

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Conflict of interest statement

Declaration of interests M.S. reports grants from Biogen, Astellas, Bridgebio, and Aucta; past Scientific Advisory Boards (SABs) for Roche, SpringWorks, and Alkermes; and current SABs for Neurogene, Jaguar Gene Therapy, and Noema.

Update of

AKT-mediated phosphorylation of TSC2 controls stimulus- and tissue-specific mTORC1 signaling and organ growth.
Cormerais Y, Lapp SC, Kalafut KC, Cissé MY, Shin J, Stefadu B, Personnaz J, Schrotter S, D'Amore A, Martin ER, Salussolia CL, Sahin M, Menon S, Byles V, Manning BD. Cormerais Y, et al. bioRxiv [Preprint]. 2024 Sep 23:2024.09.23.614519. doi: 10.1101/2024.09.23.614519. bioRxiv. 2024. Update in: Dev Cell. 2025 May 30:S1534-5807(25)00319-3. doi: 10.1016/j.devcel.2025.05.008. PMID: 39386441 Free PMC article. Updated. Preprint.

References

1. Valvezan AJ, and Manning BD (2019). Molecular logic of mTORC1 signalling as a metabolic rheostat. Nat. Metab. 1, 321–333. 10.1038/s42255-019-0038-7. - DOI - PubMed
1. Reynolds IV TH, Bodine SC, and Lawrence JC (2002). Control of Ser2448 phosphorylation in the mammalian target of rapamycin by insulin and skeletal muscle load. J. Biol. Chem. 277, 17657–17662. 10.1074/jbc.M201142200. - DOI - PubMed
1. Navé BT, Ouwens DM, Withers DJ, Alessi DR, and Shepherd PR (1999). Mammalian target of rapamycin is a direct target for protein kinase B: identification of a convergence point for opposing effects of insulin and amino-acid deficiency on protein translation. Biochem. J. 344, 427. 10.1042/0264-6021:3440427. - DOI - PMC - PubMed
1. Sekulić A, Hudson CC, Homme JL, Yin P, Otterness DM, Karnitz LM, and Abraham RT (2000). A direct linkage between the phosphoinositide 3-kinase-AKT signaling pathway and the mammalian target of rapamycin in mitogen-stimulated and transformed cells. Cancer Res. 60, 3504–3513. - PubMed
1. Rosner M, and Hengstschläger M (2008). Cytoplasmic and nuclear distribution of the protein complexes mTORC1 and mTORC2: rapamycin triggers dephosphorylation and delocalization of the mTORC2 components rictor and sin1. Hum. Mol. Genet. 17, 2934–2948. 10.1093/HMG/DDN192. - DOI - PubMed

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[1] Valvezan AJ, and Manning BD (2019). Molecular logic of mTORC1 signalling as a metabolic rheostat. Nat. Metab. 1, 321–333. 10.1038/s42255-019-0038-7. - DOI - PubMed

[2] Valvezan AJ, and Manning BD (2019). Molecular logic of mTORC1 signalling as a metabolic rheostat. Nat. Metab. 1, 321–333. 10.1038/s42255-019-0038-7. - DOI - PubMed

[3] Reynolds IV TH, Bodine SC, and Lawrence JC (2002). Control of Ser2448 phosphorylation in the mammalian target of rapamycin by insulin and skeletal muscle load. J. Biol. Chem. 277, 17657–17662. 10.1074/jbc.M201142200. - DOI - PubMed

[4] Reynolds IV TH, Bodine SC, and Lawrence JC (2002). Control of Ser2448 phosphorylation in the mammalian target of rapamycin by insulin and skeletal muscle load. J. Biol. Chem. 277, 17657–17662. 10.1074/jbc.M201142200. - DOI - PubMed

[5] Navé BT, Ouwens DM, Withers DJ, Alessi DR, and Shepherd PR (1999). Mammalian target of rapamycin is a direct target for protein kinase B: identification of a convergence point for opposing effects of insulin and amino-acid deficiency on protein translation. Biochem. J. 344, 427. 10.1042/0264-6021:3440427. - DOI - PMC - PubMed

[6] Navé BT, Ouwens DM, Withers DJ, Alessi DR, and Shepherd PR (1999). Mammalian target of rapamycin is a direct target for protein kinase B: identification of a convergence point for opposing effects of insulin and amino-acid deficiency on protein translation. Biochem. J. 344, 427. 10.1042/0264-6021:3440427. - DOI - PMC - PubMed

[7] Sekulić A, Hudson CC, Homme JL, Yin P, Otterness DM, Karnitz LM, and Abraham RT (2000). A direct linkage between the phosphoinositide 3-kinase-AKT signaling pathway and the mammalian target of rapamycin in mitogen-stimulated and transformed cells. Cancer Res. 60, 3504–3513. - PubMed

[8] Sekulić A, Hudson CC, Homme JL, Yin P, Otterness DM, Karnitz LM, and Abraham RT (2000). A direct linkage between the phosphoinositide 3-kinase-AKT signaling pathway and the mammalian target of rapamycin in mitogen-stimulated and transformed cells. Cancer Res. 60, 3504–3513. - PubMed

[9] Rosner M, and Hengstschläger M (2008). Cytoplasmic and nuclear distribution of the protein complexes mTORC1 and mTORC2: rapamycin triggers dephosphorylation and delocalization of the mTORC2 components rictor and sin1. Hum. Mol. Genet. 17, 2934–2948. 10.1093/HMG/DDN192. - DOI - PubMed

[10] Rosner M, and Hengstschläger M (2008). Cytoplasmic and nuclear distribution of the protein complexes mTORC1 and mTORC2: rapamycin triggers dephosphorylation and delocalization of the mTORC2 components rictor and sin1. Hum. Mol. Genet. 17, 2934–2948. 10.1093/HMG/DDN192. - DOI - PubMed

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AKT-mediated phosphorylation of TSC2 controls stimulus- and tissue-specific mTORC1 signaling and organ growth

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AKT-mediated phosphorylation of TSC2 controls stimulus- and tissue-specific mTORC1 signaling and organ growth

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