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

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 mammali...

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Published inDevelopmental cell
Main Authors Cormerais, Yann, Lapp, Samuel C., Kalafut, Krystle C., Cissé, Madi Y., Shin, Jong, Stefadu, Benjamin, Personnaz, Jean, Schrötter, Sandra, Freed, Jessica, D’Amore, Angelica, Martin, Emma R., Salussolia, Catherine L., Sahin, Mustafa, Menon, Suchithra, Byles, Vanessa, Manning, Brendan D.
Format Journal Article
LanguageEnglish
Published United States 30.05.2025
Subjects
microcephaly
lean mass
PI3K
insulin
RHEB
feeding
myotubes
lysosome
neurons
phosphoinositide 3-kinase
Online AccessGet full text
ISSN1534-5807
1878-1551
1878-1551
DOI10.1016/j.devcel.2025.05.008

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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.
AbstractList 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.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.
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.
Author Byles, Vanessa
Lapp, Samuel C.
Stefadu, Benjamin
Cormerais, Yann
D’Amore, Angelica
Menon, Suchithra
Shin, Jong
Martin, Emma R.
Cissé, Madi Y.
Sahin, Mustafa
Personnaz, Jean
Schrötter, Sandra
Freed, Jessica
Manning, Brendan D.
Kalafut, Krystle C.
Salussolia, Catherine L.
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Keywords microcephaly
lean mass
PI3K
insulin
RHEB
feeding
myotubes
lysosome
neurons
phosphoinositide 3-kinase
Language English
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  article-title: A germ-line Tsc1 mutation causes tumor development and embryonic lethality that are similar, but not identical to, those caused by Tsc2 mutation in mice
  publication-title: Proc. Natl. Acad. Sci. USA
  doi: 10.1073/pnas.151033798
– reference: 39386441 - bioRxiv. 2024 Sep 23:2024.09.23.614519. doi: 10.1101/2024.09.23.614519.
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Snippet Mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) integrates diverse growth signals to regulate cell and tissue growth. How the molecular mechanisms...
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Title AKT-mediated phosphorylation of TSC2 controls stimulus- and tissue-specific mTORC1 signaling and organ growth
URI https://www.ncbi.nlm.nih.gov/pubmed/40480230
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