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

• Published in: Developmental 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
• Language: English
• Published: United States 30.05.2025
• Subjects: microcephaly; lean mass; PI3K; insulin; RHEB; feeding; myotubes; lysosome; neurons; phosphoinositide 3-kinase
• ISSN: 1534-5807; 1878-1551; 1878-1551
• DOI: 10.1016/j.devcel.2025.05.008

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.