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Cited by 3,083PI3K/AKT/mTOR signaling in cancerTuberous Sclerosis Complex ResearchMetabolism, Diabetes, and Cancer

TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling

Inoki, Ken, Li, Yong, Zhu, Tianquan, Wu, Jun, Guan, Kun-Liang·2002·Nature Cell Biology
DOI 10.1038/ncb839
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Abstract

Tuberous sclerosis (TSC) is an autosomal dominant disorder characterized by the formation of hamartomas in a wide range of human tissues. Mutation in either the TSC1 or TSC2 tumour suppressor gene is responsible for both the familial and sporadic forms of this disease. TSC1 and TSC2 proteins form a physical and functional complex in vivo. Here, we show that TSC1-TSC2 inhibits the p70 ribosomal protein S6 kinase 1 (an activator of translation) and activates the eukaryotic initiation factor 4E binding protein 1 (4E-BP1, an inhibitor of translational initiation). These functions of TSC1-TSC2 are mediated by inhibition of the mammalian target of rapamycin (mTOR). Furthermore, TSC2 is directly phosphorylated by Akt, which is involved in stimulating cell growth and is activated by growth stimulating signals, such as insulin. TSC2 is inactivated by Akt-dependent phosphorylation, which destabilizes TSC2 and disrupts its interaction with TSC1. Our data indicate a molecular mechanism for TSC2 in insulin signalling, tumour suppressor functions and in the inhibition of cell growth.

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Crossref · 10.1038/ncb839

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  • TSC2 functions as a GTPase-activating protein to convert active Rheb-GTP to inactive Rheb-GDP, resulting in inhibition of mTOR, the mTORC1 complex, and the mTOR signaling pathway p70S6K.

    “TSC2, also known as tuberous sclerosis protein 2, functions as a GTPase-activating protein (GAP) to convert active Rheb-GTP to the inactive GDP-bound form (Rheb-GDP) resulting in the inhibition of mTOR, the mTORC1 complex [26], and the mTOR signaling pathway p70S6K [27].”

    From Tuberous Sclerosis Protein 2 (TSC2) Modulates CCN4 Cytoprotection During Apoptotic Amyloid Toxicity in Microglia (2013) · cites this paper as [26]

  • TSC2 blocks mTOR activity.

    “tuberous sclerosis complex 2 (TSC2), that also blocks mTOR activity [26]”

    From Tuberous Sclerosis Protein 2 (TSC2) Modulates CCN4 Cytoprotection During Apoptotic Amyloid Toxicity in Microglia (2013) · cites this paper as [26]

  • TSC2 can be inhibited by Akt phosphorylation that destabilizes TSC2 and disrupts its interaction with TSC1.

    “Subsequently, TSC2 can be inhibited by Akt phosphorylation that serves to destabilize TSC2 and disrupt its interaction with TSC1 [26, 28].”

    From Tuberous Sclerosis Protein 2 (TSC2) Modulates CCN4 Cytoprotection During Apoptotic Amyloid Toxicity in Microglia (2013) · cites this paper as [26]

  • The integration of the majority of external and survival signals feeding into the (m)TORC1 pathway occurs through the TSC complex (TSCC), composed of TSC1, TSC2, and TBC1D7, which is the key signal integrator and negative regulator upstream of Rheb.

    “The integration of the majority of external and survival signals feeding into the (m)TORC1 pathway occurs through the TSC complex (TSCC), composed of tuberous sclerosis complex protein 1 (TSC1) and TSC2, also known as hamartin and tuberin, and TBC1D7, which is the key signal integrator and negative regulator upstream of Rheb.”

    From Signal integration in the (m)TORC1 growth pathway (2018) · cites this paper as Inoki et al., 2002

  • TSC1-TSC2 were unequivocally identified as inhibitors of the mTORC1 signaling pathway, specifically by virtue of TSC2 GAP activity toward the small GTPase Rheb.

    “This identification of this regulatory mechanism, shown using the human proteins, unequivocally identified TSC1-TSC2 as inhibitors of the mTORC1 signaling pathway (Inoki et al., 2002; Tee et al., 2002), specifically by virtue of TSC2 GAP activity toward the small GTPase Rheb (Castro et al., 2003; Garami et al., 2003; Inoki et al., 2003; Saucedo et al., 2003;”

    From Signal integration in the (m)TORC1 growth pathway (2018) · cites this paper as Inoki et al., 2002

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Authors
Inoki, K., Li, Y., Zhu, T., Wu, J., & Guan, K.-L.
Affiliations
University of Michigan (US)
Corresponding author
Guan, Kun-Liang
ORCID
Venue
Nature Cell Biology
Publisher
Springer Science and Business Media LLC
Published
2002-08-12
Volume
4
Issue
9
Pages
648-657
ISSN
  • 1465-7392 (ISSN-L)
  • 1476-4679
DOI
10.1038/ncb839
OpenAlex
W2011282245
Cited by
3,083
References
50
Citations by year
2026: 64 · 2025: 77 · 2024: 101 · 2023: 115 · 2022: 121 · 2021: 139 · 2020: 136 · 2019: 111 · 2018: 131 · 2017: 148 · 2016: 143 · 2015: 180 · 2014: 161 · 2013: 159 · 2012: 168
FWCI
34.62
Type
journal article
Language
en
Open access
closed
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature Cell Biology (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK124709)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
  • Health Sciences › Medicine › Physiology › Tuberous Sclerosis Complex Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Keywords
TSC2, tuberous sclerosis complex, TSC1/TSC2 complex, Akt phosphorylation, mTOR signaling, 4E-BP1, translational regulation, insulin signaling, tumor suppression, protein stability, cell growth inhibition
MeSH terms
Tuberous Sclerosis Complex 1 Protein, Tuberous Sclerosis Complex 2 Protein, Binding Sites, Carrier Proteins, Cell Line, Humans, Insulin, Models, Biological, Mutation, Phosphoproteins, Phosphorylation, Protein Kinases, Proteins, Proto-Oncogene Proteins, Repressor Proteins, Tuberous Sclerosis, Signal Transduction, Genes, Tumor Suppressor, Protein Serine-Threonine Kinases, Cell Cycle Proteins, Ribosomal Protein S6 Kinases, Tumor Suppressor Proteins, Protein Kinase Inhibitors, Adaptor Proteins, Signal Transducing, Proto-Oncogene Proteins c-akt, TOR Serine-Threonine Kinases

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