PreprintCited by 1,911PI3K/AKT/mTOR signaling in cancerTuberous Sclerosis Complex ResearchMetabolism, Diabetes, and Cancer

Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling

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Inoki, Ken, Li, Yong, Xu, Tian, Guan, Kun-Liang·2003·Genes & Development

Abstract

Tuberous sclerosis complex (TSC) is a genetic disease caused by mutation in either TSC1 or TSC2 . The TSC1 and TSC2 gene products form a functional complex and inhibit phosphorylation of S6K and 4EBP1. These functions of TSC1/TSC2 are likely mediated by mTOR. Here we report that TSC2 is a GTPase-activating protein (GAP) toward Rheb, a Ras family GTPase. Rheb stimulates phosphorylation of S6K and 4EBP1. This function of Rheb is blocked by rapamycin and dominant-negative mTOR. Rheb stimulates the phosphorylation of mTOR and plays an essential role in regulation of S6K and 4EBP1 in response to nutrients and cellular energy status. Our data demonstrate that Rheb acts downstream of TSC1/TSC2 and upstream of mTOR to regulate cell growth.

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  • The TSC complex acts as a GTPase activating protein for Rheb, employing a GAP domain within the TSC2 subunit.

    “The TSC complex (TSCC) acts as a GTPase activating protein (GAP) for Rheb, employing a GAP domain within the TSC2 subunit”

    From Signal integration in the (m)TORC1 growth pathway (2018) · cites this paper as Inoki et al., 2003

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Authors
Inoki, K., Li, Y., Xu, T., & Guan, K.-L.
Affiliations
  • University of Michigan (US)
  • Howard Hughes Medical Institute (US)
Venue
Genes & Development
Published
2003-07-17
Volume
17
Issue
15
Pages
1829-1834
ISSN
  • 0890-9369 (ISSN-L)
  • 1549-5477
OpenAlex
W2056137479
Cited by
1,911
References
34
Citations by year
2026: 44 · 2025: 68 · 2024: 75 · 2023: 78 · 2022: 72 · 2021: 107 · 2020: 103 · 2019: 73 · 2018: 97 · 2017: 112 · 2016: 111 · 2015: 127 · 2014: 92 · 2013: 101 · 2012: 94
Type
posted content
Language
en
Open access
Locations
  • Genes & Development (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (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, GTPase-activating protein, mTOR signaling, tuberous sclerosis complex, S6K phosphorylation, 4E-BP1 phosphorylation, rapamycin, nutrient signaling, cellular energy status, cell growth regulation, Ras family GTPases
MeSH terms
Ras Homolog Enriched in Brain Protein, Tuberous Sclerosis Complex 1 Protein, Tuberous Sclerosis Complex 2 Protein, Antibiotics, Antineoplastic, Cell Division, Cell Line, Dose-Response Relationship, Drug, Genes, Dominant, Guanosine Triphosphate, Humans, Hydrolysis, Models, Biological, Mutation, Neuropeptides, Phosphorylation, Plasmids, Protein Binding, Protein Kinases, Proteins, Repressor Proteins, Time Factors, Protein Biosynthesis, Signal Transduction, Protein Structure, Tertiary, Sirolimus, GTP Phosphohydrolases, Monomeric GTP-Binding Proteins, Tumor Suppressor Proteins, Ribosomal Protein S6 Kinases, 70-kDa, TOR Serine-Threonine Kinases

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