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Cited by 1,005PI3K/AKT/mTOR signaling in cancerProtein Kinase Regulation and GTPase SignalingTuberous Sclerosis Complex Research

Rheb Binds and Regulates the mTOR Kinase

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Long, Xiaomeng, Lin, Yenshou, Ortiz-Vega, Sara, Yonezawa, Kazuyoshi, Avruch, Joseph·2005·Current Biology
DOI 10.1016/j.cub.2005.02.053
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Abstract

Background The target of rapamycin (TOR), in complex with the proteins raptor and LST8 (TOR complex 1), phosphorylates the p70S6K and 4E-BP1 to promote mRNA translation. Genetic evidence establishes that TOR complex activity in vivo requires the small GTPase Rheb, and overexpression of Rheb can rescue TOR from inactivation in vivo by amino-acid withdrawal. The Tuberous Sclerosis heterodimer (TSC1/TSC2) functions as a Rheb GTPase activator and inhibits TOR signaling in vivo.Results Here, we show that Rheb binds to the TOR complex specifically, independently of its ability to bind TSC2, through separate interactions with the mTOR catalytic domain and with LST8. Rheb binding to the TOR complex in vivo and in vitro does not require Rheb guanyl nucleotide charging but is modulated by GTP and impaired by certain mutations (Ile39Lys) in the switch 1 loop. Nucleotide-deficient Rheb mutants, although capable of binding mTOR in vivo and in vitro, are inhibitory in vivo, and the mTOR polypeptides that associate with nucleotide-deficient Rheb in vivo lack kinase activity in vitro. Reciprocally, mTOR polypeptides bound to Rheb(Gln64Leu), a mutant that is nearly 90% GTP charged, exhibit substantially higher protein kinase specific activity than mTOR bound to wild-type Rheb.Conclusions The TOR complex 1 is a direct target of Rheb-GTP, whose binding enables activation of the TOR kinase.

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  • TSC1 and TSC2 are negative regulators of mTOR phosphorylation by blocking the small GTPase Rheb activity.

    “Recently, it has been demonstrated that two tumour suppressor genes, the tuberous sclerosis complex (TSC) gene TSC1 (or Hamartin) and TSC2 (or Tuberin) were negative regulators of mTOR phosphorylation [78] by blocking the small GTPase Rheb activity, which is a positive regulator of mTOR [79, 80].”

    From PKR, the double stranded RNA‐dependent protein kinase as a critical target in Alzheimer's disease (2009) · cites this paper as [79]

  • Full mTORC1 activation requires its recruitment to the lysosome by heterodimeric Rag GTPases, whereupon GTP-bound Rheb GTPases allosterically activate the kinase.

    “Full mTORC1 activation requires its recruitment to the lysosome by heterodimeric Rag GTPases (Sancak et al., 2008), whereupon GTP-bound Rheb GTPases allosterically activate the kinase (Long et al., 2005; Sato et al., 2009)”

    From Signal integration in the (m)TORC1 growth pathway (2018) · cites this paper as Long et al., 2005

  • In almost all eukaryotes, RhebGTP is an essential coactivator of (m)TORC1, required for catalytic activity.

    “In almost all eukaryotes, RhebGTP is an essential coactivator of (m)TORC1, required for catalytic activity.”

    From Signal integration in the (m)TORC1 growth pathway (2018) · cites this paper as Long et al., 2005

  • Rheb is known to function on endomembranes in the mTORC1 pathway as a potent activator of the kinase and is the physiologic target of TSC2.

    “Despite a lack of clear experimental evidence pointing to a defined localization pattern, Rheb is known to function on endomembranes in the mTORC1 pathway as a potent activator of the kinase (Long et al., 2005; Sato et al., 2009) and is the physiologic target of TSC2 (Castro et al., 2003; Garami et al., 2003; Inoki et al., 2003; Saucedo et al., 2003; Stocker et al., 2003; Tee et al., 2003; Zhang e”

    From Signal integration in the (m)TORC1 growth pathway (2018) · cites this paper as Long et al., 2005

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Authors
Long, X., Lin, Y., Ortiz-Vega, S., Yonezawa, K., & Avruch, J.
Affiliations
  • Harvard University (US)
  • Japan Science and Technology Agency (JP)
Corresponding author
Avruch, Joseph
ORCID
Venue
Current Biology
Publisher
Elsevier BV
Published
2005-04
Volume
15
Issue
8
Pages
702-713
ISSN
0960-9822 (ISSN-L)
DOI
10.1016/j.cub.2005.02.053
OpenAlex
W2089632625
Cited by
1,005
References
47
Citations by year
2026: 19 · 2025: 28 · 2024: 31 · 2023: 54 · 2022: 37 · 2021: 75 · 2020: 47 · 2019: 55 · 2018: 55 · 2017: 44 · 2016: 42 · 2015: 51 · 2014: 40 · 2013: 35 · 2012: 50
FWCI
22.04
Type
journal article
Language
en
Open access
Licence
Locations
  • Current Biology (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Cancer Institute (CA-73818, R01CA073818)
  • National Institute of Diabetes and Digestive and Kidney Diseases (DK-17776, DK007028, T32DK007028)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
  • Health Sciences › Medicine › Physiology › Tuberous Sclerosis Complex Research
Keywords
Rheb, mTOR, LST8, TSC2, GTP binding, kinase activation, protein-protein interaction, amino acid signaling, mRNA translation, p70S6K, 4E-BP1, tuberous sclerosis complex
MeSH terms
Ras Homolog Enriched in Brain Protein, Regulatory-Associated Protein of mTOR, Tuberous Sclerosis Complex 2 Protein, Cells, Cultured, Enzyme Activation, Guanosine Triphosphate, Humans, Mutation, Neuropeptides, Phosphorylation, Plasmids, Protein Kinases, Proteins, Repressor Proteins, RNA, Messenger, Transfection, Protein Biosynthesis, Immunoblotting, Signal Transduction, DNA Primers, Monomeric GTP-Binding Proteins, Tumor Suppressor Proteins, Ribosomal Protein S6 Kinases, 70-kDa, Adaptor Proteins, Signal Transducing, TOR Serine-Threonine Kinases

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