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Hyperactivation of mammalian target of rapamycin (mTOR) signaling by a gain-of-function mutant of the Rheb GTPase

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Date
2006-07-21
ICR Author
Lamb, Richard
Procter, Julia
Author
Yan, L
Findlay, GM
Jones, R
Procter, J
Cao, Y
Lamb, RF
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Type
Journal Article
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Abstract
Gain-of-function mutants of Ras and Rho family small GTPases have proven to be important tools in analyzing signaling downstream of these small GTPases. The Ras- related GTPase Rheb has emerged as a key player downstream of TSC1-2 in activating signaling to mammalian target of rapamycin ( mTOR) effectors of cell growth such as S6K and 4E-BP1. The TSC1-2 tumor suppressor complex has been shown to act as a RhebGAP, converting Rheb from a GTP-bound to a GDP-bound form. Here we report the identification of a mutant Rheb (S16HRheb) that exhibits gain-of-function properties. At endogenous levels of expression S16HRheb exhibits increased GTP loading in vivo and is resistant to TSC1-2 GAP in vitro. Compared with wild-type Rheb, S16HRheb is more active at promoting the phosphorylation of the mTOR effectors S6K1 and 4E-BP1. Thus S16HRheb will help to identify proximal signaling events downstream of Rheb and allow potential Rheb-independent functions downstream of TSC1-2 to be investigated.
URI
https://repository.icr.ac.uk/handle/internal/2517
DOI
https://doi.org/10.1074/jbc.C600028200
Collections
  • Breast Cancer Research
Research team
Target Validation and DNA Damage Response
Language
eng
License start date
2006-07-21
Citation
JOURNAL OF BIOLOGICAL CHEMISTRY, 2006, 281 pp. 19793 - 19797
Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC

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