The Rheb family of GTP-binding proteins

Aspuria, Paul‐Joseph; Tamanoi, Fuyuhiko

doi:10.1016/j.cellsig.2004.03.019

Cited by 178 publications

(185 citation statements)

References 52 publications

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“…The tsc1 + and tsc2 + genes analogous to the mammalian TSC genes are present in fission yeast and their gene products form a complex which functions as a downregulator of Rheb GTPase. 8,[27][28][29] Two homologues of mTOR, Tor1 and Tor2, are also present in fission yeast. 8 Tor2 forms a complex with a Raptor homologue, Mip1, as well as with a G b L homologue, Wat1/Pop3.…”

Section: Fission Yeast Is a Model System For The Analysis Of The Tor mentioning

confidence: 99%

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The TSC/Rheb/TOR Signaling Pathway in Fission Yeast and Mammalian Cells: Temperature Sensitive and Constitutive Active Mutants of TOR

Aspuria

Sato²,

Tamanoi³

2007

Cell Cycle

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Section: Fission Yeast Is a Model System For The Analysis Of The Tor mentioning

confidence: 99%

“…4 mTOR kinase is the key enzyme in the signaling pathway and is activated by Rheb GTPase. 2,[6][7][8][9][10][11][12][13][14][15] mTOR exists in two complexes, mTORC1 and mTORC2. In mTORC1, mTOR is complexed with Raptor and G b L and phosphorylates S6K and 4E-BP1.…”

Section: Introductionmentioning

confidence: 99%

The TSC/Rheb/TOR Signaling Pathway in Fission Yeast and Mammalian Cells: Temperature Sensitive and Constitutive Active Mutants of TOR

Aspuria

Sato²,

Tamanoi³

2007

Cell Cycle

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“…Rheb is a Ras family small GTPase, conserved from yeast to mammals (30). Rheb specifically activates TORC1 and enhances S6K phosphorylation in a rapamycin-sensitive manner (31) but does not activate TORC2 (31,32).…”

mentioning

confidence: 99%

Bnip3 Mediates the Hypoxia-induced Inhibition on Mammalian Target of Rapamycin by Interacting with Rheb

Wang²,

Kim

et al. 2007

Journal of Biological Chemistry

238

196

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The mammalian target of rapamycin (mTOR) is a central controller of cell growth, and it regulates translation, cell size, cell viability, and cell morphology. mTOR integrates a wide range of extracellular and intracellular signals, including growth factors, nutrients, energy levels, and stress conditions. Rheb, a Ras-related small GTPase, is a key upstream activator of mTOR. In this study, we found that Bnip3, a hypoxia-inducible Bcl-2 homology 3 domain-containing protein, directly binds Rheb and inhibits the mTOR pathway. Bnip3 decreases Rheb GTP levels in a manner depending on the binding to Rheb and the presence of the N-terminal domain. Both knockdown and overexpression experiments show that Bnip3 plays an important role in mTOR inactivation in response to hypoxia. Moreover, Bnip3 inhibits cell growth in vivo by suppressing the mTOR pathway. These observations demonstrate that Bnip3 mediates the inhibition of the mTOR pathway in response to hypoxia.Target of rapamycin (TOR), 2 is an evolutionarily conserved serine/threonine kinase that plays a central role in cell growth (1-3). TOR regulates many processes, including protein translation, ribosome biogenesis, autophagy, and metabolism. TOR functions to integrate a wide range of extracellular and intracellular signals to produce a concerted cellular response, such as to stimulate cell growth. For example, mammalian target of rapamycin (mTOR) is activated by growth factor and nutrient availability. In contrast, mTOR is inhibited by cellular energy starvation and various stress conditions, including osmotic stress and hypoxia. These observations established a fundamental importance of mTOR in signal integration in regulation of cell growth.Recent studies have demonstrated that TOR exists in two functionally distinct protein complexes, termed TOR complex 1 (TORC1) and TOR complex 2 (TORC2) (3, 4). The two TOR complexes were initially identified in yeast and subsequently were also characterized in Drosophila and mammalian cells. TORC1 contains mTOR, mLST8, PRAS40, and Raptor, whereas TORC2 contains mTOR, mLST8, Rictor, and Sin1 (5-12). TORC1 is responsible for phosphorylation of Thr 389 of S6K1 (ribosomal protein S6 kinase) and 4EBP1 (eukaryote initiation factor 4E-binding protein), two important regulators in protein synthesis (1). In contrast, TORC2 has different substrates and is responsible for phosphorylation of the hydrophobic sites in both AKT and PKC (9, 13). Interestingly, TORC1 but not TORC2 is inhibited by rapamycin (6,8,9). These observations clearly demonstrate that the two TOR complexes have different physiological functions in vivo.Much progress has been made regarding the mechanisms of TORC1 regulation. Tuberous sclerosis complex (TSC) is a genetic disease characterized by benign hamartomas in various tissues (14). Mutations in either the TSC1 or TSC2 tumor suppressor gene are responsible for TSC development. TORC1 is highly activated in TSC tumors or cells with mutation of either TSC1 or TSC2. Both genetic and biochemical data have demonstrated th...

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“…Akt links to the mTOR signaling via the tuberous sclerosis complex protein (TSC complex) and Rheb GTPase. The TSC complex consists of TSC1 (hamartin), TSC2 (tuberin) and TBC1D7 (Dibble et al, 2012) and inhibits the activity of the small GTPase Rheb by acting as a GTPase activating protein (GAP) towards Rheb (Gao and Pan, 2001;Potter et al, 2001;Tapon et al, 2001;Inoki et al, 2002;Inoki et al, 2003;Manning and Cantley, 2003;Tee et al, 2003;Saucedo et al, 2003;Zhang et al, 2003;Aspuria and Tamanoi, 2004;Hay and Sonenberg, 2004;Li et al, 2004a,b). In vitro, Akt phosphorylates TSC2 at conserved consensus phosphorylation sequences and down-regulates its GAP activity (Inoki et al, 2002(Inoki et al, , 2003.…”

Section: Rheb Signaling Pathwaymentioning

confidence: 99%

“…Ras homolog enriched in brain (Rheb), is a member of the Ras family of small GTPbinding proteins containing Rheb1 (called from here on Rheb) and Rheb2 (Yamagata et al, 1994;Gromov et al, 1995;Tee et al, 2005;Campbell et al, 2009). Rheb and Rheb2 proteins share 51% amino acid identity (Aspuria and Tamanoi, 2004).…”

Section: Introductionmentioning

confidence: 99%

Rheb in neuronal degeneration, regeneration, and connectivity

Potheraveedu

Schöpel

Stoll

et al. 2017

Biological Chemistry

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Abstract:The small GTPase Rheb was originally detected as an immediate early response protein whose expression was induced by NMDA-dependent synaptic activity in the brain. Rheb's activity is highly regulated by its GTPase activating protein (GAP), the tuberous sclerosis complex protein, which stimulates the conversion from the active, GTP-loaded into the inactive, GDP-loaded conformation. Rheb has been established as an evolutionarily conserved molecular switch protein regulating cellular growth, cell volume, cell cycle, autophagy, and amino acid uptake. The subcellular localization of Rheb and its interacting proteins critically regulate its activity and function. In stem cells, constitutive activation of Rheb enhances differentiation at the expense of self-renewal partially explaining the adverse effects of deregulated Rheb in the mammalian brain. In the context of various cellular stress conditions such as oxidative stress, ER-stress, death factor signaling, and cellular aging, Rheb activation surprisingly enhances rather than prevents cellular degeneration. This review addresses cell type-and cell state-specific function(s) of Rheb and mainly focuses on neurons and their surrounding glial cells. Mechanisms will be discussed in the context of therapy that interferes with Rheb's activity using the antibiotic rapamycin or low molecular weight compounds.

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The Rheb family of GTP-binding proteins

Cited by 178 publications

References 52 publications

The TSC/Rheb/TOR Signaling Pathway in Fission Yeast and Mammalian Cells: Temperature Sensitive and Constitutive Active Mutants of TOR

The TSC/Rheb/TOR Signaling Pathway in Fission Yeast and Mammalian Cells: Temperature Sensitive and Constitutive Active Mutants of TOR

Bnip3 Mediates the Hypoxia-induced Inhibition on Mammalian Target of Rapamycin by Interacting with Rheb

Rheb in neuronal degeneration, regeneration, and connectivity

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