Recent progress in the study of the Rheb family GTPases

Heard, Jeffrey J.; Fong, Valerie; Bathaie, S. Zahra; Tamanoi, Fuyuhiko

doi:10.1016/j.cellsig.2014.05.011

Cited by 70 publications

(76 citation statements)

References 83 publications

(116 reference statements)

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“…The small GTPase Rheb is a major regulator of the mTORC1 kinase complex that controls protein synthesis and cell growth (Heard et al, 2014). The top hit with the GTP-bound form of Rheb is the mTORC1 subunit Raptor that is located next to the Rheb binding site on mTor ( Figure 8D).…”

Section: Rhebmentioning

confidence: 99%

In vivo identification of GTPase interactors by mitochondrial relocalization and proximity biotinylation

Gillingham

Bertram

Begum

et al. 2019

Preprint

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The GTPases of the Ras superfamily regulate cell growth, membrane traffic and the cytoskeleton, and a wide range of diseases are caused by mutations in particular members. They function as switchable landmarks with the active GTP-bound form recruiting to the membrane a specific set of effector proteins. The GTPases are precisely controlled by regulators that promote acquisition of GTP (GEFs) or its hydrolysis to GDP (GAPs). We report here MitoID, a method for identifying effectors and regulators by performing in vivo proximity biotinylation with mitochondriallylocalized forms of the GTPases. Applying this to 11 human Rab GTPases identified many known effectors and GAPs, as well as putative novel effectors, with examples of the latter validated for Rab2, Rab5 and Rab9. MitoID can also efficiently identify effectors and GAPs of Rho and Ras family GTPases such as Cdc42, RhoA, Rheb, and N-Ras, and can identify GEFs by use of GDP-bound forms.

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Section: Rhebmentioning

confidence: 99%

In vivo identification of GTPase interactors by mitochondrial relocalization and proximity biotinylation

Gillingham

Bertram

Begum

et al. 2019

Preprint

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“…The average 15 [1,3] and the secondary structure elements are indicated at the top. Filled gray arrows represent b-sheet conformation and gray spirals helical conformation.…”

Section: Resultsmentioning

confidence: 99%

NMR analysis of the backbone dynamics of the small GTPase Rheb and its interaction with the regulatory protein FKBP38

2017

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Ras homolog enriched in brain (Rheb) is a small GTPase that regulates mammalian/mechanistic target of rapamycin complex 1 (mTORC1) and, thereby, cell growth and metabolism. Here we show that cycling between the inactive GDP‐ and the active GTP‐bound state modulates the backbone dynamics of a C‐terminal truncated form, RhebΔCT, which is suggested to influence its interactions. We further investigated the interactions between RhebΔCT and the proposed Rheb‐binding domain of the regulatory protein FKBP38. The observed weak interactions with the GTP‐analogue‐ (GppNHp‐) but not the GDP‐bound state, appear to accelerate the GDP to GTP exchange, but only very weakly compared to a genuine GEF. Thus, FKBP38 is most likely not a GEF but a Rheb effector that may function in membrane targeting of Rheb.

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“…Previous studies have demonstrated that over-expression of Rheb in mammalian cells directly leads to mTOR activation [38]. As an upstream regulator of mTOR, Rheb is regulated by kinases, such as Akt, AMP-activated protein kinase (AMPK), and glycogen synthase kinase-3, which control Rheb through modulating the heterodimer consisting of tuberous sclerosis 1/tuberous sclerosis 2 complex (TSC1/TSC2) [39]. The mTOR signaling integrates and transmits signals to regulate cell growth, metabolism, ribosomal biogenesis, as well as autophagy [40, 41].…”

Section: Discussionmentioning

confidence: 99%

Ox-LDL-Induced MicroRNA-155 Promotes Autophagy in Human Endothelial Cells via Repressing the Rheb/ mTOR Pathway

Lv¹,

Yang²,

Guo³

et al. 2017

Cell Physiol Biochem

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Background/Aims: Autophagy, an evolutionary conserved biological process, is activated in cells to cope with various types of stress. MicroRNAs control several activities related to autophagy. However, the role of autophagy-related microRNAs during atherosclerosis is far from known. MicroRNA-155 was identified to be a crucial regulator of atherosclerosis. The objectives of the study were to analyze the effect of microRNA-155 on autophagic signaling and explore its mechanism in human endothelial cells under ox-LDL stress. Methods: The study included human endothelial cells surrogate EA.hy926 lines (EA.hy926 cells). The expression of microRNA-155 was analyzed by quantitative reverse transcription polymerase chain reaction (qRT-PCR). The effect of microRNA-155 on endothelial autophagy was observed along with the expression levels of Rheb, LC3B, Beclin1, and P62/SQSTM1 by western blotting (WB) and immunofluorescence through microRNA-155 overexpression or inhibition. Bioinformatics analysis and Luciferase reporter assay were used to explore the target gene of microRNA-155. Cell viability and apoptosis were examined by 3-[4,5-dimethylthiazol-2-yl]-5- [3-carboxy-methoxyphenyl]-2-[4-sulfophenyl]-2H-tetrazolium inner salt (MTS) assay and TdT-mediated dUTP Nick-End Labeling (TUNEL) apoptosis assay. Results: MicroRNA-155 expression was significantly increased under ox-LDL stress. MicroRNA-155 increased autophagic activity, while inhibition of it alleviated ox-LDL-induced autophagy in EA.hy926 endothelial cells. In addition, dual-luciferase reporter assays showed that microRNA-155 suppressed Rheb transcription. MicroRNA-155 increased autophagic activity in EA.hy926 cells via inhibition of Rheb-mediated mTOR/P70S6kinase/4EBP signaling pathway. Furthermore, we demonstrated that microRNA-155 could regulate not only autophagy but also apoptosis in EA.hy926 cells. Conclusions: MicroRNA-155 works as a regulator of endothelial function under ox-LDL stress, making it a potential candidate for the novel therapeutic strategies against atherosclerotic diseases.

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Recent progress in the study of the Rheb family GTPases

Cited by 70 publications

References 83 publications

In vivo identification of GTPase interactors by mitochondrial relocalization and proximity biotinylation

In vivo identification of GTPase interactors by mitochondrial relocalization and proximity biotinylation

NMR analysis of the backbone dynamics of the small GTPase Rheb and its interaction with the regulatory protein FKBP38

Ox-LDL-Induced MicroRNA-155 Promotes Autophagy in Human Endothelial Cells via Repressing the Rheb/ mTOR Pathway

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