ArticleThe Journal of biological chemistry2010
Ras homolog enriched in brain (Rheb) enhances apoptotic signaling.
Article in The Journal of biological chemistry, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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Who cites it
31 citing papers in PubMed, 52 citations in OpenAlex.
- Intracerebellar upregulation of Rheb(S16H) ameliorates motor dysfunction in mice with SCA2.Acta pharmacologica Sinica · 2025Article
- Neuronal Protection by Ha-RAS-GTPase Signaling through Selective Downregulation of Plasmalemmal Voltage-Dependent Anion Channel-1.International journal of molecular sciences · 2024Article
- Unraveling the Role of Ras Homolog Enriched in Brain (Rheb1 and Rheb2): Bridging Neuronal Dynamics and Cancer Pathogenesis through Mechanistic Target of Rapamycin Signaling.International journal of molecular sciences · 2024Review
- Therapeutic Potential of AAV1-Rheb(S16H) Transduction against Neurodegenerative Diseases.International journal of molecular sciences · 2021Review
- Article
- Proteomic Analysis of Red Ginseng on Prolonging the Life Span of MaleFrontiers in pharmacology · 2021Article
- Rheb1 protects against cisplatin-induced tubular cell death and acute kidney injury via maintaining mitochondrial homeostasis.Cell death & disease · 2020Article
- Therapeutic Potential of AAV1-Rheb(S16H) Transduction Against Alzheimer's Disease.Journal of clinical medicine · 2019Article
- Single-cell RNA-seq of esophageal squamous cell carcinoma cell line with fractionated irradiation reveals radioresistant gene expression patterns.BMC genomics · 2019Article
- AKT3 Gene Transfer Promotes Anabolic Reprogramming and Photoreceptor Neuroprotection in a Pre-clinical Model of Retinitis Pigmentosa.Molecular therapy : the journal of the American Society of Gene Therapy · 2019Article
- Perspectives of RAS and RHEB GTPase Signaling Pathways in Regenerating Brain Neurons.International journal of molecular sciences · 2018Review
- A small molecule inhibitor of Rheb selectively targets mTORC1 signaling.Nature communications · 2018Article
- Human melanoma inhibitory protein binds to the FN12-14 Hep II domain of fibronectin.Biointerphases · 2017Article
- Rheb may complex with RASSF1A to coordinate Hippo and TOR signaling.Oncotarget · 2016Article
- Small Molecules Antagonise the MIA-Fibronectin Interaction in Malignant Melanoma.Scientific reports · 2016Article
- Analysis of PI3K pathway components in human cancers.Oncology letters · 2016Article
- Targeting the PI3K/Akt signaling pathway in gastric carcinoma: A reality for personalized medicine?World journal of gastroenterology · 2015Review
- The MAPK and PI3K pathways mediate CNTF-induced neuronal survival and process outgrowth in hypothalamic organotypic cultures.Journal of cell communication and signaling · 2015Article
- Roles of Rheb(S16H) in substantia nigra pars compacta dopaminergic neuronsBiomedical reports · 2015Article
- Activation of CNTF/CNTFRα signaling pathway by hRheb(S16H) transduction of dopaminergic neurons in vivo.PloS one · 2015Article
Corrections and comments
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Authors and funding
12 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Rheb is a homolog of Ras GTPase that regulates cell growth, proliferation, and regeneration via mammalian target of rapamycin (mTOR). Because of the well established potential of activated Ras to promote survival, we sought to investigate the ability of Rheb signaling to phenocopy Ras. We found that overexpression of lipid-anchored Rheb enhanced the apoptotic effects induced by UV light, TNFα, or tunicamycin in an mTOR complex 1 (mTORC1)-dependent manner. Knocking down endogenous Rheb or applying rapamycin led to partial protection, identifying Rheb as a mediator of cell death. Ras and c-Raf kinase opposed the apoptotic effects induced by UV light or TNFα but did not prevent Rheb-mediated apoptosis. To gain structural insight into the signaling mechanisms, we determined the structure of Rheb-GDP by NMR. The complex adopts the typical canonical fold of RasGTPases and displays the characteristic GDP-dependent picosecond to nanosecond backbone dynamics of the switch I and switch II regions. NMR revealed Ras effector-like binding of activated Rheb to the c-Raf-Ras-binding domain (RBD), but the affinity was 1000-fold lower than the Ras/RBD interaction, suggesting a lack of functional interaction. shRNA-mediated knockdown of apoptosis signal-regulating kinase 1 (ASK-1) strongly reduced UV or TNFα-induced apoptosis and suppressed enhancement by Rheb overexpression. In conclusion, Rheb-mTOR activation not only promotes normal cell growth but also enhances apoptosis in response to diverse toxic stimuli via an ASK-1-mediated mechanism. Pharmacological regulation of the Rheb/mTORC1 pathway using rapamycin should take the presence of cellular stress into consideration, as this may have clinical implications.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.