ArticleMolecular biology of the cell2019
Weak membrane interactions allow Rheb to activate mTORC1 signaling without major lysosome enrichment.
Article in Molecular biology of the cell, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 40 papers.
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Who cites it
40 citing papers in PubMed, 61 citations in OpenAlex.
- Farnesyl Transferase Inhibitor KO-2806 (Darlifarnib) Enhances the Antitumor Activity of Tyrosine Kinase Inhibitors in RCC.Molecular cancer therapeutics · 2026Article
- Genetically targeted mTORC1 inhibitor reveals transcriptional control by nuclear mTORC1.Nature chemical biology · 2026Article
- Rheb membrane orientation dynamics and functional consequences elucidated by molecular simulations, single-molecule-FRET and signaling assays.bioRxiv : the preprint server for biology · 2026Article
- mTOR signaling networks: mechanistic insights and translational frontiers in disease therapeutics.Signal transduction and targeted therapy · 2025Review
- Prefrontal oxytocin receptor positive cells mediate stress-induced anxiety in tuberous sclerosis complex.Communications biology · 2025Article
- Article
- The deubiquitinase USP45 inhibits autophagy through actin regulation by Coronin 1B.The Journal of cell biology · 2025Article
- Lysosomes as Dynamic Regulators of Metabolic Signaling and Organ Physiology in Aging: From Mechanism to Therapy.Aging and disease · 2025Review
- Calmodulin enhances mTORC1 signaling by preventing TSC2-Rheb binding.The Journal of biological chemistry · 2025Article
- mTORC1, the maestro of cell metabolism and growth.Genes & development · 2025Review
- Crosstalk between dysregulated amino acid sensing and glucose and lipid metabolism in colorectal cancer.Frontiers in oncology · 2025Review
- Structural basis for growth factor and nutrient signal integration on the lysosomal membrane by mTORC1.bioRxiv : the preprint server for biology · 2024Article
- Spatial and functional separation of mTORC1 signalling in response to different amino acid sources.Nature cell biology · 2024Article
- Rag-Ragulator is the central organizer of the physical architecture of the mTORC1 nutrient-sensing pathway.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Intrinsically Disordered Membrane Anchors of Rheb, RhoA, and DiRas3 Small GTPases: Molecular Dynamics, Membrane Organization, and Interactions.The journal of physical chemistry. B · 2024Article
- Phosphorylated S6K1 and 4E-BP1 play different roles in constitutively active Rheb-mediated retinal ganglion cell survival and axon regeneration after optic nerve injury.Neural regeneration research · 2023Article
- Hierarchical inhibition of mTORC1 by glucose starvation-triggered AXIN lysosomal translocation and by AMPK.Life metabolism · 2023Article
- The role of lysosomes in metabolic and autoimmune diseases.Nature reviews. Nephrology · 2023Review
- Arf5-mediated regulation of mTORC1 at the plasma membrane.Molecular biology of the cell · 2023Article
- GOLPH3 protein controls organ growth by interacting with TOR signaling proteins in Drosophila.Cell death & disease · 2022Article
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
Stable localization of the Rheb GTPase to lysosomes is thought to be required for activation of mTOR complex 1 (mTORC1) signaling. However, the lysosome targeting mechanisms for Rheb remain unclear. We therefore investigated the relationship between Rheb subcellular localization and mTORC1 activation. Surprisingly, we found that Rheb was undetectable at lysosomes. Nonetheless, functional assays in knockout human cells revealed that farnesylation of the C-terminal CaaX motif on Rheb was essential for Rheb-dependent mTORC1 activation. Although farnesylated Rheb exhibited partial endoplasmic reticulum (ER) localization, constitutively targeting Rheb to ER membranes did not support mTORC1 activation. Further systematic analysis of Rheb lipidation revealed that weak, nonselective, membrane interactions support Rheb-dependent mTORC1 activation without the need for a specific lysosome targeting motif. Collectively, these results argue against stable interactions of Rheb with lysosomes and instead that transient membrane interactions optimally allow Rheb to activate mTORC1 signaling.
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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 Socratic graph.