MCRS1 Binds and Couples Rheb to Amino Acid-Dependent mTORC1 Activation
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Ras homolog enriched in brain (Rheb) is critical for mechanistic target of rapamycin complex 1 (mTORC1) activation in response to growth factors and amino acids (AAs). Whereas growth factors inhibit the tuberous sclerosis complex (TSC1-TSC2), a negative Rheb regulator, the role of AAs in Rheb activation remains unknown. Here, we identify microspherule protein 1 (MCRS1) as the essential link between Rheb and mTORC1 activation. MCRS1, in an AA-dependent manner, maintains Rheb at lysosome surfaces, connecting Rheb to mTORC1. MCRS1 suppression in human cancer cells using small interference RNA or mouse embryonic fibroblasts using an inducible-Cre/Lox system reduces mTORC1 activity. MCRS1 depletion promotes Rheb/TSC2 interaction, rendering Rheb inactive and delocalizing it from lysosomes to recycling endocytic vesicles, leading to mTORC1 inactivation. These findings have important implications for signaling mechanisms in various pathologies, including diabetes mellitus and cancer.
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More recent evidence suggests that microspherule protein 1 (MCRS1) retains Rheb on the lysosome surface in the presence of amino acids, thus coordinating the localization of functional Rheb with the Rag signaling axis.
“More recent evidence suggests that microspherule protein 1 (MCRS1) retains Rheb on the lysosome surface in the presence of amino acids, thus coordinating the localization of functional Rheb with the Rag signaling axis (Fawal et al., 2015).”
From Signal integration in the (m)TORC1 growth pathway (2018) · cites this paper as Fawal et al., 2015
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- Authors
- Fawal, M.-A., Brandt, M., & Djouder, N.
- Affiliations
- Spanish National Cancer Research Centre (ES)
- Corresponding author
- Djouder, Nabil
- Venue
- Developmental Cell
- Publisher
- Elsevier BV
- Published
- 2015-04
- Volume
- 33
- Issue
- 1
- Pages
- 67-81
- ISSN
- 1534-5807 (ISSN-L)
- OpenAlex
- W2093359582
- Cited by
- 70
- References
- 63
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 3 · 2023: 3 · 2022: 6 · 2021: 8 · 2020: 8 · 2019: 10 · 2018: 6 · 2017: 7 · 2016: 9 · 2015: 5
- FWCI
- 3.90
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Developmental Cell (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- MCRS1, Rheb, mTORC1 activation, amino acid signaling, lysosomes, TSC2, tuberous sclerosis complex, cancer, diabetes mellitus
- MeSH terms
- Ras Homolog Enriched in Brain Protein, Mechanistic Target of Rapamycin Complex 1, Tuberous Sclerosis Complex 2 Protein, Adenosine Triphosphate, Amino Acids, Animals, Cells, Cultured, Endocytosis, Fibroblasts, Fluorescent Antibody Technique, Humans, Immunoenzyme Techniques, Lysosomes, Neuropeptides, Nuclear Proteins, Mass Spectrometry, Blotting, Western, Colorectal Neoplasms, RNA-Binding Proteins, Mice, Knockout, Integrases, Monomeric GTP-Binding Proteins, Tumor Suppressor Proteins, RNA, Small Interfering, Intercellular Signaling Peptides and Proteins, Multiprotein Complexes, Immunoprecipitation, Mice, TOR Serine-Threonine Kinases
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