The DOI matches its Crossref record; 20 of the 20 references it cites were found in a registry or an index.
Rheb Activates mTOR by Antagonizing Its Endogenous Inhibitor, FKBP38
Abstract
The mammalian target of rapamycin, mTOR, is a central regulator of cell growth. Its activity is regulated by Rheb, a Ras-like small guanosine triphosphatase (GTPase), in response to growth factor stimulation and nutrient availability. We show that Rheb regulates mTOR through FKBP38, a member of the FK506-binding protein (FKBP) family that is structurally related to FKBP12. FKBP38 binds to mTOR and inhibits its activity in a manner similar to that of the FKBP12-rapamycin complex. Rheb interacts directly with FKBP38 and prevents its association with mTOR in a guanosine 5′-triphosphate (GTP)–dependent manner. Our findings suggest that FKBP38 is an endogenous inhibitor of mTOR, whose inhibitory activity is antagonized by Rheb in response to growth factor stimulation and nutrient availability.
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In the citing paper
“Taken together, our findings provide another example that the underlying principles of molecular glue mechanisms might be rooted in the partial mimicry of naturally occurring PPIs at preexisting sites of high PPI propensity, interactions that are further enhanced by a matching molecular glue1,10,11,50–54.”
From Cereblon induces G3BP2 neosubstrate degradation using molecular surface mimicry (2026) · cites this paper as [50]
In the citing paper
“mTOR is present in two complexes, mTORC1 (associated with ‘raptor’) and mTORC2 (associated with ‘rictor’), accounting for the diversity, specificity and selectivity of rapamycin-mediated inhibition of TOR signalling”
From Mitochondrial and metabolic dysfunction in ageing and age-related diseases (2022) · cites this paper as [32]
In the citing paper
“which was discovered after it was shown that rapamycin is able to inhibit mTORC1 via binding to the protein FKBP12 (REFS31,32).”
From Mitochondrial and metabolic dysfunction in ageing and age-related diseases (2022) · cites this paper as [32]
Citations
Cites
TOR signaling in growth and metabolism
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Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling
Inoki, K., Li, Y., Xu, T., & Guan, K.-L. (2003) · Genes & Development · doi:10.1101/gad.1110003 · Cited by 1,911
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Raptor, a Binding Partner of Target of Rapamycin (TOR), Mediates TOR Action
Hara, K., Maruki, Y., Long, X., Yoshino, K.-I., Oshiro, N., Sujuti, H., Tokunaga, C., Avruch, J., & Yonezawa, K. (2002) · Cell · doi:10.1016/s0092-8674(02)00833-4 · Cited by 1,810
Insulin Activation of Rheb, a Mediator of mTOR/S6K/4E-BP Signaling, Is Inhibited by TSC1 and 2
Garami, A., Zwartkruis, F. J. T., Nobukuni, T., Joaquin, M., Roccio, M., Stocker, H., Kozma, S. C., Hafen, E., Bos, J. L., & Thomas, G. (2003) · Molecular Cell · doi:10.1016/s1097-2765(03)00220-x · Cited by 1,043
Rheb Binds and Regulates the mTOR Kinase
Long, X., Lin, Y., Ortiz-Vega, S., Yonezawa, K., & Avruch, J. (2005) · Current Biology · doi:10.1016/j.cub.2005.02.053 · Cited by 1,005
Rheb is a direct target of the tuberous sclerosis tumour suppressor proteins
Zhang, Y., Gao, X., Saucedo, L. J., Ru, B., Edgar, B. A., & Pan, D. (2003) · Nature Cell Biology · doi:10.1038/ncb999 · Cited by 924
The expanding TOR signaling network
Martin, D. E., & Hall, M. N. (2005) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2005.02.008 · Cited by 496
Rheb fills a GAP between TSC and TOR
Manning, B. (2003) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2003.09.003 · Cited by 483
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Self-citationThe TSC1–TSC2 complex: a molecular switchboard controlling cell growth
Huang, J., & Manning, B. D. (2008) · Biochemical Journal · doi:10.1042/bj20080281 · Cited by 1,237
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Mitochondrial and metabolic dysfunction in ageing and age-related diseases
Amorim, J. A., Coppotelli, G., Rolo, A. P., Palmeira, C. M., Ross, J. M., & Sinclair, D. A. (2022) · Nature Reviews Endocrinology · doi:10.1038/s41574-021-00626-7 · Cited by 990
Metformin, independent of AMPK, inhibits mTORC1 in a rag GTPase-dependent manner
Kalender, A., Selvaraj, A., Kim, S. Y., Gulati, P., Brûlé, S., Viollet, B., Kemp, B. E., Bardeesy, N., Dennis, P., Schlager, J. J., et al. (2010) · Cell Metabolism · doi:10.1016/j.cmet.2010.03.014 · Cited by 889
Metadata
- Authors
- Bai, X., Ma, D., Liu, A., Shen, X., Wang, Q. J., Liu, Y., & Jiang, Y.
- Affiliations
- University of Pittsburgh (US)
- Corresponding author
- Jiang, Yu
- Venue
- Science
- Published
- 2007-11-09
- Volume
- 318
- Issue
- 5852
- Pages
- 977-980
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W1970707895
- Cited by
- 382
- References
- 20
- Citations by year
- 2026: 5 · 2025: 5 · 2024: 16 · 2023: 9 · 2022: 12 · 2021: 16 · 2020: 17 · 2019: 6 · 2018: 8 · 2017: 16 · 2016: 14 · 2015: 23 · 2014: 15 · 2013: 19 · 2012: 26
- FWCI
- 18.66
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (R01CA129821)
- National Institute of General Medical Sciences (R01GM068832, GM068832)
- 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 › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- Rheb, mTOR, FKBP38, FKBP12, FKBP, small GTPases, mTOR inhibition, growth factor signaling, nutrient availability, cell growth regulation
- MeSH terms
- Ras Homolog Enriched in Brain Protein, Mechanistic Target of Rapamycin Complex 1, Amino Acids, Cell Line, Culture Media, Guanosine Triphosphate, Humans, Insulin, Neuropeptides, Phosphorylation, Protein Binding, Protein Kinases, Proteins, Recombinant Proteins, Transcription Factors, Signal Transduction, Protein Structure, Tertiary, Sirolimus, Monomeric GTP-Binding Proteins, Tacrolimus Binding Proteins, Intercellular Signaling Peptides and Proteins, Serum, Multiprotein Complexes, Mutant Proteins, TOR Serine-Threonine Kinases
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