The DOI matches its Crossref record; 131 of the 133 references it cites were found in a registry or an index.
The TSC1–TSC2 complex: a molecular switchboard controlling cell growth
Open accessAbstract
TSC1 and TSC2 are the tumour-suppressor genes mutated in the tumour syndrome TSC (tuberous sclerosis complex). Their gene products form a complex that has become the focus of many signal transduction researchers. The TSC1–TSC2 (hamartin–tuberin) complex, through its GAP (GTPase-activating protein) activity towards the small G-protein Rheb (Ras homologue enriched in brain), is a critical negative regulator of mTORC1 (mammalian target of rapamycin complex 1). As mTORC1 activity controls anabolic processes to promote cell growth, it is exquisitely sensitive to alterations in cell growth conditions. Through numerous phosphorylation events, the TSC1–TSC2 complex has emerged as the sensor and integrator of these growth conditions, relaying signals from diverse cellular pathways to properly modulate mTORC1 activity. In the present review we focus on the molecular details of TSC1–TSC2 complex regulation and function as it relates to the control of Rheb and mTORC1.
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“Whereas it appears that specific metabolites signal to mTORC1 through the Rag GTPase axis, stress conditions such as hypoxia, DNA damage stress, ER stress, and growth factor and survival signaling, are filtered through to the Rheb GTPase through TSCC by post-translational modification (Kwiatkowski, 2003; Huang and Manning, 2008; Tomasoni and Mondino, 2011; Demetriades et al., 2016).”
From Signal integration in the (m)TORC1 growth pathway (2018) · cites this paper as Huang and Manning, 2008
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1 retracted
Dan, H. C., Sun, M., Yang, L., Feldman, R. I., Sui, X.-M., Ou, C. C., Nellist, M. D., Yeung, R. S. W., Halley, D. J. J., Nicosia, S. V., et al. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m205838200 · Cited by 370
RetractedPhosphorylation and regulation of Akt/PKB by the rictor-mTOR complex
Sarbassov, D. D., Guertin, D. A., Ali, S. M., & Sabatini, D. M. (2005) · Science · doi:10.1126/science.1106148 · Cited by 6,216
AKT/PKB signaling: navigating downstream
Manning, B. D., & Cantley, L. C. (2007) · Cell · doi:10.1016/j.cell.2007.06.009 · Cited by 6,115
Self-citationTOR signaling in growth and metabolism
Wullschleger, S., Loewith, R., & Hall, M. N. (2006) · Cell · doi:10.1016/j.cell.2006.01.016 · Cited by 5,787
Upstream and downstream of mTOR
Hay, N., & Sonenberg, N. (2004) · Genes & Development · doi:10.1101/gad.1212704 · Cited by 4,181
TSC2 Mediates Cellular Energy Response to Control Cell Growth and Survival
Inoki, K., Zhu, T., & Guan, K.-L. (2003) · Cell · doi:10.1016/s0092-8674(03)00929-2 · Cited by 3,914
TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling
Inoki, K., Li, Y., Zhu, T., Wu, J., & Guan, K.-L. (2002) · Nature Cell Biology · doi:10.1038/ncb839 · Cited by 3,083
Defining the role of mTOR in cancer
Guertin, D. A., & Sabatini, D. M. (2007) · Cancer Cell · doi:10.1016/j.ccr.2007.05.008 · Cited by 2,833
Sarbassov, D. D., Ali, S. M., Kim, D.-H., Guertin, D. A., Latek, R. R., Erdjument-Bromage, H., Tempst, P., & Sabatini, D. M. (2004) · Current Biology · doi:10.1016/j.cub.2004.06.054 · Cited by 2,665
Prolonged Rapamycin Treatment Inhibits mTORC2 Assembly and Akt/PKB
Sarbassov, D. D., Ali, S. M., Sengupta, S., Sheen, J.-H., Hsu, P. P., Bagley, A. F., Markhard, A. L., & Sabatini, D. M. (2006) · Molecular Cell · doi:10.1016/j.molcel.2006.03.029 · Cited by 2,365
Cited by
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mTOR Signaling in Growth, Metabolism, and Disease
Saxton, R. A., & Sabatini, D. M. (2017) · Cell · doi:10.1016/j.cell.2017.02.004 · Cited by 7,555
Targeting PI3K signalling in cancer: opportunities, challenges and limitations
Engelman, J. A. (2009) · Nature Reviews Cancer · doi:10.1038/nrc2664 · Cited by 2,445
Activation of a metabolic gene regulatory network downstream of mTOR complex 1
Düvel, K., Yecies, J. L., Menon, S., Raman, P., Lipovsky, A. I., Souza, A. L., Triantafellow, E., Ma, Q., Gorski, R., Cleaver, S., et al. (2010) · Molecular Cell · doi:10.1016/j.molcel.2010.06.022 · Cited by 2,020
“In its GTP-bound state, the Ras-related GTPase Rheb is a potent and essential activator of mTORC1 (Avruch et al., 2006; Huang and Manning, 2008).”
InfluentialSelf-citationEpidermal Growth Factor Receptor Cell Proliferation Signaling Pathways
Wee, P., & Wang, Z. (2017) · Cancers · doi:10.3390/cancers9050052 · Cited by 2,027
“TSC1 and TSC2 suppress the activity of RHEB (Ras-like GTPase), which are needed to activate mTORC1 [287].”
BackgroundThe LKB1-AMPK pathway: metabolism and growth control in tumour suppression
Shackelford, D. B., & Shaw, R. J. (2009) · Nature Reviews Cancer · doi:10.1038/nrc2676 · Cited by 1,943
Metadata
- Authors
- Huang, J., & Manning, B. D.
- Affiliations
- Harvard University (US)
- Venue
- Biochemical Journal
- Publisher
- Portland Press Ltd.
- Published
- 2008-05-14
- Volume
- 412
- Issue
- 2
- Pages
- 179-190
- ISSN
- 0264-6021 (ISSN-L)
- 1470-8728
- PMC
- PMC2735030
- OpenAlex
- W1993431258
- Cited by
- 1,237
- References
- 133
- Citations by year
- 2026: 26 · 2025: 58 · 2024: 53 · 2023: 62 · 2022: 77 · 2021: 83 · 2020: 77 · 2019: 69 · 2018: 74 · 2017: 79 · 2016: 68 · 2015: 82 · 2014: 70 · 2013: 72 · 2012: 73
- FWCI
- 5.48
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Biochemical Journal (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (R01CA122617, P01CA120964)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Health Sciences › Medicine › Genetics (clinical) › Tuberous Sclerosis Complex Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hippo pathway signaling and YAP/TAZ
- Keywords
- TSC1/TSC2 complex, hamartin, tuberin, tuberous sclerosis complex, Rheb, GTPase-activating protein, mTORC1, cell growth regulation, signal transduction, phosphorylation, anabolic processes, tumor suppressor
- MeSH terms
- Ras Homolog Enriched in Brain Protein, Tuberous Sclerosis Complex 1 Protein, Tuberous Sclerosis Complex 2 Protein, Amino Acid Sequence, Animals, Cell Cycle, Humans, Insulin, Insulin-Like Growth Factor I, Molecular Sequence Data, Neuropeptides, Protein Kinases, Transcription Factors, Signal Transduction, Genes, Tumor Suppressor, Sequence Alignment, Ribosomal Protein S6 Kinases, Monomeric GTP-Binding Proteins, Tumor Suppressor Proteins, Intercellular Signaling Peptides and Proteins, Cell Growth Processes, TOR Serine-Threonine Kinases
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