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The TSC1–TSC2 complex: a molecular switchboard controlling cell growth
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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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“majority of published experiments, phosphorylation of these sites does not affect the association between TSC1 and TSC2 (reviewed in [16].”
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“On the other hand, Rheb is controlled by numerous stimuli affecting mTORC1, including growth factors, hormones and cytokines, cellular energy levels, and stress (Huang and Manning, 2008; Laplante and Sabatini, 2012).”
Self-citationMorrison, D. K. (2008) · Trends in Cell Biology · doi:10.1016/j.tcb.2008.10.003 · Cited by 609
“Also functioning upstream of TORC1 is the tuberous sclerosis complex TSC1–TSC2, which inhibits TORC1 signaling as a result of the GTPase-activating protein (GAP) activity that is intrinsic to TSC2 and that inactivates Rheb [19].”
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“TSC, another example of a metabolic signal integrator, receives inputs from Akt [44], AMPK [45], GSK3 [46], ERK (extracellular signalregulated kinase) [47] and RSK (ribosomal protein S6 kinase) [48] to carefully control the activity of the mammalian target of rapamycin complex 1 (mTORC1) in response to growth factors…”
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“…is activated by direct interaction with the GTP-bound form of Rheb (Sancak et al., 2008, 2010), which is regulated by the TSC complex [TSC1, TSC2, and Tre2Bub2-Cdc16-1 domain family member 7 (TBC1D7) Dibble and Manning, 2013], a GAP of Rheb (Huang and Manning, 2008; Saxton and Sabatini, 2017).”
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Lymphatic Malformations: Genetics, Mechanisms and Therapeutic Strategies
Mäkinen, T., Boon, L. M., Vikkula, M., & Alitalo, K. K. (2021) · Circulation Research · doi:10.1161/circresaha.121.318142 · Cited by 237
Amino Acid Signaling in TOR Activation
Kim, J., & Guan, K. (2011) · Annual Review of Biochemistry · doi:10.1146/annurev-biochem-062209-094414 · Cited by 239
The mTORC1/4E-BP1 axis represents a critical signaling node during fibrogenesis
Woodcock, H. V., Eley, J. D., Guillotin, D., Platé, M., Nanthakumar, C. B., Martufi, M., Peace, S., Joberty, G., Poeckel, D., Good, R. B., et al. (2019) · Nature Communications · doi:10.1038/s41467-018-07858-8 · Cited by 224
AKT and ERK dual inhibitors: The way forward?
Cao, Z., Liao, Q., Su, M., Huang, K., Jin, J., & Cao, D. (2019) · Cancer Letters · doi:10.1016/j.canlet.2019.05.025 · Cited by 244
PEComa: morphology and genetics of a complex tumor family
Thway, K., & Fisher, C. (2015) · Annals of Diagnostic Pathology · doi:10.1016/j.anndiagpath.2015.06.003 · Cited by 234
“mammalian LST8/G-protein β-subunit like protein (mLST8/GβL) [170], and the recently identified partners PRAS40 and DEPTOR [171].”
BackgroundGlutamate excitotoxicity: Potential therapeutic target for ischemic stroke
Shen, Z., Xiang, M., Chen, C., Ding, F., Wang, Y., Shang, C., Xin, L., Zhang, Y., & Cui, X. (2022) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2022.113125 · Cited by 241
Gallinetti, J., Harputlugil, E., & Mitchell, J. R. (2012) · Biochemical Journal · doi:10.1042/bj20121098 · Cited by 234
Wang, S., Li, H., Yuan, M., Fan, H., & Cai, Z. (2022) · Frontiers in Physiology · doi:10.3389/fphys.2022.1015500 · Cited by 236
Soliman, G. A., Acosta-Jaquez, H. A., Dunlop, E. A., Üstünel, B. E., Maj, N. E., Tee, A. R., & Fingar, D. C. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.096222 · Cited by 239
Chakrabarti, P., English, T., Shi, J., Smas, C. M., & Kandror, K. V. (2010) · Diabetes · doi:10.2337/db09-1602 · Cited by 242
“On the contrary, lack of nutrients/energy rapidly suppresses mTORC1 and mTORC1-controlled anabolic processes and activates autophagy (2,3).”
BackgroundBreuleux, M., Klopfenstein, M., Stephan, C., Doughty, C. A., Barys, L., Maira, S.-M., Kwiatkowski, D. J., & Lane, H. A. (2009) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-08-0668 · Cited by 233
mTOR-Mediated Regulation of Immune Responses in Cancer and Tumor Microenvironment
Mafi, S., Mansoori, B., Taeb, S., Sadeghi, H., Abbasi, R., Cho, W. C. S., & Rostamzadeh, D. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2021.774103 · Cited by 238
“Thus, suppression of TSC allows the GTP-bound Rheb to bind and activate mTORC1 (Figure 1) (19, 20).”
BackgroundAMPK directly activates mTORC2 to promote cell survival during acute energetic stress
Kazyken, D., Magnuson, B., Bodur, Ç., Acosta-Jaquez, H. A., Zhang, D., Tong, X., Barnes, T. M., Steinl, G. K., Patterson, N., Altheim, C. H., et al. (2019) · Science Signaling · doi:10.1126/scisignal.aav3249 · Cited by 226
Roberts, M. D., McCarthy, J. J., Hornberger, T. A., Phillips, S. M., Mackey, A. L., Nader, G. A., Boppart, M. D., Kavazis, A. N., Reidy, P. T., Ogasawara, R., et al. (2023) · Physiological Reviews · doi:10.1152/physrev.00039.2022 · Cited by 214
“Malignant” Perivascular Epithelioid Cell Neoplasm: Risk Stratification and Treatment Strategies
Bleeker, J. S., Quevedo, J. F., & Folpe, A. L. (2012) · Sarcoma · doi:10.1155/2012/541626 · Cited by 216
“Complete loss of either TSC1 or TSC2 due to a second hit to either TSC locus leads to a dysfunctional TSC1TSC2 complex and unchecked cell proliferation through unregulated mammalian target of rapamycin complex 1 (mTORC1) activation [75] and impaired mammalian target of rapamycin complex 2 (mTORC2) activation [76].”
Bakula, D., Müller, A. J., Zuleger, T., Takács, Z., Franz‐Wachtel, M., Thost, A.-K., Brigger, D., Tschan, M. P., Frickey, T., Robenek, H., et al. (2017) · Nature Communications · doi:10.1038/ncomms15637 · Cited by 216
Loss of Tsc1 In Vivo Impairs Hippocampal mGluR-LTD and Increases Excitatory Synaptic Function
Bateup, H. S., Takasaki, K. T., Saulnier, J. L., Denefrio, C. L., & Sabatini, B. L. (2011) · Journal of Neuroscience · doi:10.1523/jneurosci.1617-11.2011 · Cited by 204
“This finding is consistent with the somatic hypertrophy observed in many cell types due to loss of Tsc1/2 and may reflect overactivation of mTOR-regulated cell growth processes (Hay and Sonenberg, 2004; Tavazoie et al., 2005; Meikle et al., 2007; Huang and Manning, 2008).”
BackgroundResultStructural basis for the docking of mTORC1 on the lysosomal surface
Rogala, K. B., Gu, X., Kedir, J. F., Abu-Remaileh, M., Bianchi, L. F., Bottino, A. M. S., Dueholm, R., Niehaus, A., Overwijn, D., Fils, A.-C. P., et al. (2019) · Science · doi:10.1126/science.aay0166 · Cited by 214
Regulation of YAP by mTOR and autophagy reveals a therapeutic target of tuberous sclerosis complex
Liang, N., Zhang, C., Dill, P., Panasyuk, G., Pion, D., Koka, V., Gallazzini, M., Olson, E. N., Lam, H., Henske, E. P., et al. (2014) · Journal of Experimental Medicine · doi:10.1084/jem.20140341 · Cited by 205
Gibbons, J. J., Abraham, R. T., & Yu, K. (2009) · Seminars in Oncology · doi:10.1053/j.seminoncol.2009.10.011 · Cited by 212
Regulation of muscle protein synthesis and the effects of catabolic states
Gordon, B. S., Kelleher, A. R., & Kimball, S. R. (2013) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2013.05.039 · Cited by 219
“As noted above, impaired insulin and Akt signaling to mTORC1 may be a consequence of concomitant activation of AMPK.”
BackgroundInfluentialEverolimus long-term safety and efficacy in subependymal giant cell astrocytoma
Krueger, D. A., Caré, M. M., Agricola, K. D., Tudor, C., Mays, M., & Franz, D. N. (2013) · Neurology · doi:10.1212/wnl.0b013e3182815428 · Cited by 208
“A deficiency in TSC1 or TSC2 leads to hyperactivation of mTORC1, resulting in increased protein synthesis, and abnormal cellular growth and proliferation.(14,15) Clinical data not only support the use of mTOR inhibitors for the treatment of SEGA, but also renal angiomyolipomas, lymphangioleiomyomatosis, and facial ang…”
BackgroundSomatic Mutations in TSC1 and TSC2 Cause Focal Cortical Dysplasia
Lim, J. S., Gopalappa, R., Kim, S. H., Ramakrishna, S., Lee, M., Kim, J., Kim, J., Park, S. M., Lee, J., Oh, J., et al. (2017) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2017.01.030 · Cited by 205
Genetically engineered human cortical spheroid models of tuberous sclerosis
Blair, J. D., Hockemeyer, D. F., & Bateup, H. S. (2018) · Nature Medicine · doi:10.1038/s41591-018-0139-y · Cited by 205
mTOR-Dependent Cell Survival MechanismsPreprint
Hung, C., García-Haro, L., Sparks, C. A., & Guertin, D. A. (2012) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a008771 · Cited by 215
mTORC1-dependent and -independent regulation of stem cell renewal, differentiation, and mobilization
Gan, B., Sahin, E., Jiang, S., Sánchez‐Aguilera, A., Scott, K. L., Chin, L., Williams, D. A., Kwiatkowski, D. J., & DePinho, R. A. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0810584105 · Cited by 204
“The TSC1/TSC2 complex thus inhibits mTORC1 activity by stimulating Rheb GTP hydrolysis (2).”
BackgroundSato, T., Nakashima, A., Guo, L., & Tamanoi, F. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m809207200 · Cited by 196
Apoptotic Pathways and Alzheimer’s Disease: Probing Therapeutic Potential
Sharma, V., Singh, T. G., Singh, S., Garg, N., & Dhiman, S. (2021) · Neurochemical Research · doi:10.1007/s11064-021-03418-7 · Cited by 201
Nutrient control of TORC1, a cell-cycle regulator
Wang, X., & Proud, C. G. (2009) · Trends in Cell Biology · doi:10.1016/j.tcb.2009.03.005 · Cited by 197
The lysosome: a crucial hub for AMPK and mTORC1 signalling
Carroll, B., & Dunlop, E. A. (2017) · Biochemical Journal · doi:10.1042/bcj20160780 · Cited by 192
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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