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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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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
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Child, N. D., & Benarroch, E. E. (2014) · Neurology · doi:10.1212/wnl.0000000000000922 · Cited by 17
“The TSC1/TSC2 complex, via TSC2, stimulates Rheb GTPase activity, rendering an inactive Rheb-GDP complex that is unable to activate mTORC1.(23,26) This inhibitory GTPase-activating protein (GAP) mechanism is differentially regulated by TSC’s phosphorylation by different kinases(1) (figure).”
BackgroundSekihara, K., Saitoh, K., Han, L., Ciurea, S. O., Yamamoto, S., Kikkawa, M., Kazuno, S., Taka, H., Kaga, N., Arai, H., et al. (2017) · Oncotarget · doi:10.18632/oncotarget.16602 · Cited by 17
Liu, G., Pan, Y., Liu, Y., Hu, J., Zhang, X., Zhang, D., Wang, Y., Feng, Y., Yu, J., & Cheng, Y. (2020) · The Kaohsiung Journal of Medical Sciences · doi:10.1002/kjm2.12188 · Cited by 17
“The AKT/mTOR signaling pathway is important for cell growth, survival, proliferation, angiogenesis, translation, transcription, and metabolism.28 mTOR is a downstream target of the P13K/AKT signaling pathway, which is activated through phosphorylation by activated AKT.29 Studies have reported that AKT/mTOR plays an im…”
BackgroundTuberous sclerosis complex: disease modifiers and treatments
Au, K. S., Ward, C. H., & Northrup, H. (2008) · Current Opinion in Pediatrics · doi:10.1097/mop.0b013e328318c529 · Cited by 17
Cachexia Alters Central Nervous System Morphology and Functionality in Cancer Patients
Simoes, E., Uchida, R. R., Nucci, M. P., Duran, F., Lima, J. D. C. C., Gama, L. R., da Costa, N. A., Otaduy, M. C. G., Bin, F. C., Otoch, J. P., et al. (2025) · Journal of Cachexia Sarcopenia and Muscle · doi:10.1002/jcsm.13742 · Cited by 16
Lysosomal EGFR acts as a Rheb-GEF independent of its kinase activity to activate mTORC1
He, X., Wang, Q.-X., Wei, D., Lin, Y., Zhang, X., Wu, Y., Qian, X., Lin, Z., Xiao, B.-B., Wu, Q., et al. (2025) · Cell Research · doi:10.1038/s41422-025-01110-x · Cited by 21
Zhao, M., Danneskiold‐Samsøe, N. B., Uličná, L., Nguyen, Q., Coassolo, L., Lee, D. E., White, J. P., Jiang, Z., Cuthbert, N., Paramasivam, S., et al. (2022) · eLife · doi:10.7554/elife.80014 · Cited by 17
Ryner, R. F., Derera, I. D., Armbruster, M., Kansara, A., Sommer, M., Pirone, A., Noubary, F., Jacob, M. H., & Dulla, C. G. (2023) · Journal of Neuroscience · doi:10.1523/jneurosci.0572-22.2022 · Cited by 16
“TSC1/2 functions as a repressor of b -catenin, and conditional deletion of TSC1/2 in GABAergic IN progenitors decreases seizure threshold (Mak et al., 2005; J. Huang and Manning, 2008; Carson et al., 2013).”
BackgroundBakar, N. A., Ibrahim, W. N. W., Zulkiflli, A. R., Hodin, N. A. S., Kim, T., Ling, Y. S., Ajat, M., Shaari, K., Shohaimi, S., Nasruddin, N. S., et al. (2023) · Ecotoxicology and Environmental Safety · doi:10.1016/j.ecoenv.2023.114862 · Cited by 16
Targeted therapies for sarcomas: new roles for the pathologist
Al-Zaid, T. J., Somaiah, N., & Lazar, A. J. (2013) · Histopathology · doi:10.1111/his.12297 · Cited by 16
“Complete loss of either TSC1 or TSC2 due to a second hit to either TSC locus leads to a dysfunctional TSC1–TSC2 complex and unchecked cell proliferation through unregulated mTOR complex 1 (mTORC1) activation and impaired complex 2 (mTORC2) activation.(58,59) Given this finding, mTOR inhibitors drugs were tried in AML…”
BackgroundRapalog resistance is associated with mesenchymal-type changes in Tsc2-null cells
Valianou, M., Filippidou, N., Johnson, D. L., Vogel, P., Zhang, E. Y., Liu, X., Lu, Y., Yu, J. J., Bissler, J. J., & Astrinidis, A. (2019) · Scientific Reports · doi:10.1038/s41598-019-39418-5 · Cited by 16
Zhang, Z., Amorosa, L. F., Петрова, А., Coyle, S. M., Macor, M., Nair, M., Lee, L. Y., & Haimovich, B. (2019) · Scientific Reports · doi:10.1038/s41598-019-43347-8 · Cited by 16
Matsuda, S., Kikkawa, U., Uda, H., & Nakashima, A. (2020) · Journal of Cell Science · doi:10.1242/jcs.247817 · Cited by 16
“This complex serves as the GAP for the small G protein Rheb (Huang and Manning, 2008; Saxton and Sabatini, 2017).”
BackgroundInfluentialSekine, S., Terada, S., & AOYAMA, T. (2013) · Journal of Nutritional Science and Vitaminology · doi:10.3177/jnsv.59.123 · Cited by 16
New insights into the activation interaction partners and possible functions of MK5 PRAK
Seternes, O. M. (2015) · Frontiers in bioscience · doi:10.2741/4394 · Cited by 16
McKenna, J., Kapfhamer, D., Kinchen, J. M., Wasek, B. L., Dunworth, M., Stewart, T. M., Bottiglieri, T., Casero, R. A., & Gambello, M. J. (2018) · Human Molecular Genetics · doi:10.1093/hmg/ddy118 · Cited by 16
Yamada, O., Ozaki, K., Nakatake, M., Kakiuchi, Y., Akiyama, M., Mitsuishi, T., Kawauchi, K., & Matsuoka, R. (2010) · Histochemistry and Cell Biology · doi:10.1007/s00418-010-0764-0 · Cited by 16
“Although the exact mechanisms by which the two mTOR complexes are regulated in response to differentiation remain unknown (Huang and Manning 2008), our results provide an important first step towards understanding the regulation of mTORC2 and its related proteins that occur during myeloid cell differentiation (Fig.”
ResultEmendation of autophagic dysfuction in neurological disorders: a potential therapeutic target
Sainani, S. R., Pansare, P. A., Rode, K., Bhalchim, V. M., Doke, R. R., & Desai, S. M. (2020) · International Journal of Neuroscience · doi:10.1080/00207454.2020.1822356 · Cited by 16
“Therefore TSC1 and TSC2 are important regulators of Rheb and hence of mTOR [54].”
BackgroundThe molecular genetics of PI3K/PTEN/AKT/mTOR pathway in the malformations of cortical development
Ma, Q., Chen, G., Li, Y., Guo, Z., & Zhang, X. (2023) · Genes & Diseases · doi:10.1016/j.gendis.2023.04.041 · Cited by 18
“…the GTPase-activating protein domain for a small G-protein Rheb (Ras homologue enriched in the brain), TSC1 acts as a scaffold that binds and stabilizes both TSC2 and TBC1D7 124,125 ; TBC1D7 binds to and is stabilized by TSC1, and knockdown of TBC1D7 can decrease the association of TSC1 and TSC2.”
Patel, C. H., Dong, Y. W., Koleini, N., Wang, X., Dunkerly-Eyring, B. L., Wen, J., Ranek, M. J., Bartle, L. M., Henderson, D. B., Sagert, J. G., et al. (2023) · JCI Insight · doi:10.1172/jci.insight.167829 · Cited by 13
“…of memory CD8 + T cells (12). mTORC2 ablation in CD8 + T cells also promotes memory T cell generation but does not inhibit effector T cells (10). mTORC1 activity is tightly regulated upstream by the tuberous sclerosis complex (TSC), which consists of hamartin (TSC1) and tuberin (TSC2) (13, 14).”
BackgroundAksoylu, I. S., Martin, P., Robert, F., Szkop, K. J., Redmond, N. E., Bhattacharyya, S., Wang, J. P., Chen, S., Beauchamp, R. L., Nobeli, I., et al. (2023) · Molecular Autism · doi:10.1186/s13229-023-00572-3 · Cited by 15
“The TSC proteins act as a central hub relaying signals from diverse cellular pathways to con-trol mammalian/mechanistic target of rapamycin complex 1 (mTORC1) activity, which regulates cell growth and proliferation [3, 4].”
BackgroundBi-steric mTORC1 inhibitors induce apoptotic cell death in tumor models with hyperactivated mTORC1
Du, H., Yang, Y. C., Liu, H.-J., Yuan, M., Asara, J. M., Wong, K., Henske, E. P., Singh, M., & Kwiatkowski, D. J. (2023) · Journal of Clinical Investigation · doi:10.1172/jci167861 · Cited by 15
“Complete loss of TSC1 or TSC2 , occurring in both tuberous sclerosis complex (TSC) tumors and a variety of cancer types (6–8), leads to constitutive unregulated activation of mTORC1 (9).”
BackgroundNursing Implications for the Lifelong Management of Tuberous Sclerosis Complex
Agricola, K. D., Tudor, C., Krueger, D. A., & Franz, D. N. (2013) · Journal of Neuroscience Nursing · doi:10.1097/jnn.0b013e3182986146 · Cited by 15
“Normally, the proteins encoded by the two genes form a tumor suppressor complex that limits activation of the mammalian target of rapamycin (mTOR; Brugarolas et al., 2004; Curatolo et al., 2008a; Ellisen, 2005; Huang & Manning, 2008; Wang & Proud, 2006).”
BackgroundSragovich, S., Gershovits, M., Lam, J. C. K., Li, V. O. K., & Gozes, I. (2021) · Journal of Alzheimer s Disease · doi:10.3233/jad-201158 · Cited by 13
“The Tuberous Sclerosis 1 ( TSC1 ) gene encodes the growth inhibitory protein hamartin, negatively regulating mammalian target of rapamycin complex 1 (mTORC1) signaling, with mutations in this gene previously associated with Tuberous Sclerosis [37].”
TSC2 Mutations Were Associated with the Early Recurrence of Patients with HCC Underwent Hepatectomy
Song, K., He, F., Xin, Y., Guan, G., Huo, J., Zhu, Q., Fan, N., Guo, Y., Zang, Y.-J., & Wu, L.-Q. (2021) · Pharmacogenomics and Personalized Medicine · doi:10.2147/pgpm.s294307 · Cited by 15
“Tuberous sclerosis complex 2 (TSC2) is an important tumor-suppressor gene, which was firstly found in tuberous sclerosis complex.(4) Many studies have demonstrated that TSC2 closely related with several cancers.”
D’Hulst, G., Masschelein, E., & Bock, K. D. (2021) · Nutrients · doi:10.3390/nu13051396 · Cited by 16
“Growth factors, energetic stress, and muscular contractions control mTORC1 directly or via its upstream inhibitor tuberous sclerosis complex 1/2 (TSC1/2) [8].”
BackgroundConservation of the Tsc/Rheb/TORC1/S6K/S6 Signaling in Fission Yeast
Nakashima, A., & Tamanoi, F. (2010) · The Enzymes · doi:10.1016/s1874-6047(10)28008-3 · Cited by 15
“The TSC–Rheb pathway mediates inputs from numerous signaling, such as growth factor, hypoxia, or energy status, to mTORC1 to control cell growth and other cellular processes [4, 5].”
BackgroundClinical management of tuberous sclerosis complex over the lifetime of a patient
Frost, M., & Hulbert, J. C. (2015) · Pediatric Health Medicine and Therapeutics · doi:10.2147/phmt.s67342 · Cited by 15
Arena, F. P. (2014) · Cancer Management and Research · doi:10.2147/cmar.s56802 · Cited by 15
ABC-transporters as stem-cell markers in brain dysplasia/tumor epilepsies
Czornyj, L. (2014) · Frontiers in bioscience · doi:10.2741/4293 · Cited by 15
“When either TSC1 or TSC2 is deficient, mTOR complex 1 is constitutively upregulated, leading to abnormal cellular growth, proliferation, and protein synthesis (22,23).”
BackgroundZhu, X., Dahlmans, V. E. H., Thali, R. F., Preisinger, C., Viollet, B., Voncken, J. W., & Neumann, D. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.c116.740498 · Cited by 15
“AMPK is involved in control of cell growth via phosphorylation of regulatory-associated protein of mTOR (mechanistic target of rapamycin, Raptor) and tuberous sclerosis 2 (TSC2, tumor suppressor) (11, 12).”
BackgroundSalto, R., Girón, M. D., Manzano, M., Martín, M. J., Vílchez, J. D., Bueno-Vargas, P., Cabrera, E., Pérez-Alegre, M., Andújar, E., Rueda, R., et al. (2020) · Nutrients · doi:10.3390/nu12020528 · Cited by 15
Serfontein, J., Nisbet, R. E. R., Howe, C. J., & de Vries, P. J. (2011) · Behavior Genetics · doi:10.1007/s10519-010-9440-3 · Cited by 15
“It is possible that the two human sites that can be aligned with Drosophila Ser924 are a duplication of several residues in an ancestral form of TSC2 represented by Drosophila ( Huang and Manning 2008 ).”
BackgroundInfluentialIs viral E6 oncoprotein a viable target? A critical analysis in the context of cervical cancer
Kumar, A., Rathi, E., Hariharapura, R. C., & Kini, S. G. (2020) · Medicinal Research Reviews · doi:10.1002/med.21697 · Cited by 14
Devos, M., Nunes, J. D., Jiatsa, N. D., & Demeestere, I. (2023) · Scientific Reports · doi:10.1038/s41598-023-41954-0 · Cited by 13
Driedger, J. H., Schröter, J., PROTECT-Study Group, Hertzberg, C., Weschke, B., Kaindl, A. M., Lücke, T., Thiels, C., Klotz, K. A., Fazeli, W., et al. (2025) · Orphanet Journal of Rare Diseases · doi:10.1186/s13023-024-03495-1 · Cited by 15
“By inhibiting mTORC1, sirolimus counteracts the hyperactivation caused by pathogenic TSC1/TSC2 variants [7].”
Erythropoietin-driven proliferation of cells with mutations in the tumor suppressor geneTSC2
Ikeda, Y., Taveira‐DaSilva, A. M., Pacheco–Rodriguez, G., Steagall, W. K., El‐Chemaly, S., Gochuico, B. R., May, R. M., Hathaway, O. M., Li, S., Wang, J., et al. (2010) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.00095.2010 · Cited by 14
“Although we find a small number of cells immunoreactive to antibodies directed to activated EPOR and proliferative cells (PCNA-positive cells), it is possible that proliferative LAM cells could be driven by multiple factors, such as angiotensin II (49), or by the alterations of the TSC complex (19, 37).”
BackgroundLabor inhibits placental mechanistic target of rapamycin complex 1 signaling
Lager, S., Aye, I. L. M. H., Gaccioli, F., Ramirez, V. I., Jansson, T., & Powell, T. L. (2014) · Placenta · doi:10.1016/j.placenta.2014.10.006 · Cited by 15
“However, phosphorylation of TSC2 at S1387 is only one of multiple activity regulating phosphorylation sites [20].”
BackgroundBertuccio, C. A., & Caplan, M. J. (2013) · PubMed · Cited by 14
ALA-PDT suppressed the cell growth by Akt-/Erk-mTOR-p70 s6k pathway in human SZ95 sebocytes in vitro
Liu, W., Wang, Q., Tuo, J., Chang, Y., Ying, J., Jiang, M., Zouboulis, C. C., & Xiang, L. F. (2018) · Photodiagnosis and Photodynamic Therapy · doi:10.1016/j.pdpdt.2018.06.024 · Cited by 14
Lee, E., Lee, H., Kim, M.-A., Do, G. Y., Cho, H. J., Kim, G., Jung, H., Song, J. H., Cho, J. M., & Kim, I. (2018) · Clinical and Experimental Pharmacology and Physiology · doi:10.1111/1440-1681.13022 · Cited by 14
Ni, J., Yan, F., Qin, W., Yu, L., Zhang, G., Liu, F., Yang, X., Yang, B., Hao, C., Wang, T., et al. (2019) · Scientific Reports · doi:10.1038/s41598-019-49814-6 · Cited by 14
Phosphorylation Modifications Regulating Cardiac Protein Quality Control Mechanisms
Mishra, S., Dunkerly-Eyring, B. L., Keceli, G., & Ranek, M. J. (2020) · Frontiers in Physiology · doi:10.3389/fphys.2020.593585 · Cited by 15
“ERK is a negative regulator of TSC2, thereby activating mTORC1 which is known to suppress autophagy and accelerate cellular growth (Huang and Manning, 2008; Sciarretta et al., 2014, 2018a; Wang et al., 2019).”
BackgroundWang, J., Du, T., Lu, Y., Lv, Y. Y., Du, Y., Wu, J., Ma, R., Xu, C., & Feng, J. (2021) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.17053 · Cited by 14
Xu, B., Li, Z., Li, S., Ke, H., Zhang, Q., Qin, Y., & Guo, T. (2022) · Fertility and Sterility · doi:10.1016/j.fertnstert.2022.08.853 · Cited by 14
Synaptic Plasticity as a Therapeutic Target in the Treatment of Autism-related Single-gene Disorders
Pignatelli, M., Feligioni, M., Piccinin, S., Molinaro, G., Nicoletti, F., & Nisticò, R. (2013) · Current Pharmaceutical Design · doi:10.2174/1381612811319360008 · Cited by 14
“Several lines of evidence suggest that selective deletion of either TSC1 or TSC2 is sufficient to disrupt the TSC1/2 complex and results into an aberrant activation of the mammalian target of rapamycin complex 1 (mTORC1) leading to up-regulation of protein translation, unchecked cell growth and proliferation [137-139].”
BackgroundPhosphorylation, protein kinases and ADPKD
Li, X. (2011) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2011.03.001 · Cited by 14
Ou, X.-H., Liu, M., Luo, H.-R., Dong, L. Q., & Liu, F. (2014) · PLoS ONE · doi:10.1371/journal.pone.0095393 · Cited by 15
“Insulin-stimulated activation of the PI3K/Akt signaling pathway leads to the inhibition of TSC1/TSC2, resulting in activation of small GTPase Rheb and subsequent activation of mTORC1 [13,14,15].”
BackgroundA Genome-Wide siRNA Screen in Mammalian Cells for Regulators of S6 Phosphorylation
Papageorgiou, A., Rapley, J., Mesirov, J. P., Tamayo, P., & Avruch, J. (2015) · PLoS ONE · doi:10.1371/journal.pone.0116096 · Cited by 13
“Many of these inputs operate by modifying the activity of the Tuberous Sclerosis complex (TSC), a GTPase activator for and negative regulator of Rheb [6].”
BackgroundEverolimus tablets for patients with subependymal giant cell astrocytoma
Turner, S., Peters, K. B., Vredenburgh, J. J., Desjardins, A., Friedman, H. S., & Reardon, D. A. (2011) · Expert Opinion on Pharmacotherapy · doi:10.1517/14656566.2011.601742 · Cited by 14
“When either TSC1 or TSC2 is deficient, mTOR complex 1 is constitutively activated, leading to abnormal cellular growth, proliferation and protein synthesis [15,16].”
BackgroundRevealing protein networks and gene-drug connectivity in cancer from direct information
Jiang, X., Martínez-Ledesma, E., & Morcos, F. (2017) · Scientific Reports · doi:10.1038/s41598-017-04001-3 · Cited by 14
Lee, J., An, S., Jung, J. H., Kim, K., Kim, J. E., An, I., & Bae, S. (2019) · International Journal of Oncology · doi:10.3892/ijo.2019.4730 · Cited by 14
Tuberous Sclerosis Complex and DNA Repair
Habib, S. L. (2010) · Advances in experimental medicine and biology · doi:10.1007/978-1-4419-6448-9_8 · Cited by 14
Cho, J., Lee, J., Kim, J.-S., Kim, S. T., Lee, S., Kim, S. Y., Ha, S. Y., Park, C.-K., & Lim, H. Y. (2016) · Translational Oncology · doi:10.1016/j.tranon.2016.08.009 · Cited by 14
“Everolimus is an effective treatment for TSC manifestations, a rare disease associated with mutations in TSC1 and TSC2 that result in high mTOR activity [13].”
BackgroundInfluentialCho, C., Kim, Y., Park, S.-R., Kim, B. Y., Davis, C. S., Hwang, I., Brooks, S. V., Lee, J. H., & Kim, M. (2021) · Autophagy · doi:10.1080/15548627.2021.2016255 · Cited by 13
“TSC contains TSC1 and TSC2 proteins [12], while GATOR1 is a trimeric complex of”
BackgroundMetabolic adaption of cancer cells toward autophagy: Is there a role for ER-phagy?
Gentile, D., Esposito, M., & Grumati, P. (2022) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2022.930223 · Cited by 13
“TSC2 forms a functional complex with TSC1 to inhibit the two key regulators of mTOR mediated translation: S6K and 4EBP1 (Huang and Manning, 2008).”
BackgroundEvolutionary analysis of the mTOR pathway provide insights into lifespan extension across mammals
Yang, F. Y., Liu, X., Li, Y., Yu, Z., Huang, X. H., Yang, G. Z., & Xu, S. (2023) · BMC Genomics · doi:10.1186/s12864-023-09554-4 · Cited by 14
“Moreover, TSC1 and TSC2 form tumor suppressor complex to control cell growth and prevent disease [38].”
BackgroundMetformin and sex: why suppression of aging may be harmful to young male mice
Blagosklonny, M. V. (2010) · Aging · doi:10.18632/aging.100264 · Cited by 13
“and testosterone stimulate cellular growth in part by activating the mTOR pathway [19-30].”
BackgroundProlonging the survival of Tsc2 conditional knockout mice by glutamine supplementation
Rozas, N. S., Redell, J. B., McKenna, J., Moore, A. N., Gambello, M. J., & Dash, P. K. (2015) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2015.01.039 · Cited by 13
“form, thus resulting in decreased mTORC1 activity [16,20,22,36].”
Karpathakis, A., Caplin, M. E., & Thirlwell, C. (2012) · Endocrine Related Cancer · doi:10.1530/erc-12-0050 · Cited by 13
“The hamartin–tuberin complex normally inactivates the protein Ras homologue enriched in brain (Rheb) that functions to activate the mTOR signalling pathway (Huang & Manning 2008).”
BackgroundMiles, L., Greiner, H. M., Miles, M. V., Mangano, F. T., Horn, P. S., Leach, J. L., Seo, J. H., & Lee, K. H. (2013) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/nen.0b013e3182a38d88 · Cited by 13
Kaur, H., & Moreau, R. F. (2021) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2021.01.070 · Cited by 13
A New Perspective on The Potential Application of Ripk1 in the Treatment of Sepsis
Wang, X., Chai, Y., Guo, Z., Wang, Z., Liao, H., Wang, Z., & Wang, Z. (2023) · Immunotherapy · doi:10.2217/imt-2022-0219 · Cited by 13
Śmiałek, D., Jóźwiak, S., & Kotulska, K. (2023) · Journal of Clinical Medicine · doi:10.3390/jcm12010365 · Cited by 13
“Its selective activation results in a kinase signaling cascade that increases cell proliferation and growth; hence, multiple benign tumors are formed in different organs [2,3].”
BackgroundPelvic lymphangioleiomyomatosis treated successfully with everolimus
Wahid, S., Chiang, P. C., Luo, H., Huang, S., Tsai, E., & Chiang, P. (2017) · Medicine · doi:10.1097/md.0000000000004562 · Cited by 13
“Conclusions: This case series demonstrates the enormous value of mTOR inhibitors (specifically everolimus) in the management of extrapulmonary pelvic LAM, of which there is no effective treatment currently available.”
Signaling responses to high and moderate load strength exercise in trained muscle
Lysenko, E. A., Popov, D. V., Vepkhvadze, T. F., Sharova, A. P., & Vinogradova, O. L. (2019) · Physiological Reports · doi:10.14814/phy2.14100 · Cited by 12
Profiling the Surfaceome Identifies Therapeutic Targets for Cells with Hyperactive mTORC1 Signaling
Wei, J., Leung, K., Truillet, C., Ruggero, D., Wells, J. A., & Evans, M. J. (2019) · Molecular & Cellular Proteomics · doi:10.1074/mcp.ra119.001785 · Cited by 12
“plex, focal cortical dysplasia) (8), underscoring the clinical”
BackgroundTuberous Sclerosis: A Case Report and Review of the Literature
Dzefi‐Tettey, K., Edzie, E. K. M., Gorleku, P. N., Piersson, A. D., & Cudjoe, O. (2021) · Cureus · doi:10.7759/cureus.12481 · Cited by 13
Kim, H. S., Kim, S. T., Kang, S. H., Sung, D. J., Kim, C. H., Shin, S. W., Kim, Y. H., Cho, W. Y., & Park, K. H. (2014) · Journal of Medical Case Reports · doi:10.1186/1752-1947-8-95 · Cited by 13
“Either of these mutations results in constitutive mTOR expression and impaired tumor suppression in multiple tissues [17,18].”
BackgroundThe Role of Chemokines in Migration of Metastatic-like Lymphangioleiomyomatosis Cells
Pacheco–Rodriguez, G., & Moss, J. (2010) · Critical Reviews in Immunology · doi:10.1615/critrevimmunol.v30.i4.40 · Cited by 13
Signal integration in the (m)TORC1 growth pathway
Ramlaul, K., & Aylett, C. H. S. (2018) · Frontiers in Biology · doi:10.1007/s11515-018-1501-7 · Cited by 12
Cardiomyocyte S1PR1 promotes cardiac regeneration via AKT/mTORC1 signaling pathway
Liu, X., Yue, J., Zhou, C., Duan, Y., Chen, X., Liu, J., Zhuang, S., Luo, Y., Wu, J., Zhang, Y., et al. (2024) · Theranostics · doi:10.7150/thno.103797 · Cited by 12
Single serine on TSC2 exerts biased control over mTORC1 activation mediated by ERK1/2 but not Akt
Dunkerly-Eyring, B. L., Pan, S., Pinilla-Vera, M., McKoy, D., Mishra, S., Martinez, M. I. G., Oeing, C. U., Ranek, M. J., & Kass, D. A. (2022) · Life Science Alliance · doi:10.26508/lsa.202101169 · Cited by 12
“MTORC1 is activated upon GTP binding to the G-protein Rheb (Ras homolog enriched in brain) which is in turn negatively controlled by the GTPase-activating protein tuberin (tuberous sclerosis complex-2, TSC2) (Huang & Manning, 2008).”
Models of KPTN-related disorder implicate mTOR signalling in cognitive and overgrowth phenotypes
Levitin, M. O., Rawlins, L. E., Sánchez-Andrade, G., Arshad, O. A., Collins, S. C., Sawiak, S. J., Iffland, P. H., Andersson, M. H. L., Bupp, C. P., Cambridge, E. L., et al. (2023) · Brain · doi:10.1093/brain/awad231 · Cited by 13
Fallone, L., Walzer, T., & Marçais, A. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241612736 · Cited by 13
“The regulation of TSC through the disruption of the complex itself or through its degradation is still debated (reviewed in [40]).”
BackgroundMcGrath, M. K., Abolhassani, A., Guy, L., Elshazly, A. M., Barrett, J. T., Mivechi, N. F., Gewirtz, D. A., & Schoenlein, P. V. (2024) · Frontiers in Endocrinology · doi:10.3389/fendo.2024.1298423 · Cited by 13
“In addition, in MCF-7 cells, CRISPR-mediated genetic depletion of tuberous sclerosis complex 2 (TSC2), a negative regulator of mTORC1 (174), in combination with palbociclib for 14 or 21 days induced sustained growth arrest, fl attened morphology, and intense SA-b -Gal staining as compared to the…”
BackgroundFailure of Autophagy in Pompe Disease
Do, H., Meena, N. K., & Raben, N. (2024) · Biomolecules · doi:10.3390/biom14050573 · Cited by 13
Unraveling the function of TSC1-TSC2 complex: implications for stem cell fate
Wang, S., Ma, R., Gao, C., Tian, Y.-N., Hu, R., Zhang, H., Li, L., & Li, Y. (2025) · Stem Cell Research & Therapy · doi:10.1186/s13287-025-04170-3 · Cited by 15
Lipert, B. A., Siemens, K. N., Khan, A., Airey, R., Dam, G. H., Lu, M., Flinterman, M., Yong, Q., Lee, T. W., Hunter, F. W., et al. (2025) · Breast Cancer Research · doi:10.1186/s13058-025-02000-1 · Cited by 12
“These genes have not previously been implicated in T-DM1 sensitivity; however, they negatively regulate mTOR complex 1 (mTORC1) [61], and mTOR signalling has been shown to influence trastuzumab [62, 63] and T-DM1 activity [64, 65].”
Xu, W., Kim, J., Jung, W. J., Koh, Y., & Yoon, S. (2017) · Cancer Research and Treatment · doi:10.4143/crt.2016.357 · Cited by 12
Pfirmann, P., Aupy, J., Jambon, E., Idier, L., Prezelin‐Reydit, M., Fermis, M., Devillard, R., Grenier, N., Combe, C., & Rigothier, C. (2020) · Journal of Medical Genetics · doi:10.1136/jmedgenet-2019-106607 · Cited by 12
Stability of tuberous sclerosis complex 2 is controlled by methylation at R1457 and R1459
Gen, S., Matsumoto, Y., Kobayashi, K., Suzuki, T., Inoue, J., & Yamamoto, Y. (2020) · Scientific Reports · doi:10.1038/s41598-020-78274-6 · Cited by 12
Translational Aspects of the Mammalian Target of Rapamycin Complexes in Diabetic Nephropathy
Daher, A. A., Alkhansa, S., Azar, W. S., Rafeh, R. W., Ghadieh, H. E., & Eid, A. A. (2021) · Antioxidants and Redox Signaling · doi:10.1089/ars.2021.0217 · Cited by 12
“The kinases that sense many of the extracellular conditions phosphorylate and regulate TSC2 mainly and TSC1 to a lesser extent, usually to stop the activation of mTORC1 (55).”
Arcidiacono, D., Zaramella, A., Fabris, F., Sánchez‐Rodríguez, R., Nucci, D., Fassan, M., Nardi, M., Benna, C., Cristofori, C., Morbin, T., et al. (2021) · Nutrients · doi:10.3390/nu13103638 · Cited by 12
“The upregulation observed for the TSC2 protein could be explained by the necessity to limit and control the events responsible for cell transformation [41].”
BackgroundWang, W., Zhang, Z., Zhao, M., Wang, Y., Ge, Y., & Lin, S. (2022) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2022.102812 · Cited by 12
Hurtado-Sierra, D., Garzón, J. X. R., Rojas, L. Z., Fernández-Gómez, Ó., & Manrique-Rincón, F. (2023) · Frontiers in Pediatrics · doi:10.3389/fped.2023.1109646 · Cited by 12
Parathyroid Carcinoma: Update on Pathogenesis and Therapy
Marini, F., Giusti, F., Palmini, G., Aurilia, C., Donati, S., & Brandi, M. L. (2023) · Endocrines · doi:10.3390/endocrines4010018 · Cited by 12
“is impaired, the mTOR increases, activating the PI3K/AKT/mTOR pathway and resulting in cell dysplasia, tumorigenesis, and angiogenesis [74].”
BackgroundCamillo, B. D., Irving, B. A., Schimke, J. M., Sanavia, T., TOFFOLO, G. M., Cobelli, C., & Nair, K. S. (2012) · PLoS ONE · doi:10.1371/journal.pone.0032391 · Cited by 13
“Mechanistically, TSC1 (hamartin) forms a complex with TSC2 (tuberin) [TSC1–TSC2 complex], which functions as a critical regulator of protein synthesis and cell growth [34,35].”
BackgroundZitserman, D., Gupta, S., Kruger, W. D., Karbowniczek, M., & Roegiers, F. (2012) · PLoS ONE · doi:10.1371/journal.pone.0048720 · Cited by 12
T2 weighted MRI for assessing renal lesions in transgenic mouse models of tuberous sclerosis
Kalogerou, M., Zhang, Y., Yang, J., Garrahan, N. J., Paisey, S. J., Tokarczuk, P. F., Stewart, A., Gallacher, J., Sampson, J. R., & Shen, M. H. (2011) · European Journal of Radiology · doi:10.1016/j.ejrad.2011.06.054 · Cited by 12
“The gene products TSC1 (hamartin) and SC2 (tuberin) are tumour suppressors and are part of a comlex that down-regulates the mammalian target of rapamycin mTOR) signalling pathway [2–4].”
BackgroundFilipczak, P. T., Thomas, C., Chen, W., Salzman, A. L., McDonald, J. D., Lin, Y., & Belinsky, S. A. (2016) · Cancer Research · doi:10.1158/0008-5472.can-16-1052 · Cited by 12
Kútna, V., O’Leary, V. B., Newman, E. L., Höschl, C., & Ovsepian, S. V. (2021) · Neurotherapeutics · doi:10.1007/s13311-020-01000-7 · Cited by 12
Regulation of the mTOR signaling pathway: from laboratory bench to bedside and back again
Abraham, R. T. (2009) · F1000 Biology Reports · doi:10.3410/b1-8 · Cited by 12
“A nodal point of convergence for mTORC1 regulatory signals delivered by growth factors, hypoxia, and ATP is a heterodimeric protein complex consisting of tuberous sclerosis complex 1 (TSC1) and TSC2 subunits (hereafter termed TSC1/2), which functions as a GTPase-activating protein (GAP) for the Ras-related GTPase Rheb…”
BackgroundPrevalence of thoracoabdominal imaging findings in tuberous sclerosis complex
Ritter, D. M., Fessler, B. K., Ebrahimi‐Fakhari, D., Wei, J. J., Franz, D. N., Krueger, D. A., Trout, A. T., & Towbin, A. J. (2022) · Orphanet Journal of Rare Diseases · doi:10.1186/s13023-022-02277-x · Cited by 11
“In TSC, hamartin and tuberbin function is reduced allowing for overactivation of mTOR [8].”
BackgroundFarach, L. S., Richard, M. A., Wulsin, A. C., Bebin, E. M., Krueger, D. A., Şahin, M., Porter, B. E., McPherson, T., Peters, J. M., O’Kelley, S. E., et al. (2024) · Pediatric Neurology · doi:10.1016/j.pediatrneurol.2024.06.012 · Cited by 11
Exploring etiologic contributions to the occurrence of external apical root resorption
Burnheimer, J. M., Baxter, D. J., Deeley, K. B., Vieira, A. R., & Bezamat, M. (2024) · American Journal of Orthodontics and Dentofacial Orthopedics · doi:10.1016/j.ajodo.2024.05.017 · Cited by 11
Tsc2, a positional candidate gene underlying a quantitative trait locus for hepatic steatosis
Wang, C., Stapleton, D. S., Schueler, K. L., Rabaglia, M. E., Oler, A. T., Keller, M. P., Kendziorski, C. M., Broman, K. W., Yandell, B. S., Schadt, E. E., et al. (2012) · Journal of Lipid Research · doi:10.1194/jlr.m025239 · Cited by 11
Two novel TSC2 mutations in pediatric patients with tuberous sclerosis complex
Gao, S., Wang, Z., & Xie, Y. (2018) · Medicine · doi:10.1097/md.0000000000011533 · Cited by 11
Rocktäschel, P., Sen, A., & Cader, M. Z. (2019) · Epilepsy & Behavior · doi:10.1016/j.yebeh.2019.106581 · Cited by 12
“Nevertheless, hyperactivation of the mechanistic target of rapamycin (mTOR) pathway is hypothesized to be a major contributor to clinical features in TSC as knockout of the TSC1:TSC2 complex deregulates the mTOR complex 1 (mTORC1) [27], and the mTOR inhibitor everolimus was recently licensed for the treatment of refra…”
BackgroundTang, Y., Luo, J., Yang, Y., Liu, S., Zheng, H., Zhan, Y., Fan, S., & Wen, Q. (2022) · PLoS ONE · doi:10.1371/journal.pone.0265465 · Cited by 11
“Besides activating MNKs to enhance eIF4E phosphorylation, Erk also mediate the activation of mTORC1 pathway through phosphorylation of tuberous sclerosis complex 2 (TSC2) on multiple sites to promote phosphorylation of 4EBP1 [34].”
Background
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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