Cited by 1,237PI3K/AKT/mTOR signaling in cancerTuberous Sclerosis Complex ResearchHippo pathway signaling and YAP/TAZ

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The TSC1–TSC2 complex: a molecular switchboard controlling cell growth

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Huang, Jingxiang, Manning, Brendan D.·2008·Biochemical Journal

DOI 10.1042/bj20080281PMC PMC2735030

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Abstract

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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1 retracted

Phosphatidylinositol 3-Kinase/Akt Pathway Regulates Tuberous Sclerosis Tumor Suppressor Complex by Phosphorylation of Tuberin
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
Retracted
Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex
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Self-citation
TOR 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
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TSC2 Mediates Cellular Energy Response to Control Cell Growth and Survival
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TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling
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“Furthermore, ERK and RSK can inhibit TSC1-TSC2 complex activity via phosphorylation (159).”
Background
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“Complete loss of either TSC1 or TSC2 inactivates the TSC1/TSC2/ TBC1D7 leading to constitutive high-level activation of mTORC1 in TSC tumors (9, 10).”
Background
Pharmacological and Genetic Evaluation of Proposed Roles of Mitogen-activated Protein Kinase/Extracellular Signal-regulated Kinase Kinase (MEK), Extracellular Signal-regulated Kinase (ERK), and p90RSK in the Control of mTORC1 Protein Signaling by Phorbol Esters
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“In recent studies, germ cell conditional knockouts were created for Tsc1 and Tsc2 [26, 29], which encode upstream negative regulators of mTORC1 and mTORC2 (reviewed in [30-34]).”
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Background
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Background
KPT-9274, an Inhibitor of PAK4 and NAMPT, Leads to Downregulation of mTORC2 in Triple Negative Breast Cancer Cells
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“At themolecular level, many of these signals converge on TSC1/TSC2 and small GTPase Rheb to regulate mTORC1 (10).”
Background
Inherited Cancer Syndromes in Children and Young Adults
D'Orazio, J. A. (2010) · Journal of Pediatric Hematology/Oncology · doi:10.1097/mph.0b013e3181ced34c · Cited by 45
“In normal cells, tuberin heterodimerizes with hamartin to form a regulatory GTPase-activating protein complex that inhibits cellular growth and proliferation through the mTOR pathway.(256,257) Loss-of-function mutations in either TSC1 or TSC2 promote allelic insufficiency and tumors develop through somatic loss of the…”
Background
Sustained mTORC1 activity during palbociclib-induced growth arrest triggers senescence in ER+ breast cancer cells
Maskey, R. S., Wang, F., Lehman, E., Wang, Y., Emmanuel, N., Zhong, W., Jin, G., Abraham, R. T., Arndt, K. T., Myers, J. S., et al. (2020) · Cell Cycle · doi:10.1080/15384101.2020.1859195 · Cited by 45
“AKT is also known to regulate mTORC1 activity by inhibiting TSC2 function [35].”
Background
Targeting autophagy and neuroinflammation pathways with plant‐derived natural compounds as potential antidepressant agents
Mokhtari, T. (2022) · Phytotherapy Research · doi:10.1002/ptr.7551 · Cited by 46
Epidemiology, Genetic Etiology, and Intervention of Premature Ovarian Insufficiency
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“It is well-established that mTORC1 signalling can be activated by PKB via phosphorylation of TSC1/2 (15).”
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Comparison of three rapamycin dosing schedules in A/J Tsc2+/- mice and improved survival with angiogenesis inhibitor or asparaginase treatment in mice with subcutaneous tuberous sclerosis related tumors
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“The multiple roles of this important regulatory pathway have been described in recent reviews [12-16].”
Background
Molecular brakes regulating mTORC1 activation in skeletal muscle following synergist ablation
Hamilton, D. L., Philp, A., MacKenzie, M. G., Patton, A., Towler, M. C., Gallagher, I. J., Bodine, S. C., & Baar, K. (2014) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00674.2013 · Cited by 49
“lated by AMPK and PKB, respectively (23).”
Background
Integration of signals generated by nutrients, hormones, and exercise in skeletal muscle.
Kimball, S. (2014) · American Journal of Clinical Nutrition · doi:10.3945/ajcn.113.068387 · Cited by 46
“5 Abbreviations used: Akt, Ak transforming; AMPK, AMP-activated protein kinase; ca, constitutively active; c7orf59, chromosome 7 open reading frame 59; eIF, eukaryotic initiation factor; ERK, extracellular-regulated protein kinase; FKBP12, FK506 binding protein 12; GAP, GTPase activator protein; GATOR, GAP activity to…”
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“activity is enhanced by TSC1–TSC2 complex [21].”
BackgroundInfluential
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“To determine whether such dissociation occurs, we carried out co-immunoprecipitations of TSC1 and TSC2.”
BackgroundInfluential
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“TSC1 and TSC2 encode the proteins hamartin and tuberin, respectively, which together form the TSC (Tsc1-Tsc2; (7,8)).”
Background
Mechanosensitive Molecular Networks Involved in Transducing Resistance Exercise-Signals into Muscle Protein Accretion
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“In basal conditions, TSC2 stimulates Rheb’s GTPase activity, which, in turn, leads to conversion of active GTP-Rheb into inactive GDP-Rheb (Huang and Manning, 2008), thereby repressing mTORC1 activity.”
Background
Spliced X-box Binding Protein 1 Stimulates Adaptive Growth Through Activation of mTOR
Wang, X., Deng, Y., Zhang, G., Li, C., Ding, G., May, H. I., Tran, D. H., Luo, X., Jiang, D.-S., Li, D. ‘., et al. (2019) · Circulation · doi:10.1161/circulationaha.118.038924 · Cited by 43
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Background
Rapamycin treatment dose‐dependently improves the cystic kidney in a new ADPKD mouse model via the mTORC 1 and cell‐cycle‐associated CDK 1/cyclin axis
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“Previous studies demonstrated that rapamycin can effectively inhibit mTORC1 and its downstream factors [59, 60].”
Background
A pathway and network review on beta-adrenoceptor signaling and beta blockers in cardiac remodeling
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Background
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Background
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“Rheb activates mTOR signaling, including increased p-p70S6K and p-4E-BP1 (Huang and Manning 2008).”
Background
Quercetin mediates TSC2-RHEB-mTOR pathway to regulate chondrocytes autophagy in knee osteoarthritis
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Background
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Li, Y.-Y., Feun, L. G., Thongkum, A., Tu, C.-H., Chen, S.-M., Wangpaichitr, M., Wu, C., Kuo, M. T., & Savaraj, N. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18061297 · Cited by 40
“It is known that TSC2 complex inhibits mTOR activation to promote autophagy through its GTPase protein (GAP) activity toward small GTPase Rheb [9,10].”
Background
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“To investigate whether there is an overlap between the acquisition of resistance by CRISPR-derived knockout cells versus resistance generated by prolonged exposure to drugs, we evaluated the activity of MTORC1 and MAPK pathways.”
Influential
Role of TSC1 in physiology and diseases
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“REDD1 is known to interact with TSC2 and to increase the inhibitory effect of the TSC1/TSC2 heterodimer on mTORC1 activity [45].”
Background
Drug discovery for polycystic kidney disease
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“of RHEB from its active GTP-bound state to its inactive GDPbound form [4].”
Background
EFFECTS OF RAPAMYCIN ON CEREBRAL OXYGEN SUPPLY AND CONSUMPTION DURING REPERFUSION AFTER CEREBRAL ISCHEMIA
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“Active Akt impinges on mTORC1 signaling via negative regulation of TSC1/2 and consequently relieves suppression of mTORC1 by TSC1/2 (Huang and Manning, 2008).”
Background
What Happens in TBI? A Wide Talk on Animal Models and Future Perspective
Kundu, S., & Singh, S. (2022) · Current Neuropharmacology · doi:10.2174/1570159x20666220706094248 · Cited by 39
TSC2 mediates hyperosmotic stress-induced inactivation of mTORC1
Plescher, M., Teleman, A. A., & Demetriades, C. (2015) · Scientific Reports · doi:10.1038/srep13828 · Cited by 36
The potential for chemical mixtures from the environment to enable the cancer hallmark of sustained proliferative signalling
Engström, W., Darbre, P. D., Eriksson, S., Gulliver, L., Hultman, T., Karamouzis, M. V., Klaunig, J. E., Mehta, R., Moorwood, K., Sanderson, J. T., et al. (2015) · Carcinogenesis · doi:10.1093/carcin/bgv030 · Cited by 40
“Akt also suppresses TSC1/2 (the tuberous sclerosis complex), a GTPase-activating protein that inhibits the GTPase, Rheb (28).”
Background
Efficacy and Safety of Sirolimus for Renal Angiomyolipoma in Patients with Tuberous Sclerosis Complex or Sporadic Lymphangioleiomyomatosis: A Systematic Review
Peng, Z., Yang, L., Wang, T., Han, P., Liu, Z., & Wei, Q. (2014) · The Journal of Urology · doi:10.1016/j.juro.2014.04.096 · Cited by 39
The E3 Ubiquitin Ligase Protein Associated with Myc (Pam) Regulates Mammalian/Mechanistic Target of Rapamycin Complex 1 (mTORC1) Signaling in Vivo through N- and C-terminal Domains
Han, S., Kim, S. Y., Bahl, S., Li, L., Burande, C. F., Smith, N., James, M. F., Beauchamp, R. L., Bhide, P. G., DiAntonio, A., et al. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.353987 · Cited by 39
“The TSC proteins act as a central hub relaying signals from diverse cellular pathways to control mTORC1 activity (2, 3).”
Background
Structure of the TBC1D7–TSC1 complex reveals that TBC1D7 stabilizes dimerization of the TSC1 C-terminal coiled coil region
Gai, Z., Chu, W., Deng, W., Li, W., Li, H. L., He, A., Nellist, M. D., & Wu, G. (2016) · Journal of Molecular Cell Biology · doi:10.1093/jmcb/mjw001 · Cited by 41
Roles of mechanistic target of rapamycin and transforming growth factor-β signaling in the molting gland (Y-organ) of the blackback land crab, Gecarcinus lateralis
Abuhagr, A. M., MacLea, K. S., Mudron, M. R., Chang, S. A., Chang, E. S., & Mykles, D. L. (2016) · Comparative Biochemistry and Physiology Part A Molecular & Integrative Physiology · doi:10.1016/j.cbpa.2016.03.018 · Cited by 39
“…cascade involving PI3K, PDK1, and Akt 86 protein kinases (Teleman, 2010). mTORC1 is activated by Rheb-GTP and is inactivated when 87 Rheb-GTPase activating protein (Rheb-GAP or tuberous sclerosis complex 1/2) promotes the 88 hydrolysis of GTP to GDP by Rheb (Huang and Manning, 2008).”
BackgroundInfluential
Import of extracellular ATP in yeast and man modulates AMPK and TORC1 signalling
Forte, G. M. A., Davie, E., Lie, S., Franz‐Wachtel, M., Ovens, A. J., Wang, T., Oakhill, J. S., Maček, B., Hagan, I., & Petersen, J. (2019) · Journal of Cell Science · doi:10.1242/jcs.223925 · Cited by 39
“Consequently, loss of Tsc1/2 function in mammalian cells enhances TORC1 activity (Huang and Manning, 2008).”
Background
Oncogenic KRAS signaling activates mTORC1 through COUP‐TFII‐mediated lactate production
Byun, J., Park, M., Yun, J. W., Lee, J., Kim, J. S., Cho, S. J., Lee, Y. M., Lee, I., Choi, Y., & Park, K. (2019) · EMBO Reports · doi:10.15252/embr.201847451 · Cited by 39
“It is well established that aberrantly activated PI3K/Akt signaling in cancer cells upregulates mTORC1 activity by deactivating the TSC1-TSC2 complex [2].”
Supply of methionine and arginine alters phosphorylation of mechanistic target of rapamycin (mTOR), circadian clock proteins, and α-s1-casein abundance in bovine mammary epithelial cells
Hu, L., Chen, Y., Martínez-Cortés, I., Coleman, D. N., Dai, H., Liang, Y., Parys, C., Fernández, C., Wang, M., & Loor, J. J. (2020) · Food & Function · doi:10.1039/c9fo02379h · Cited by 42
Evidence for the Contribution of Gut Microbiota to Age-Related Anabolic Resistance
Watson, M. D., Cross, B. L., & Grosicki, G. J. (2021) · Nutrients · doi:10.3390/nu13020706 · Cited by 41
A specialized Hsp90 co-chaperone network regulates steroid hormone receptor response to ligand
Backe, S. J., Sager, R., Regan, B., Sit, J., Major, L., Bratslavsky, G., Woodford, M. R., Bourboulia, D., & Mollapour, M. (2022) · Cell Reports · doi:10.1016/j.celrep.2022.111039 · Cited by 40
“Previous work has dissected FNIP1 and Tsc1 interaction with Hsp90 in detail, identifying the C terminus of FNIP1 (FNIP1-D) and Tsc1 (Tsc1-D) as the critical Hsp90-binding element (Baba et al., 2006; Huang and Manning, 2008; Woodford et al., 2016, 2017) (Figure 2A).”
Interneuron Dysfunction in Syndromic Autism: Recent Advances
Takano, T. (2015) · Developmental Neuroscience · doi:10.1159/000434638 · Cited by 41
PRAS40: Target or modulator of mTORC1 signalling and insulin action?
Nascimento, E. B. M., & Ouwens, D. M. (2009) · Archives of Physiology and Biochemistry · doi:10.1080/13813450902988580 · Cited by 39
The novel combination of dual mTOR inhibitor AZD2014 and pan-PIM inhibitor AZD1208 inhibits growth in acute myeloid leukemia via HSF pathway suppression
Harada, M., Benito, J., Yamamoto, S., Kaur, S., Arslan, D., Ramírez, S., Jacamo, R. O., Platanias, L. C., Matsushita, H., Fujimura, T., et al. (2015) · Oncotarget · doi:10.18632/oncotarget.6122 · Cited by 38
“FLT3 is the most frequently mutated gene in AML cells, and approximately 30% of AML patients harbor constitutively activating internal tandem duplication (ITD) mutations known to be associated with poor prognosis [2, 4-6].”
Background
Everolimus improves neuropsychiatric symptoms in a patient with tuberous sclerosis carrying a novel TSC2 mutation
Hwang, S., Lee, J., Yang, J.-E., Lim, C., Lee, J., Lee, Y., Lee, K., & Kaang, B. (2016) · Molecular Brain · doi:10.1186/s13041-016-0222-6 · Cited by 40
“Furthermore, the loss of the Cterminal GTPase activating protein (GAP) domain of TSC2 would also be predicted to disrupt the action of the TSC1-TSC2 complex on the GTPase Ras homolog expressed in brain (RHEB), thus activating RHEB–GTPdependent stimulation of the mammalian target of rapamycin complex 1 (mTORC1) [41].”
Background
Targeting mTOR pathway inhibits tumor growth in different molecular subtypes of triple-negative breast cancers
Hatem, R., Botty, R. E., Château‐Joubert, S., Servely, J., Labiod, D., de Plater, L., Assayag, F., Coussy, F., Callens, C., Vacher, S., et al. (2016) · Oncotarget · doi:10.18632/oncotarget.10195 · Cited by 40
“Both are tumor suppressor genes that negatively regulate mTOR [16, 17].”
Background
PEX5 regulates autophagy via the mTORC1-TFEB axis during starvation
Eun, S. Y., Lee, J. N., Nam, I.-K., Liu, Z., So, H., Choe, S., & Park, R. (2018) · Experimental & Molecular Medicine · doi:10.1038/s12276-017-0007-8 · Cited by 38
Natural killer cells in sepsis: Underprivileged innate immune cells
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Cryo-EM insight into the structure of MTOR complex 1 and its interactions with Rheb and substrates
Chao, L. H., & Avruch, J. (2019) · F1000Research · doi:10.12688/f1000research.16109.1 · Cited by 41
Moments in autophagy and disease: Past and present
Wen, X., Yang, Y., & Klionsky, D. J. (2021) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2021.100966 · Cited by 39
The Role of Hsp90-R2TP in Macromolecular Complex Assembly and Stabilization
Lynham, J., & Houry, W. A. (2022) · Biomolecules · doi:10.3390/biom12081045 · Cited by 43
Autophagy: Mechanisms, regulation, and its role in tumorigenesis
Parkhitko, A. A., Favorova, O. O., & Henske, E. P. (2013) · Biochemistry (Moscow) · doi:10.1134/s0006297913040044 · Cited by 39
Cilium, centrosome and cell cycle regulation in polycystic kidney disease
Lee, K., Battini, L., & Gusella, G. L. (2011) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2011.02.008 · Cited by 38
“The serine/threonine kinase mTOR is the key component of the multiprotein complexes mTORC1, which positively controls protein translation, cell metabolism and proliferation, and mTORC2, which is involved in actin cytoskeleton organization and cell survival [56, 57].”
Background
Epileptogenic but MRI-normal perituberal tissue in Tuberous Sclerosis Complex contains tuber-specific abnormalities
Sosunov, A. A., McGovern, R. A., Mikell, C. B., Wu, X., Coughlin, D. G., Crino, P. B., Weiner, H. L., Ghatan, S., Goldman, J. E., & McKhann, G. M. (2015) · Acta Neuropathologica Communications · doi:10.1186/s40478-015-0191-5 · Cited by 40
“Loss of function of these genes leads to activation of the mTOR cascade, which is critical for cellular growth and development of numerous organ systems [2-4].”
Background
Targeting mTORC1/2 Complexes Inhibit Tumorigenesis and Enhance Sensitivity to 5-Flourouracil (5-FU) in Hepatocellular Carcinoma: A Preclinical Study of mTORC1/2-Targeted Therapy in Hepatocellular Carcinoma (HCC)
Zhang, Y., Jia, Q., Kadel, D., Zhang, X.-F., & Zhang, Q. (2018) · Medical Science Monitor · doi:10.12659/msm.907514 · Cited by 37
“The TSC1/TSC2 complex is a key negative regulator of mTORC1 [11].”
Background
LYCHOS is a human hybrid of a plant-like PIN transporter and a GPCR
Bayly-Jones, C., Lupton, C. J., Keen, A. C., Dong, S., Mastos, C., Luo, W., Qian, C., Jones, G. D., Venugopal, H., Chang, Y., et al. (2024) · Nature · doi:10.1038/s41586-024-08012-9 · Cited by 36
“Activated mTORC1 phosphorylates downstream effectors, including ribosomal S6 kinase and eukaryotic initiation factor 4E binding protein 1 (4EBP1), which are crucial regulators of protein synthesis and cell growth 8 .”
Therapeutic Targeting of Cellular Metabolism in Cells with Hyperactive mTORC1: A Paradigm Shift
Medvetz, D. A., Priolo, C., & Henske, E. P. (2014) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-14-0343 · Cited by 37
“Mol Cancer Res; 13(1) January 2015 Molecular Cancer Research 6”
BackgroundInfluential
Seizure outcome after epilepsy surgery in tuberous sclerosis complex: Results and analysis of predictors from a multicenter study
Vannicola, C., Tassi, L., Barba, C., Boniver, C., Cossu, M., de Curtis, M., Palma, L. D., D’Errico, I., Didato, G., Guerrini, R., et al. (2021) · Journal of the Neurological Sciences · doi:10.1016/j.jns.2021.117506 · Cited by 39
Polymorphic variants in TSC1 and TSC2 and their association with breast cancer phenotypes
Mehta, M. S., Vázquez, A., Kulkarni, D. A., Kerrigan, J. E., Atwal, G. S., Metsugi, S., Toppmeyer, D., Levine, A. J., & Hirshfield, K. M. (2010) · Breast Cancer Research and Treatment · doi:10.1007/s10549-010-1062-1 · Cited by 37
“TSC1 acts to stabilize TSC2, preventing its degradation and both function together as the TSC1/TSC2 heterodimer [8, 10].”
Background
Ribosomal protein S 6 phosphorylation is controlled by TOR and modulated by PKA in C andida albicans
Chowdhury, T., & Köhler, J. R. (2015) · Molecular Microbiology · doi:10.1111/mmi.13130 · Cited by 37
“A major component of the mTOR pathway, S6K, phosphorylates ribosomal protein S6 during active growth (Hay and Sonenberg, 2004; Huang and Manning, 2008).”
Background
Identification of a region required for TSC1 stability by functional analysis of TSC1missense mutations found in individuals with tuberous sclerosis complex
Mozaffari, M., Hoogeveen-Westerveld, M., Kwiatkowski, D., Sampson, J., Ekong, R., Povey, S., den Dunnen, J. T., van den Ouweland, A., Halley, D., & Nellist, M. (2009) · BMC Medical Genetics · doi:10.1186/1471-2350-10-88 · Cited by 36
“Inactivation of the TSC1-TSC2 complex results in activation of mTOR and phosphorylation of the mTOR targets p70 S6 kinase (S6K), ribosomal protein S6 and 4EBP1 [15].”
Gene therapy for tuberous sclerosis complex type 2 in a mouse model by delivery of AAV9 encoding a condensed form of tuberin
Cheah, P.-S., Prabhakar, S., Yellen, D., Beauchamp, R. L., Zhang, X., Kasamatsu, S., Bronson, R. T., Thiele, E. A., Kwiatkowski, D. J., Stemmer-Rachamimov, A., et al. (2021) · Science Advances · doi:10.1126/sciadv.abb1703 · Cited by 38
“We felt it was also important to retain the hamartin-binding domain at the N terminus, as hamartin and tuberin function together as a complex with Tre2-Bub2-Cdc16 (TBC) 1 domain family, member 7 (TBC1D7) to accelerate guanosine triphosphate (GTP) to guanosine diphosphate conversion of Rheb-GTP (3, 22).”
Influential
The space between notes: emerging roles for translationally silent ribosomes
Smith, P. R., Pandit, S. C., Loerch, S., & Campbell, Z. T. (2022) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2022.02.003 · Cited by 35
Recommendations for the radiological diagnosis and follow-up of neuropathological abnormalities associated with tuberous sclerosis complex
Rovira, À., Ruiz-Falcó, M. L., Esparza, E. G., López‐Laso, E., Macaya, A., Málaga, I., Méndez, E. V., & Vicente, J. (2014) · Journal of Neuro-Oncology · doi:10.1007/s11060-014-1429-y · Cited by 36
“Spontaneous or inherited mutations in any of these tumor-suppressor genes, which are found in over 85 % of patients with TSC, result in activation of the mammalian target of rapamycin complex 1 (mTORC1) and, consequently, in the formation of hamartomas in different organs [5, 7–11].”
Background
Inhibitors of phosphatidylinositol-3-kinase in cancer therapy
Ihle, N., & Powis, G. (2010) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2010.02.003 · Cited by 40
“The activation of Rheb allows mTor to be activated through association with raptor and other TORC1 complex members, stimulating TOR dependent mRNA translation through p70S6Kinase, and cap-dependent translation thorough inhibition of the eiF4e repressor, 4E-BP (Huang and Manning, 2008).”
Background
mTOR as a senescence manipulation target: A forked road
Saoudaoui, S., Bernard, M., Cardin, G. B., Malaquin, N., Christopoulos, A., & Rodier, F. (2021) · Advances in cancer research · doi:10.1016/bs.acr.2021.02.002 · Cited by 36
How can we turn the PI3K/AKT/mTOR pathway down? Insights into inhibition and treatment of cancer
Afify, S. M., Oo, A. K. K., Hassan, G., Seno, A., & Seno, M. (2021) · Expert Review of Anticancer Therapy · doi:10.1080/14737140.2021.1918001 · Cited by 36
“and invasion of prostate cancer cells [62,63].”
Effects of Mutations in TSC Genes on Neurodevelopment and Synaptic Transmission
Bassetti, D., Luhmann, H. J., & Kirischuk, S. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22147273 · Cited by 40
“The complex itself is modulated by phosphorylation via, for example, Akt or AMPK (Figure 1, [3]).”
Background
Optimal management of seizures associated with tuberous sclerosis complex: current and emerging options
Fallah, A., & Wang, S. (2014) · Neuropsychiatric Disease and Treatment · doi:10.2147/ndt.s51789 · Cited by 36
mTOR-related neuropathology in mutant tsc2 zebrafish: Phenotypic, transcriptomic and pharmacological analysis
Scheldeman, C., Mills, J. D., Siekierska, A., Serra, I., Copmans, D., Iyer, A. M., Whalley, B. J., Maes, J., Jansen, A., Lagae, L. G., et al. (2017) · Neurobiology of Disease · doi:10.1016/j.nbd.2017.09.004 · Cited by 36
“These genes are classified as tumor suppressor genes that encode hamartin and tuberin, respectively (Qin et al., 2016; Huang and Manning, 2008).”
Background
AKT-mTORC1 reactivation is the dominant resistance driver for PI3Kβ/AKT inhibitors in PTEN-null breast cancer and can be overcome by combining with Mcl-1 inhibitors
Dunn, S., Eberlein, C., Yu, J., Gris‐Oliver, A., Ong, S. H., Yelland, U., Cureton, N., Staniszewska, A. D., McEwen, R. K., Fox, M., et al. (2022) · Oncogene · doi:10.1038/s41388-022-02482-9 · Cited by 37
“The TSC1-TSC2 complex is a critical negative regulator of mTORC1 signaling [36].”
Background
A pooled Cell Painting CRISPR screening platform enables de novo inference of gene function by self-supervised deep learning
Sivanandan, S., Leitmann, B., Lubeck, E., Sultan, M. M., Stanitsas, P., Ranu, N., Ewer, A., Mancuso, J. E., Phillips, Z. F., Kim, A. M., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-66778-6 · Cited by 44
Role of the TSC1-TSC2 Complex in the Integration of Insulin and Glucose Signaling Involved in Pancreatic β-Cell Proliferation
Bartolomé, A., Guillén, C., & Benito, M. (2010) · Endocrinology · doi:10.1210/en.2010-0048 · Cited by 35

Authors: Huang, J., & Manning, B. D.
Affiliations: Harvard University (US)
ORCID: Huang, Jingxiang
Manning, Brendan D.
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
DOI: 10.1042/bj20080281
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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The TSC1–TSC2 complex: a molecular switchboard controlling cell growth

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