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
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Retracted
Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex
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Self-citation
TOR signaling in growth and metabolism
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Upstream and downstream of mTOR
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TSC2 Mediates Cellular Energy Response to Control Cell Growth and Survival
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Background
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Miyazaki, M., & Takemasa, T. (2017) · FEBS Open Bio · doi:10.1002/2211-5463.12195 · Cited by 34
The mTORC1 component RPTOR is required for maintenance of the foundational spermatogonial stem cell pool in mice†
Serra, N. D., Velte, E. K., Niedenberger, B. A., Kirsanov, O., & Geyer, C. B. (2018) · Biology of Reproduction · doi:10.1093/biolre/ioy198 · Cited by 30
Structure of the Tuberous Sclerosis Complex 2 (TSC2) N Terminus Provides Insight into Complex Assembly and Tuberous Sclerosis Pathogenesis
Zech, R., Kiontke, S., Mueller, U., Oeckinghaus, A., & Kümmel, D. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.m116.732446 · Cited by 29
“Orthologues of TSC1 and TSC2 exist in a range of eukaryotes (30), including the thermophilic fungus Chaetomium thermophilum, which we used for recombinant production of TSC proteins.”
Background
Exhaustive Training Leads to Hepatic Fat Accumulation
da Rocha, A. L., Pinto, A. P., Teixeira, G. R., Pereira, B. C., Oliveira, L. C., Caldo‐Silva, A., Morais, G. P., Cintra, D. E., Pauli, J. R., & da Silva, A. S. R. (2016) · Journal of Cellular Physiology · doi:10.1002/jcp.25625 · Cited by 29
“There was no significant difference between the experimental groups for the protein levels of pAMPK (Ser485/ 491), pTSC2 (Ser939), and PTEN (Fig.”
BackgroundInfluential
The effects of TORC signal interference on lipogenesis in the oleaginous yeast Trichosporon oleaginosus
Bracharz, F., Redai, V., Bach, K., Qoura, F., & Brück, T. (2017) · BMC Biotechnology · doi:10.1186/s12896-017-0348-3 · Cited by 29
“involvement of other factors, especially in reaction to low nutrient content is feasible [23].”
Background
FGF401 and vinorelbine synergistically mediate antitumor activity and vascular normalization in FGF19-dependent hepatocellular carcinoma
Huynh, H. T., Prawira, A., Le, T. B. U., Vu, T. C., Hao, H.-X., Huang, A., Wang, Y., & Porta, D. G. (2020) · Experimental & Molecular Medicine · doi:10.1038/s12276-020-00524-4 · Cited by 28
The Epigenetic Regulatory Protein CBX2 Promotes mTORC1 Signalling and Inhibits DREAM Complex Activity to Drive Breast Cancer Cell Growth
Bilton, L. J., Warren, C., Humphries, R. M., Kalsi, S., Waters, E. V., Francis, T., Dobrowinski, W., Beltrán-Álvarez, P., & Wade, M. (2022) · Cancers · doi:10.3390/cancers14143491 · Cited by 29
“TSC1 and TSC2 form a GTPase‐activating protein complex that inhibits RHEB, a crucial activator of mTORC1 signalling [29].”
Background
GADD34 inhibits activation-induced apoptosis of macrophages through enhancement of autophagy
Ito, S., Tanaka, Y., Oshino, R., Aiba, K., Thanasegaran, S., Nishio, N., & Isobe, K.-I. (2015) · Scientific Reports · doi:10.1038/srep08327 · Cited by 28
Recent Development in Targeting PI3K-Akt-mTOR Signaling for Anticancer Therapeutic Strategies
Qazi, A. K., Hussain, A., Hamid, A., Qurishi, Y., Majeed, R., Ahmad, M., Najar, R. A., Bhat, J. A., Singh, S. K., Zargar, M. A., et al. (2013) · Anti-Cancer Agents in Medicinal Chemistry · doi:10.2174/1871520613666131125123241 · Cited by 29
“This complex functions as a GTPase-activating protein (GAP) for the small G protein Ras homolog enriched in brain (RHEB) [21].”
Background
Uterine Histotroph and Conceptus Development. I. Cooperative Effects of Arginine and Secreted Phosphoprotein 1 on Proliferation of Ovine Trophectoderm Cells via Activation of the PDK1-Akt/PKB-TSC2-MTORC1 Signaling Cascade1
Wang, X., Johnson, G. A., Burghardt, R. C., Wu, G., & Bazer, F. W. (2014) · Biology of Reproduction · doi:10.1095/biolreprod.114.125971 · Cited by 29
AMPK-mediated activation of Akt protects renal tubular cells from stress-induced apoptosis in vitro and ameliorates ischemic AKI in vivo
Lieberthal, W., Tang, M., Abate, M. T., Lusco, M. A., & Levine, J. S. (2019) · American Journal of Physiology-Renal Physiology · doi:10.1152/ajprenal.00553.2018 · Cited by 28
“Antibodies to phosphorylated (Thr172) AMPK, phosphorylated (Thr308) Akt, phosphorylated (Ser473) Akt, phosphorylated (Ser792) regulatory-associated protein of mechanistic target of rapamycin (Raptor), phosphorylated (Ser302) insulin receptor substrate-1 (IRS1), phosphorylated (Ser1387) tuberous sclerosis complex (TSC)…”
BackgroundInfluential
Mammalian Target of Rapamycin Inhibitors Resistance Mechanisms in Clear Cell Renal Cell Carcinoma
Kornakiewicz, A., Solarek, W., Bielecka, Z. F., Lian, F., Szczylik, C. A., & Czarnecka, A. M. (2014) · Current Signal Transduction Therapy · doi:10.2174/1574362409666140206222746 · Cited by 29
4E-BPs Control Fat Storage by Regulating the Expression of Egr1 and ATGL
Singh, M., Shin, Y., Yang, X., Zehr, B., Chakrabarti, P., & Kandror, K. V. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.631895 · Cited by 29
“TSC2-null MEFs that have hyperactive mTORC1 (38).”
Rheb1 deletion in myeloid cells aggravates OVA-induced allergic inflammation in mice
Li, K., Zhang, Y., Liang, K., Xu, S., Zhou, X. J., Tan, K. W., Lin, J., Bai, X. C., & Yang, C. L. (2017) · Scientific Reports · doi:10.1038/srep42655 · Cited by 28
4-(Difluoromethyl)-5-(4-((3 R ,5 S )-3,5-dimethylmorpholino)-6-(( R )-3-methylmorpholino)-1,3,5-triazin-2-yl)pyridin-2-amine (PQR626), a Potent, Orally Available, and Brain-Penetrant mTOR Inhibitor for the Treatment of Neurological Disorders
Borsari, C., Keleş, E., Rageot, D., Treyer, A., Bohnacker, T., Bissegger, L., Pascale, M. D., Melone, A., Sriramaratnam, R., Beaufils, F., et al. (2020) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.0c00620 · Cited by 28
Unraveling the Big Sleep: Molecular Aspects of Stem Cell Dormancy and Hibernation
Dias, I. B., Bouma, H. R., & Henning, R. H. (2021) · Frontiers in Physiology · doi:10.3389/fphys.2021.624950 · Cited by 28
“Activation and inhibition of the Akt/mTOR pathway are paramount for cell cycle arrest during torpor and proliferation during arousal (Huang and Manning, 2008; Wu and Storey, 2012b).”
Background
Efficacy of Sirolimus Treatment in PEComa–10 Years of Practice Perspective
Świtaj, T., Sobiborowicz, A., Teterycz, P., Klimczak, A., Makuła, D., Wągrodzki, M., Szumera‐Ciećkiewicz, A., Rutkowski, P. L., & Czarnecka, A. M. (2021) · Journal of Clinical Medicine · doi:10.3390/jcm10163705 · Cited by 28
Rheb promotes cancer cell survival through p27Kip1‐dependent activation of autophagy
Campos, T., Ziehe, J., Palma, M., Escobar, D., Tapia, J. C., Pincheira, R., & Castro, A. F. (2015) · Molecular Carcinogenesis · doi:10.1002/mc.22272 · Cited by 29
“We and others have shown that Rheb activity is controlled by the TSC1/2 tumor suppressor complex, with Rheb being a direct target of TSC2 GAP activity [14,15].”
Background
The Next Step: Innovative Molecular Targeted Therapies for Treatment of Intracranial Chordoma Patients
Barry, J. J., Jian, B. J., Sughrue, M. E., Kane, A. J., Mills, S. A., Tihan, T., & Parsa, A. T. (2010) · Neurosurgery · doi:10.1227/neu.0b013e3181fd2ac5 · Cited by 29
“TSC1, TSC2, and their interactions with the RAS homolog enriched in brain play an inhibitory role in mTOR.(59,60) Inactivation of the TSC1/TSC2 complex is achieved by the phosphorylation of TSC2 by AKT or through separate RAS/ MEK/ERK signaling.”
Background
Metformin in lung cancer: rationale for a combination therapy
Morgillo, F., Sasso, F. C., Corte, C. M. D., Festino, L., Manzo, A., Martinelli, E., Troiani, T., Capuano, A., & Ciardiello, F. (2013) · Expert Opinion on Investigational Drugs · doi:10.1517/13543784.2013.828691 · Cited by 29
“synthesis is accomplished by AMPK-induced phosphorylation and activation of TSC2 and consequently inhibition of Rheb (RAS homolog enriched in brain)/mTORC1 signaling [50].”
Background
Protein kinase C and P2Y12 take center stage in thrombin‐mediated activation of mammalian target of rapamycin complex 1 in human platelets
Moore, S., Hunter, R. W., & Hers, I. (2014) · Journal of Thrombosis and Haemostasis · doi:10.1111/jth.12552 · Cited by 29
The molecular biology of WHO grade I astrocytomas
Marko, N. F., & Weil, R. J. (2012) · Neuro-Oncology · doi:10.1093/neuonc/nos257 · Cited by 28
“Deficiencies of hamartin or tuberin lead to constitutive mTOR activation and subsequently to unregulated cellular growth.(99,100) CNS-specific investigations of this process remain in their early stages, but it is generally hypothesized that abnormalities in TSC1, TSC2, or their gene products in subependymal astrocyte…”
Background
Prognostic implication of TSC1 and mTOR expression in gastric carcinoma
Byeon, S., Han, N., Choi, J., Kim, M. A., & Kim, W. H. (2014) · Journal of Surgical Oncology · doi:10.1002/jso.23585 · Cited by 28
“The TSC1 mutations are non‐sense or frame‐shift mutations and result in an improper coiled‐coil domain (719–998 amino acids) [13].”
Background
Pharmacokinetics and pharmacodynamics of everolimus in patients with renal angiomyolipoma and tuberous sclerosis complex or lymphangioleiomyomatosis
Budde, K., Zonnenberg, B. A., Frost, M., Cheung, W. K., Urva, S., Brechenmacher, T., Stein, K. F., Chen, D., Kingswood, J. C., & Bissler, J. J. (2015) · British Journal of Clinical Pharmacology · doi:10.1111/bcp.12834 · Cited by 28
Tuberous sclerosis complex: Hamartin and tuberin expression in renal cysts and its discordant expression in renal neoplasms
Bonsib, S. M., Boils, C. L., Gökden, N., Grignon, D. J., Gu, X., Higgins, J., Leroy, X., McKenney, J. K., Nasr, S. H., Phillips, C. L., et al. (2016) · Pathology - Research and Practice · doi:10.1016/j.prp.2016.04.005 · Cited by 28
“The products of TSC1 and TSC2, hamartin and tuberin, are multifunctional proteins that form a cooperative complex [21-25].”
Background
Geranylgeraniol Prevents Statin‐Dependent Myotoxicity in C2C12 Muscle Cells through RAP1 GTPase Prenylation and Cytoprotective Autophagy
Jaśkiewicz, A., Pająk, B., Litwiniuk, A., Urbańska, K., & Orzechowski, A. (2018) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2018/6463807 · Cited by 28
“Thus, as long as TSC1/TSC2 complex is inhibited by AKT, RAP1 GTPase stimulates mTOR/mLST8/raptor complex and cell growth [13].”
Cerebral dopamine neurotrophic factor protects microglia by combining with AKT and by regulating FoxO1/mTOR signaling during neuroinflammation
Zhang, Y., Xiang, Y., Wang, X., Zhu, L., Li, H., Wang, S., Pan, X. L., & Zhao, H. (2018) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2018.11.028 · Cited by 28
A logic-based method to build signaling networks and propose experimental plans
Rougny, A., Gloaguen, P., Gallay, N., Reiter, É., Crépieux, P., Anne Poupon, B., & Froidevaux, C. (2018) · Scientific Reports · doi:10.1038/s41598-018-26006-2 · Cited by 27
Renal organoid modeling of tuberous sclerosis complex reveals lesion features arise from diverse developmental processes
Pietrobon, A., Yockell‐Lelièvre, J., Flood, T. A., & Stanford, W. L. (2022) · Cell Reports · doi:10.1016/j.celrep.2022.111048 · Cited by 24
Sustained activation of mTORC1 in macrophages increases AMPKα-dependent autophagy to maintain cellular homeostasis
Pan, H., Zhong, X., & Lee, S. (2016) · BMC Biochemistry · doi:10.1186/s12858-016-0069-6 · Cited by 27
“Representative Western blot of TSC1 and TSC2 in bone marrow macrophages from TSC1f/fERCre+ mice (a) and in the resident peritoneal macrophages of TSC1fl/fl LysM-Cre+ mice (b) did not detect the TSC1 and TSC2 proteins.”
BackgroundInfluential
PDGF receptor-β uses Akt/mTORC1 signaling node to promote high glucose-induced renal proximal tubular cell collagen I (α2) expression
Das, F., Ghosh‐Choudhury, N., Venkatesan, B. A., Kasinath, B. S., & Choudhury, G. G. (2017) · American Journal of Physiology-Renal Physiology · doi:10.1152/ajprenal.00666.2016 · Cited by 27
Cross Talk Networks of Mammalian Target of Rapamycin Signaling With the Ubiquitin Proteasome System and Their Clinical Implications in Multiple Myeloma
Eichner, R., Fernández‐Sáiz, V., Targosz, B., & Bassermann, F. C. (2018) · International review of cytology · doi:10.1016/bs.ircmb.2018.06.001 · Cited by 27
Rapamycin Induces an eNOS (Endothelial Nitric Oxide Synthase) Dependent Increase in Brain Collateral Perfusion in Wistar and Spontaneously Hypertensive Rats
Beard, D. J., Li, Z., Schneider, A. M., Couch, Y., Cipolla, M. J., & Buchan, A. M. (2020) · Stroke · doi:10.1161/strokeaha.120.029781 · Cited by 27
The self-fulfilling prophecy of pulmonary fibrosis: a selective inspection of pathological signalling loops
Rackow, A. R., Nagel, D. J., McCarthy, C., Judge, J., Lacy, S. H., Freeberg, M. A. T., Thatcher, T. H., Kottmann, R. M., & Sime, P. J. (2020) · European Respiratory Journal · doi:10.1183/13993003.00075-2020 · Cited by 29
“Once activated, Akt causes the activation of mTOR signalling via multiple substrates [77].”
Background
Tumorigenesis Mechanisms Found in Hereditary Renal Cell Carcinoma: A Review
Webster, B. R., Gopal, N., & Ball, M. W. (2022) · Genes · doi:10.3390/genes13112122 · Cited by 28
Therapeutic Trial of Metformin and Bortezomib in a Mouse Model of Tuberous Sclerosis Complex (TSC)
Auricchio, N., Malinowska, I. A., Shaw, R. J., Manning, B. D., & Kwiatkowski, D. J. (2012) · PLoS ONE · doi:10.1371/journal.pone.0031900 · Cited by 27
“We suspect that the complete absence of Tsc2 in these Tsc2+/2 cystadenoma lesions leads to strong activation of mTORC1 due to constitutive high levels of RHEB-GTP, which makes these lesions resistant to the lesser effect of Raptor phosphorylation.”
BackgroundInfluentialSelf-citation
Hypoxia Increases IGFBP-1 Phosphorylation Mediated by mTOR Inhibition
Damerill, I., Biggar, K. K., Shehab, M. A., Li, S. S. ‐., Jansson, T., & Gupta, M. B. (2015) · Molecular Endocrinology · doi:10.1210/me.2015-1194 · Cited by 27
Rapid resolution of cardiac rhabdomyomas following everolimus therapy
Choudhry, S., Nguyen, H. H., & Anwar, S. (2015) · BMJ Case Reports · doi:10.1136/bcr-2015-212946 · Cited by 27
VPS34 regulates TSC1/TSC2 heterodimer to mediate RheB and mTORC1/S6K1 activation and cellular transformation
Mohan, N., Shen, Y., Dokmanovic, M., Endo, Y., Hirsch, D. S., & Wu, W. J. (2016) · Oncotarget · doi:10.18632/oncotarget.10469 · Cited by 28
“Moreover, no difference in GAP activity towards recombinant RheB is detected between wild type TSC2 and phosphorylated TSC2 [6].”
Background
C16orf72/HAPSTR1 is a molecular rheostat in an integrated network of stress response pathways
Amici, D. R., Ansel, D. J., Metz, K. A., Smith, R. S., Phoumyvong, C. M., Gayatri, S., Chamera, T., Edwards, S. L., O’Hara, B. P., Srivastava, S., et al. (2022) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2111262119 · Cited by 29
“For example, TSC2—a negative regulator of mTORC1 activated by diverse stressors (14)—was the single most connected”
Background
The evolutionary tug-of-war of macrophage metabolism during bacterial infection
Almeida, L., Dhillon-LaBrooy, A., & Sparwasser, T. D. (2023) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2023.11.002 · Cited by 25
RIP3 antagonizes a TSC2-mediated pro-survival pathway in glioblastoma cell death
Fettweis, G., Di Valentin, E., L'homme, L., Lassence, C., Dequiedt, F., Fillet, M., Coupienne, I., & Piette, J. (2017) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2016.10.014 · Cited by 26
Understanding the health economic burden of patients with tuberous sclerosis complex (TSC) with epilepsy: a retrospective cohort study in the UK Clinical Practice Research Datalink (CPRD)
Shepherd, C., Koepp, M. J., Myland, M., Patel, K., Miglio, C., Siva, V., Gray, E. J., & Neary, M. P. (2017) · BMJ Open · doi:10.1136/bmjopen-2016-015236 · Cited by 26
The role of TSC2 in breast cancer: a literature review
Zhu, Q., He, Z.-M., Cao, W., & Li, B. (2023) · Frontiers in Oncology · doi:10.3389/fonc.2023.1188371 · Cited by 26
Drug Interactions and the Pharmacist: Focus on Everolimus
Grabowsky, J. A. (2013) · Annals of Pharmacotherapy · doi:10.1345/aph.1r769 · Cited by 26
Deficient TSC1/TSC2-complex suppression of SOX9-osteopontin-AKT signalling cascade constrains tumour growth in tuberous sclerosis complex
Jin, F., Jiang, K., Ji, S., Wang, L., Ni, Z., Huang, F., Li, C., Chen, R., Zhang, H., Hu, Z., et al. (2016) · Human Molecular Genetics · doi:10.1093/hmg/ddw397 · Cited by 26
Reciprocal signaling between mTORC1 and MNK2 controls cell growth and oncogenesis
Xie, J., Shen, K., Jones, A. T., Yang, J., Tee, A. R., Shen, M. H., Yu, M., Irani, S., Wong, D., Merrett, J. E., et al. (2020) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-020-03491-1 · Cited by 27
“The reason that MNKs are not required for activation of mTORC1 signaling by EGF, IGF-1 or FBS likely reflects the fact that these agents, unlike TPA, activate PI 3-kinase/ PKB signaling, which provides an alternative mechanism to turn on mTORC1 through the PKB-mediated phosphorylation and inactivation of TSC1/2 [54].”
Background
Biomolecular condensates and disease pathogenesis
Ruan, K., Bai, G., Fang, Y., Li, D., Li, T., Liu, X., Lu, B., Lü, Q., Songyang, Z., Sun, S., et al. (2024) · Science China Life Sciences · doi:10.1007/s11427-024-2661-3 · Cited by 28
“However, the guanine nucleotide exchange factor (GEF) for Rheb was still controversial (Hsu et al., 2007; Huang and Manning, 2008; Rehmann et al., 2008; Saxton and Sabatini, 2017).”
Role of mammalian target of rapamycin (mTOR) signalling in oncogenesis
El‐Tanani, M., Nsairat, H., Aljabali, A. A. A., Serrano‐Aroca, Á., Mishra, V. K., Mishra, Y., Naikoo, G. A., Alshaer, W., & Tambuwala, M. M. (2023) · Life Sciences · doi:10.1016/j.lfs.2023.121662 · Cited by 27
Updates on the Physiopathology of Group I Metabotropic Glutamate Receptors (mGluRI)-Dependent Long-Term Depression
Mango, D., & Ledonne, A. (2023) · Cells · doi:10.3390/cells12121588 · Cited by 25

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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