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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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
Sarbassov, D. D., Guertin, D. A., Ali, S. M., & Sabatini, D. M. (2005) · Science · doi:10.1126/science.1106148 · Cited by 6,216
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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
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
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“…including insulin, energy stress oxygen pathways, growth factors, etc., (Ramlaul and Aylett, 2018; González and Hall, 2017; Demetriades et al., 2014; Huang and Manning, 2008), which are generally achieved through posttranslational modifications such as phosphorylation (Supplementary Table S1).”
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Insulin Signaling Pathway Model in Adipocyte Cells
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From Classical to Emerging Biomarkers of Brain and Central Nervous System Tumors. An Evidence-Based Review with a Focus on Gliomas
Ortega, M. A., Fraile‐Μartinez, O., Boaru, D. L., León-Oliva, D. D., Castro-Martinez, P. D., García-Montero, C., García-González, B., Pérez-González, I., Alhaddadin, M. N. M., Barrena-Blázquez, S., et al. (2026) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-025-01642-1 · Cited by 4
Establishing and characterizing a novel doxorubicin-resistant acute myeloid leukaemia cell line
de Castro, I. O., Lopes-Rodrigues, V., Branco, H., Vasconcelos, M. H., & Xavier, C. P. R. (2022) · Journal of Chemotherapy · doi:10.1080/1120009x.2022.2097432 · Cited by 3
“TSC2 (tuberous sclerosis protein complex 2) or tuberin 2 is the product of the tumour supressor gene and a negative regulator of mammalian target of rapamycin complex 1 (mTORC1) [44].”
Background
Distinct Driver Pathway Enrichments and a High Prevalence of TSC2 Mutations in Right Colon Cancer in Chile: A Preliminary Comparative Analysis
Valladares, C. T., Valenzuela, G., González, E., Maureira, I., Toro, J., Freire, M., Sepúlveda-Hermosilla, G., Ampuero, D., Blanco, A., Gallegos, I., et al. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25094695 · Cited by 4
“Mutations in TSC1 / TSC2 can lead to mTOR overactivation, promoting tumor growth [43].”
Background
Role of PD-1/PD-L1 crosstalk on inhibition of T-cell activation and proliferation through blockade of PI3K/Akt/mTOR signaling pathway
Smith, J. (2024) · doi:10.32948/ajsep.2024.11.18 · Cited by 3
A rare case of a malignant hepatic perivascular epithelioid cell tumor (PEComa) with aggressive progression following the relapse of renal pecoma despite everolimus therapy
Kitagawa, A., Nishio, A., Hikita, H., Kato, T., Doi, A., Sato, K., Tahara, S., Kimura, Y., Ono, Y., & Takehara, T. (2025) · Clinical Journal of Gastroenterology · doi:10.1007/s12328-024-02085-9 · Cited by 3
“Loss-of-function mutations in TSC1 or TSC2 lead to aberrant activation of the mTOR cascade, resulting in cell proliferation and tumor formation [9].”
Novel Role of the Epstein-Barr Virus Encoded Deubiquitinating Enzyme (BPLF1) in mTOR-Mediated Cell Growth and Proliferation Pathways
Mund, R., Atkins, S., Cao, A., Diallo, A., & Whitehurst, C. B. (2025) · Viruses · doi:10.3390/v17081139 · Cited by 3
“TSC2 is a negative regulator of mTORC1, as it downregulates the activation of Rheb, a small GTPase that directly activates mTORC1 [56].”
The critical role of the proto-oncogene c-Kit in TSC renal cystogenesis
Zahedi, K. A., Barone, S., Brooks, M., Zhang, W., Yu, J. J., Zaidman, N. A., & Soleimani, M. (2025) · EMBO Molecular Medicine · doi:10.1038/s44321-025-00360-x · Cited by 4
“In TSC, RHEB is no longer under the inhibitory control of TSPC and, in its GTP-bound form, activates mTORC1, leading to unhindered cell growth and proliferation (Huang and Manning, 2008; Inoki et al, 2003).”
The mTOR Complexes in Cancer Cell Metabolism
Lynch, T. P., Moloughney, J. G., & Jacinto, E. (2016) · Cancer drug discovery and develogment/Cancer drug discovery and development · doi:10.1007/978-3-319-34211-5_2 · Cited by 3
“The insulin/PI3K signals are wired to mTOR via the tuberous sclerosis protein complex (TSC1/TSC2) [67] (Fig.”
Background
Everolimus treatment among patients with tuberous sclerosis affects serum lipid profile
Trelińska, J., Dachowska, I., Kotulska, K., Jóźwiak, S., Fendler, W. M., & Mlynarski, W. M. (2016) · Pharmacological Reports · doi:10.1016/j.pharep.2016.05.011 · Cited by 3
Heterozygous Tsc2 (Tsc2+/–) mouse model to study induced renal cancer in response to ionizing radiation at low doses
Sureshkumar, M. A., Delma, C. R., Krishnan, M., Mohan, S., Habib, S. L., & Natarajan, M. (2018) · Carcinogenesis · doi:10.1093/carcin/bgy172 · Cited by 3
Deoxyelephantopin induces ROS-mediated autophagy and apoptosis in human colorectal cancer in vitro and in vivo
Wong, P., Kadir, H. A., Chan, C. K., & Tong, K.-L. (2020) · Asian Pacific Journal of Tropical Biomedicine · doi:10.4103/2221-1691.276318 · Cited by 3
“Activation of ERK activates the TSC2-TSC1 complex whereas activation of AKT increases TSC2 phosphorylation resulting in the dissociation of the TSC2-TSC1 complex[41,42].”
Background
Use and outcomes of kidneys from donors with renal angiomyolipoma: A systematic review
Cheungpasitporn, W., Anton, D., Kovvuru, K. R., Kanduri, S. R., Aeddula, N. R., Bathini, T. J., Thongprayoon, C., Kaewput, W., Wijarnpreecha, K., Watthanasuntorn, K., et al. (2021) · Urology Annals · doi:10.4103/ua.ua_14_20 · Cited by 3
Epilepsy associated tuberous sclerosis; a case report from Bangladesh
Shrestha, A. B., Shrestha, S., Seemanta, S., Pokharel, P., & Alam, W. (2022) · Annals of Medicine and Surgery · doi:10.1016/j.amsu.2022.103738 · Cited by 3
“The products of these mutated genes cause the deactivation of the inhibition of the mammalian target of rapamycin (mTOR) signaling cascade [5].”
Background
Targeting the PI3K/Akt/mTOR Pathway in AIDS-Associated Malignancies
Damania, B. (2010) · Springer eBooks · doi:10.1007/978-1-4419-1513-9_9 · Cited by 2
“Thus, mTORC1 stimulates translation of TOR-dependent mRNAs and cap-dependent translation (Huang and Manning, 2008).”
Background
Phakomatoses and Allied Conditions
Thiele, E. A., & Korf, B. R. (2017) · Elsevier eBooks · doi:10.1016/b978-0-323-37101-8.00045-x · Cited by 3
AGC Kinases in mTOR Signaling
Jacinto, E. (2010) · The Enzymes · doi:10.1016/s1874-6047(10)27007-5 · Cited by 3
“Five phosphorylation sites in TSC2, which conform to the Akt recognition motif are Akt targets [93] (Figure 7.”
Background
The Role of AMPK in the Control of Cardiac Hypertrophy
Byrne, N. J., Sung, M. M. Y., & Dyck, J. R. B. (2014) · Springer eBooks · doi:10.1007/978-1-4939-1227-8_13 · Cited by 3
Translational and Post-translational Control of Leptin Production by Fat Cells
Kandror, K. V. (2015) · Springer eBooks · doi:10.1007/978-3-319-25124-0_10 · Cited by 3
Hereditary Renal Cell Carcinoma
Baba, M., Schmidt, L. S., & Linehan, W. M. (2017) · Springer eBooks · doi:10.1007/978-4-431-55531-5_2 · Cited by 4
Chordoma: Etiology, Pathogenesis, Diagnosis, Treatment
Travkina, J. V., Zhevak, T. N., & Litvitsky, P. F. (2018) · Вопросы современной педиатрии · doi:10.15690/vsp.v17i4.1917 · Cited by 3
“Продуктами экспрессии этих генов являются белки гамартин и туберин, ассоциированные с клеточной мембраной и оказывающие влияние на процессы дифференцировки клеток и регуляции клеточного цикла [20].”
Influential
Pharmacological inhibition of S6K1 facilitates platelet activation by enhancing Akt phosphorylation
Gao, W., Wang, K., Zhang, L., Li, J., Liu, J., Chen, X., & Luo, X. (2017) · Platelets · doi:10.1080/09537104.2017.1416075 · Cited by 3
“Although S6K1 is indirectly regulated by Akt through phosphorylation by the tuberous sclerosis complex (TSC2) tumor suppressor/mTORC1 signaling pathway [33], S6K1 was recently shown to act as an important”
Background
TORC1 selectively regulates synaptic maturation and input convergence in the developing visual system
Gobert, D., Schohl, A., Kutsarova, E., & Ruthazer, E. S. (2020) · Developmental Neurobiology · doi:10.1002/dneu.22782 · Cited by 3
“…disorders such as tuberous sclerosis and autism spectrum disorder have been associated with imbalances of protein synthesis and more specifically with dysregulation of components of the mTOR pathway like Tsc1 and 4E-BP2 (Bateup et al., 2011, 2013; Gkogkas et al., 2013; Huang & Manning, 2008).”
Background
Structural Characterization of Endogenous Tuberous Sclerosis Protein Complex Revealed Potential Polymeric Assembly
Dai, D. L., Hasan, S. M. N., Woollard, G., Abbas, Y. M., Bueler, S. A., Julien, J., Rubinstein, J. L., & Mazhab‐Jafari, M. T. (2021) · Biochemistry · doi:10.1021/acs.biochem.1c00269 · Cited by 3
Downstream Targets of mTORC1
Fonseca, B. D., & Proud, C. G. (2009) · Humana Press eBooks · doi:10.1007/978-1-60327-271-1_9 · Cited by 5
“(see chapter “mTORC1: A Signaling Integration Node Involved in Cell Growth”) or its regulation [9].”
Case Report A novel TSC1 mutation (c.1964delA) in a Chinese patient with tuberous sclerosis complex
Wang, G.-X., Dw, W., Zhao, J.-S., Wang, S., & Sun, R.-P. (2010) · Genetics and Molecular Research · doi:10.4238/vol10-1gmr977 · Cited by 3
“The molecular basis of TSC is a functional impairment of the TSC1-TSC2 complex; TSC1 in the complex is required for maintaining the stability, activity and correct intracellular localization of the complex (Huang and Manning, 2008; Mozaffari et al., 2009).”
Background
Tuberous sclerosis complex‐1 (TSC1) contributes to selective neuronal vulnerability in Alzheimer's disease
Adriaanse, B. A., Brady, S., Wang, M., Beard, D. J., Spencer, J. I., Pansieri, J., Sutherland, B. A., Esiri, M. M., Buchan, A. M., Cader, Z., et al. (2023) · Neuropathology and Applied Neurobiology · doi:10.1111/nan.12904 · Cited by 2
“mTORC1 is a pleomorphic complex involved in protein synthesis, cellular growth, proliferation and differentiation and has an inhibitory effect on autophagy [8].”
Background
The CTLH ubiquitin ligase substrates ZMYND19 and MKLN1 negatively regulate mTORC1 at the lysosomal membrane
Wang, Y., Liao, Y., Sun, Y., Mitra, B., Guo, R., Piedras, B. I., White, S., Tang, H.-Y., Asara, J. M., Tempera, I., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-65760-6 · Cited by 7
“Together with TSC2 and TBC1D7, TSC1 negatively regulatesmTORC1activationthroughGTPase-activatingprotein(GAP) activity towards the small GTPase Rheb 48 , whereas GATOR1 GAP activity negatively regulates mTORC1 lysosomal recruitment by the Ragulator-Rag complex in response to amino acid depletion 8,49 – 51 .”
Influential
ATR promotes mTORC1 activity via de novo cholesterol synthesis
Tangudu, N. K., Grumet, A. N., Fang, R., Buj, R., Cole, A. R., Uboveja, A., Amalric, A., Yang, B., Huang, Z., Happe, C., et al. (2025) · EMBO Reports · doi:10.1038/s44319-025-00451-3 · Cited by 5
“Consistent with the increase in DNA damage observed in p16 knockdown cells (Tangudu et al, 2024), we found that these cells have increased phosphorylation of ATR/ATM substrates pCHK1 and pCHK2 (Fig.”
LncRNA MRPL39 inhibits cell proliferation and migration by regulating miR-130/TSC1 axis in non-small cell lung cancer
Fan, Q., Bao, X., Zhao, H. Q., & Li, S. (2024) · 3 Biotech · doi:10.1007/s13205-024-03975-y · Cited by 2
“…pathway, contributing significantly to various cellular processes such as development, cell growth, proliferation, survival, autophagy, and ciliary development through its collaboration with a diverse array of regulatory molecules (Huang and Manning 2008; Li et al. 2017; Mallela and Kumar 2021).”
Role of radiotherapy in advanced oncogenic-driven oligometastatic non-small cell lung cancer patients: a narrative review
Zhang, M., Wang, Q., Guo, T., Gao, W., Zhang, B.-Y., & Wang, H. (2025) · Journal of Thoracic Disease · doi:10.21037/jtd-2024-1932 · Cited by 2
Utility of Drosophila for studying hypoxia-inducible factor (HIF) in neurodegenerative diseases: Advantages versus limitations
Serebrovska, Z. O., Xi, L., Khetsuriani, M., Protsenko, O. V., Morozova, N., Tolstun, D. A., & Maksymchuk, O. (2025) · Brain Research · doi:10.1016/j.brainres.2025.149953 · Cited by 2
Challenges and Progress for Treatment of Malignant Peripheral Nerve Sheath Tumors in the Context of Recent Successes for Sarcoma Therapy
Callaghan, J. F., & Mattingly, R. R. (2025) · Cancers · doi:10.3390/cancers17233781 · Cited by 2
“TSC is a negative regulator of the mTOR pathway, thus mutations in TSC increase mTOR pathway signaling in PEComa [77,78].”
TSC2 is a positive master regulator of cellulase production by affecting protein secretion in Trichoderma reesei
Wang, Y., Zhang, F., Wang, H., Pang, A., Wu, F.-G., & Lin, F. (2025) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2025.149944 · Cited by 2
mTOR signaling regulates demand-adapted hematopoiesis and metabolic reprogramming required for an effective cellular immune response in Drosophila melanogaster larvae
Ines, A., Ekström, J., Tuomela, T., Rämet, M., Salminen, T. S., & Vesala, L. (2026) · PLoS Genetics · doi:10.1371/journal.pgen.1012094 · Cited by 2
“The Tuberous Sclerosis Complex (TSC), consisting of TSC1 and TSC2 (Tsc1 and Gigas in Drosophila ), negatively regulates mTORC1, while the TSC is required for proper activation of mTORC2 [15,16].”
Crosstalk of Molecular Signaling in Hepatocellular Carcinoma
Chen, H.-R., & Yu, J. (2020) · Springer eBooks · doi:10.1007/978-3-030-24432-3_8 · Cited by 1
Inhibition of p70 Ribosomal S6 Kinase (S6K1) Reduces Cortical Blood Flow in a Rat Model of Autism-Tuberous Sclerosis
CHI, O. Z., Liu, X., Fortus, H., Werlen, G., Jacinto, E., & Weiss, H. R. (2024) · NeuroMolecular Medicine · doi:10.1007/s12017-024-08780-7 · Cited by 2
“TSC protein complexes that include TSC1 and TSC2 function as inhibitors of the mammalian target of rapamycin (mTOR) signaling pathway (Curatolo et al., 2022; Huang & Manning, 2008).”
Background
Carbonic Anhydrase 2 Deletion Delays the Growth of Kidney Cysts Whereas Foxi1 Deletion Completely Abrogates Cystogenesis in TSC
Barone, S., Zahedi, K. A., Brooks, M., & Soleimani, M. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25094772 · Cited by 2
“…at least 60 min at room temperature before incubation with primary antibodies overnight at 4 ◦ C. Afterward, slides were washed in PBS 3 × 10 min, incubated in secondary Alexa Fluor antibodies (Invitrogen; Waltham, MA, USA) for 2 h at room temperature, and cover-slipped with Vectashield…”
Method
mTORC1 hampers Hedgehog signaling in Tsc2 deficient cells
Larsen, L. J., Østergaard, E., & Møller, L. B. (2024) · Life Science Alliance · doi:10.26508/lsa.202302419 · Cited by 2
“The gene products of TSC1 and TSC2 , named hamartin/TSC1 and tuberin/ TSC2, respectively, form a protein complex that, in the absence of suf ﬁ cient amounts of nutrients, inhibits mTORC1 via inhibition of the mTORC1 activator RHEB (3).”
Background
Pure Squamous Cell Carcinoma of the Prostate With a Complete Remission to Gemcitabine-Cisplatin: Case Presentation and Literature Review
Yang, Y., Shen, Y., Zarrabi, K. K., Deng, Y., & Tester, W. J. (2024) · JU Open Plus · doi:10.1097/ju9.0000000000000215 · Cited by 2
Viewing Animal Models for Tuberous Sclerosis Complex in the Light of Evolution
Howe, C. J., Serfontein, J., Nisbet, R. E. R., & de Vries, P. J. (2014) · Neuromethods · doi:10.1007/978-1-4939-2250-5_4 · Cited by 3

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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