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The TSC1–TSC2 complex: a molecular switchboard controlling cell growth
Open accessAbstract
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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“as positive regulator of this complex [33], show great conservation within eukaryotes (Figure 1B).”
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“TSC2 Ser939 and Thr1462 could be phosphorylated by AKT, and Ser1387 could be phosphorylated by AMP-activated protein kinase (AMPK) (52, 53).”
BackgroundThe Cerebellar Involvement in Autism Spectrum Disorders: From the Social Brain to Mouse Models
Mapelli, L., Soda, T., D'Angelo, E. U., & Prestori, F. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23073894 · Cited by 114
Carboxy Terminal Tail of Polycystin-1 Regulates Localization of TSC2 to Repress mTOR
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Bone Cell Bioenergetics and Skeletal Energy Homeostasis
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“Raptor associates with the TORC1 complex to control protein synthesis, ribosome biogenesis, and nutrient transport (133), whereas Rictor is a component of the TORC2 complex that regulates cell survival, metabolism, and cytoskeletal organization (150, 300).”
BackgroundThe FoxO–BNIP3 axis exerts a unique regulation of mTORC1 and cell survival under energy stress
Lin, A., Yao, J.-C., Zhuang, L., Wang, D., Han, J., Lam, E. W. ‐., & Gan, B. (2013) · Oncogene · doi:10.1038/onc.2013.273 · Cited by 105
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Gorentla, B. K., Wan, E. C. K., & Zhong, X. (2011) · Blood · doi:10.1182/blood-2010-08-300731 · Cited by 108
Microplastic consumption induces inflammatory signatures in the colon and prolongs a viral arthritis
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“Upon activation, S6K phosphorylates subunit 6 of ribosomal protein, leading to a general activation of translation through an unclear and still highly debated mechanism (9,10).”
InfluentialKapuria, S., Karpac, J., Biteau, B., Hwangbo, D., & Jasper, H. (2012) · PLoS Genetics · doi:10.1371/journal.pgen.1003045 · Cited by 101
“Accordingly, various other regulatory events, including phosphorylation in response to several growth factors and morphogens, ubiquitination, and degradation, have been reported to influence TSC1/2 activity [37,40,44].”
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Walsh, C. M., & Edinger, A. L. (2010) · Immunological Reviews · doi:10.1111/j.1600-065x.2010.00919.x · Cited by 99
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“Rheb is negatively regulated by the tumor suppressor TSC1 (hamartin)-TSC2 (tuberin) complex which functions as a GTPase activating protein (GAP) towards Rheb (Huang and Manning, 2008).”
BackgroundThakur, S., Viswanadhapalli, S., Kopp, J. B., Shi, Q., Barnes, J. L., Block, K. L., Gorin, Y. C., & Abboud, H. E. (2015) · American Journal Of Pathology · doi:10.1016/j.ajpath.2015.04.014 · Cited by 100
“AMPK activates tuberin via direct phosphorylation on specific residues, including Ser1387.(19,20) Therefore, we investigated the role of tuberin as a potential mediator of AMPK actions in HRPTECs and MCT cells.”
Background14-3-3 zeta as novel molecular target for cancer therapy
Matta, A., Siu, K. M., & Ralhan, R. (2012) · Expert Opinion on Therapeutic Targets · doi:10.1517/14728222.2012.668185 · Cited by 98
“Another mechanism by which 14-3-3 controls cell growth is through its regulation of tumor suppressors, tuberous sclerosis genes, TSC1, encoding hamartin, and TSC2, encoding tuberin [30,31].”
BackgroundTuberous sclerosis complex, implication from a rare genetic disease to common cancer treatment
Inoki, K., & Guan, K. (2009) · Human Molecular Genetics · doi:10.1093/hmg/ddp032 · Cited by 101
Nakashima, A., Sato, T., & Tamanoi, F. (2010) · Journal of Cell Science · doi:10.1242/jcs.060319 · Cited by 97
“Discussion In mammalian cells, the TSC-Rheb-mTORC1 signaling pathway regulates phosphorylation of S6 through activation of S6K in response to several stimuli such as growth factors, nutrients and energy status (Hay and Sonenberg, 2004; Huang and Manning, 2008).”
BackgroundFocal brain malformations: Seizures, signaling, sequencing
Crino, P. B. (2009) · Epilepsia · doi:10.1111/j.1528-1167.2009.02289.x · Cited by 98
“…mTOR pathway has been shown to govern cell growth, cell proliferation, protein translation, and autophagy in multiple organ systems [for review, see (Huang & Manning, 2008)]. mTOR is modulated via several upstream routes including via IGF-1, PI3Kinase, PDK1, and Akt, and via LKB1, STRAD, and AMPK.”
BackgroundAdipocyte-specific loss of PPARγ attenuates cardiac hypertrophy
Fang, X., Stroud, M. J., Ouyang, K., Li, F., Zhang, J., Dalton, N. D., Gu, Y., Wu, T., Peterson, K. L., Huang, H., et al. (2016) · JCI Insight · doi:10.1172/jci.insight.89908 · Cited by 97
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“These two proteins behave as GAPs (GTPase-activating proteins) of the small GTP-binding protein, Rheb (Ras homologue enriched in brain), thereby restraining the activation of mTORC1 (mammalian target of rapamycin complex 1) (Huang and Manning, 2008).”
BackgroundImpaired Mitochondrial Fat Oxidation Induces FGF21 in Muscle
Vandanmagsar, B., Warfel, J. D., Wicks, S. E., Ghosh, S., Salbaum, J. M., Burk, D., Dubuisson, O. S., Mendoza, T. M., Zhang, J., Noland, R. C., et al. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.04.057 · Cited by 92
“We found significantly elevatedphosphorylationof TSC2atSer1387 inmuscle of Cpt1bm / mice, whereas phosphorylation of TSC2 at Thr1462 was not different.”
LKB1/AMPK/mTOR Signaling Pathway in Non-small-cell Lung Cancer
Han, D. G., Li, S., Zhu, Y., Liu, L., & Li, M. (2013) · Asian Pacific Journal of Cancer Prevention · doi:10.7314/apjcp.2013.14.7.4033 · Cited by 97
“TSC2 inhibits mTORC1 indirectly via regulation of the small GTPase Ras homologue enriched in brain (Rheb), such that loss of TSC1 or TSC2 leads to hyperactivation of mTORC1 (Huang and Manning, 2008).”
BackgroundSerine and one-carbon metabolism, a bridge that links mTOR signaling and DNA methylation in cancer
Zeng, J., Wu, W. K. K., Wang, H., & Li, X. (2019) · Pharmacological Research · doi:10.1016/j.phrs.2019.104352 · Cited by 96
Amino acids and autophagy: cross-talk and co-operation to control cellular homeostasis
Carroll, B., Korolchuk, V. I., & Sarkar, S. (2014) · Amino Acids · doi:10.1007/s00726-014-1775-2 · Cited by 99
Modulating mTOR in Aging and Health
Johnson, S. C., Sangesland, M., Kaeberlein, M. R., & Rabinovitch, P. S. (2014) · Interdisciplinary topics in gerontology and geriatrics · doi:10.1159/000364974 · Cited by 92
Therapeutic targeting of mTOR in tuberous sclerosis
Sampson, J. R. (2009) · Biochemical Society Transactions · doi:10.1042/bst0370259 · Cited by 94
Epilepsy Related to Developmental Tumors and Malformations of Cortical Development
Aronica, E., & Crino, P. B. (2014) · Neurotherapeutics · doi:10.1007/s13311-013-0251-0 · Cited by 94
“2) [117, 118, 207, 208].”
Modulation of mTOR signaling as a strategy for the treatment of Pompe disease
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Neural Mechanisms Underlying Repetitive Behaviors in Rodent Models of Autism Spectrum Disorders
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“phorylation events catalyzed by AMPK oppose the activating effects of AKT on mTORC1 kinase: TSC2 Ser-1387 phosphorylation, thought to decrease the Rheb-GTP-dependent activation of mTORC1 (15, 17, 19, 20, 25), and Raptor Ser792 phosphorylation, which inhibits mTORC1 kinase activity directly (26).”
BackgroundAmcheslavsky, A., Ito, N., Jiang, J., & Ip, Y. T. (2011) · The Journal of Cell Biology · doi:10.1083/jcb.201103018 · Cited by 90
“…of TSC causes defects in ISC division TSC has been dubbed a tumor suppressor because previous studies have shown that TSC mutant cells have increased cell division in addition to cell growth (Ito and Rubin, 1999; Gao and Pan, 2001; Tapon et al., 2001; Rosner et al., 2006; Huang and Manning, 2008).”
Jacobs, B. L., You, J., Frey, J. W., Goodman, C. A., Gundermann, D. M., & Hornberger, T. A. (2013) · The Journal of Physiology · doi:10.1113/jphysiol.2013.256339 · Cited by 91
“Eccentric contractions enhance the association of mTOR with the lysosome Presumably, the EC-induced dissociation of TSC2 from the lysosome would inhibit the ability of TSC2 to function as a GAP for lysosome-associated Rheb.”
BackgroundMethodInfluentialAkt and PTEN: β-cell mass and pancreas plasticity
Elghazi, L., & Bernal‐Mizrachi, E. (2009) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2009.03.002 · Cited by 93
Autophagy stimulation as a promising approach in treatment of neurodegenerative diseases
Pierzynowska, K., Gaffke, L., Cyske, Z., Puchalski, M., Rintz, E., Bartkowski, M., Osiadły, M., Pierzynowski, M., Mantej, J., Piotrowska, E., et al. (2018) · Metabolic Brain Disease · doi:10.1007/s11011-018-0214-6 · Cited by 93
“Therefore, Akt remains inactive, and no phosphorylation of the TSC complex, composed of the TSC1/2 heterodimer, is possible (Huang and Manning 2008).”
BackgroundmTORC1 Overactivation as a Key Aging Factor in the Progression to Type 2 Diabetes Mellitus
Guillén, C., & Benito, M. (2018) · Frontiers in Endocrinology · doi:10.3389/fendo.2018.00621 · Cited by 91
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Perfect match: mTOR inhibitors and tuberous sclerosis complex
Luo, C., Ye, W.-R., Shi, W., Yin, P., Chen, C., He, Y., Chen, M., Zu, X., & Cai, Y. (2022) · Orphanet Journal of Rare Diseases · doi:10.1186/s13023-022-02266-0 · Cited by 99
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“The TSC1/TSC2 complex is often inhibited under growth conditions to facilitate mTOR activation (37).”
BackgroundWoodford, M. R., Sager, R., Marris, E. T., Dunn, D. M., Blanden, A. R., Murphy, R. L., Rensing, N. R., Shapiro, O., Panaretou, B., Prodromou, C., et al. (2017) · The EMBO Journal · doi:10.15252/embj.201796700 · Cited by 89
“Lastly, silencing of TSC1 by siRNA in c-Abl / MEF cells restored Aha1 binding with Hsp90 (Fig 6I, Appendix Table S1).”
BackgroundInfluentialTOR kinase complexes and cell migration
Liu, L., & Parent, C. A. (2011) · Journal of Cell Biology · doi:10.1083/jcb.201102090 · Cited by 87
“The TSC1/ TSC2 complex physically associates with mTORC2 and positively regulates its activity independently of the Rheb-GAP activity of TSC1/TSC2 (Huang and Manning, 2008).”
InfluentialKingswood, J. C., Bruzzi, P., Curatolo, P., de Vries, P. J., Fladrowski, C., Hertzberg, C., Jansen, A., Jóźwiak, S., Nabbout, R., Sauter, M., et al. (2014) · Orphanet Journal of Rare Diseases · doi:10.1186/s13023-014-0182-9 · Cited by 88
“Mutations on either of the two genes result in constitutive activation of the mTOR pathway, which in turn leads to abnormal cellular proliferation and differentiation producing the hamartomatous lesions [23].”
BackgroundRegulation of the mTOR signaling network in hibernating thirteen-lined ground squirrels
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mTOR-Dependent Cell Proliferation in the Brain
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“In particular, mTORC1 activation is elicited by the inactivation TSC complex via its phosphorylation on specific sites through different kinases such as canonical Akt, RSK (ribosomal S6 kinases), or even IKKB (IκB kinase β) [51].”
BackgroundmTORC1 signaling activates NRF1 to increase cellular proteasome levels
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Nutrient Signaling in Protein Homeostasis: An Increase in Quantity at the Expense of Quality
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Zebrafish Tsc1 reveals functional interactions between the cilium and the TOR pathway
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Emerging evidence of a link between the polycystins and the mTOR pathways
Boletta, A. (2009) · PathoGenetics · doi:10.1186/1755-8417-2-6 · Cited by 84
“This activation mechanism is tightly controlled by the GAP activity of tuberin, the gene product of TSC2 (see below) [95].”
BackgroundInfluentialGonadotropin Signaling in the Ovary
Hunzicker-Dunn, M. E., & Mayo, K. E. (2014) · Elsevier eBooks · doi:10.1016/b978-0-12-397175-3.00020-x · Cited by 81
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“TSC is composed of TSC1, TSC2, and TBC1D7, among which TSC2 is the catalytic subunit with GTPaseactivating protein (GAP) activity toward the small GTPase Rheb which binds and directly activates mTORC1 activity through unclear mechanisms (14).”
BackgroundPhosphatidic acid mediates activation of mTORC1 through the ERK signaling pathway
Winter, J. N., Fox, T. E., KESTER, M. A., Jefferson, L. S., & Kimball, S. R. (2010) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00039.2010 · Cited by 84
“TSC2 is phosphorylated by ERK and by its downstream effector p90 (20).”
BackgroundMolecular aberrations, targeted therapy, and renal cell carcinoma: current state-of-the-art
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“TSC1 3 [16] Hamartin, tumor suppressor in conjunction with TSC2, negative regulator of mTORC1 [36]”
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Metabolic Crosstalk: Molecular Links Between Glycogen and Lipid Metabolism in Obesity
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“To determine whether mTORC1 can regulate PTG transcript levels, we examined TSC2 MEFs that have high mTORC1 activity (19).”
BackgroundHuynh, H. T., Hao, H.-X., Chan, S. L., Chen, D., Ong, R., Soo, K. C., Pochanard, P., Yang, D. T., Ruddy, D. A., Liu, M., et al. (2015) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-14-0768 · Cited by 81
The Role of ARID1A in Tumors: Tumor Initiation or Tumor Suppression?
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Does Huntingtin play a role in selective macroautophagy?
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“specific tuberous sclerosis complex-2 (TSC2; an upstream negative regulator of mTORC1 [12]) knockout mice have increased beta cell mass due to increased cell size and”
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“Moreover, rapamycin treatment robustly induced Neat1 and Neat1_2 (lower panel of Figure 2B, Figure S3B).”
BackgroundStructural Analysis and Functional Implications of the Negative mTORC1 Regulator REDD1,
Vega-Rubín-de-Celis, S., Abdallah, Z., Kinch, L. N., Grishin, N. V., Brugarolas, J., & Zhang, X. (2010) · Biochemistry · doi:10.1021/bi902135e · Cited by 81
Mammalian TOR signaling to the AGC kinases
Su, B., & Jacinto, E. (2011) · Critical Reviews in Biochemistry and Molecular Biology · doi:10.3109/10409238.2011.618113 · Cited by 79
Functional Assessment ofTSC2 Variants Identified in Individuals with Tuberous Sclerosis Complex
Hoogeveen‐Westerveld, M., Ekong, R., Povey, S., Mayer, K., Lannoy, N., Elmslie, F., Bebin, M., Dies, K. A., Thompson, C., Sparagana, S. P., et al. (2012) · Human Mutation · doi:10.1002/humu.22202 · Cited by 76
Therapeutic strategies for advanced neuroendocrine carcinomas of jejunum/ileum and pancreatic origin
Auernhammer, C. J., & Göke, B. (2011) · Gut · doi:10.1136/gut.2009.204453 · Cited by 75
Tsc1-mTORC1 signaling controls striatal dopamine release and cognitive flexibility
Kosillo, P., Doig, N. M., Ahmed, K. M., Agopyan-Miu, A. H. C. W., Wong, C. D., Conyers, L., Threlfell, S., Magill, P. J., & Bateup, H. S. (2019) · Nature Communications · doi:10.1038/s41467-019-13396-8 · Cited by 74
Sun, J., Liu, Y., Moreno, S., Baudry, M., & Bi, X. (2015) · Journal of Neuroscience · doi:10.1523/jneurosci.4276-14.2015 · Cited by 77
“In addition to AKT, ERK1/2 can inhibit TSC2 by phosphorylation at Thr1462, either directly or via the activation of RSK1 (Huang and Manning, 2008).”
BackgroundInfluentialSchade, B., Rao, T., Dourdin, N., Lesurf, R., Hallett, M. T., Cardiff, R. D., & Muller, W. J. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.018937 · Cited by 77
Death-associated protein kinase 1 promotes growth of p53-mutant cancers
Zhao, J., Zhao, D., Poage, G. M., Mazumdar, A., Zhang, Y., Hill, J. L., Hartman, Z. C., Savage, M. I., Mills, G. B., & Brown, P. H. (2015) · Journal of Clinical Investigation · doi:10.1172/jci70805 · Cited by 74
“As shown in Figure 6H, overexpression of DAPK1 increased phosphorylation of TSC2 at Ser939, which has been previously reported as destabilizing TSC1/TSC2 complex formation and activating downstream signaling (21, 22).”
BackgroundMethodInfluentialGazzaneo, M. C., Suryawan, A., Orellana, R. A., Torrazza, R. J. M., El‐Kadi, S. W., Wilson, F. A., Kimball, S. R., Srivastava, N., Nguyen, H. V., Fiorotto, M. L., et al. (2011) · Journal of Nutrition · doi:10.3945/jn.111.147520 · Cited by 74
“Insulin-activated PKB phosphorylates TSC2 on Thr(1462), resulting in inactivation of the inhibitory TCS1/TCS2 complex, followed by mTORC1 activation (36).”
BackgroundGureev, A. P., Popov, V. N., & Starkov, A. A. (2020) · Experimental Neurology · doi:10.1016/j.expneurol.2020.113285 · Cited by 75
“The major activators of TSC1/2 are GSK3β (glycogen synthase kinase 3β) and AMPK (AMP-dependent protein kinase) (Huang and Manning, 2008)”
BackgroundThe Role of Tuberous Sclerosis Complex 1 in Regulating Innate Immunity
Pan, H., O’Brien, T. F., Zhang, P., & Zhong, X. (2012) · The Journal of Immunology · doi:10.4049/jimmunol.1102187 · Cited by 74
“TSC1 stabilizes TSC2 and prevents its ubiquitin-mediated degradation (34).”
Avruch, J., Long, X., Lin, Y., Ortiz-Vega, S., Rapley, J., Papageorgiou, A., Oshiro, N., & Kikkawa, U. (2009) · Biochemical Society Transactions · doi:10.1042/bst0370223 · Cited by 78
Systems-Level Feedbacks of NRF2 Controlling Autophagy upon Oxidative Stress Response
Kapuy, O., Papp, D., Vellai, T., Bánhegyi, G., & Korcsmáros, T. (2018) · Antioxidants · doi:10.3390/antiox7030039 · Cited by 78
“Namely, AMPK blocks mTOR by phosphorylating Tuberous Sclerosis Complex 2 (TSC2) [40], an inhibitor of mTOR complex, and also inhibits one subunit of the complex, Raptor [41] (Figure 1A e).”
BackgroundMultifaceted Role of AMPK in Viral Infections
Bhutta, M., Gallo, E. S., & Borenstein, R. (2021) · Cells · doi:10.3390/cells10051118 · Cited by 71
Concomitant low-dose doxorubicin treatment and exercise
Sturgeon, K. M., Schadler, K., Muthukumaran, G., Ding, D., Bajulaiye, A., Thomas, N. J., Ferrari, V. A., Ryeom, S. W., & Libonati, J. R. (2014) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00082.2014 · Cited by 70
“several Akt phosphorylation sites (15).”
The TOR Signaling Pathway in Spatial and Temporal Control of Cell Size and Growth
Gonzalez, S., & Rallis, C. (2017) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2017.00061 · Cited by 70
“Without TSC1 or TSC2 (Huang and Manning, 2008), an increase in the activity TORC1 causes regional neuronal cell growth with axons having multiple axons (Choi et al., 2008).”
BackgroundCycD/Cdk4 and Discontinuities in Dpp Signaling Activate TORC1 in the Drosophila Wing Disc
Romero‐Pozuelo, J., Demetriades, C., Schroeder, P., & Teleman, A. A. (2017) · Developmental Cell · doi:10.1016/j.devcel.2017.07.019 · Cited by 67
Acne Transcriptomics: Fundamentals of Acne Pathogenesis and Isotretinoin Treatment
Melnik, B. C. (2023) · Cells · doi:10.3390/cells12222600 · Cited by 86
Strategic advancements in targeting the PI3K/AKT/mTOR pathway for Breast cancer therapy
Garg, P., Ramisetty, S. K., Nair, M., Kulkarni, P., Horne, D., Salgia, R., & Singhal, S. S. (2025) · Biochemical Pharmacology · doi:10.1016/j.bcp.2025.116850 · Cited by 78
Xie, J., Ponuwei, G. A., Moore, C. E., Willars, G. B., Tee, A. R., & Herbert, T. P. (2011) · Cellular Signalling · doi:10.1016/j.cellsig.2011.06.025 · Cited by 71
mTOR Kinase: A Possible Pharmacological Target in the Management of Chronic Pain
Lisi, L., Aceto, P., Navarra, P., & Russo, C. D. (2015) · BioMed Research International · doi:10.1155/2015/394257 · Cited by 71
“In this complex, TSC1 stabilizes TSC2 by preventing its degradation, while TSC2 acts as aGTPase-activating protein (GAP) for the small GTPase protein, Rheb (Ras homolog enriched in brain) [18].”
BackgroundMashimo, T., Hadjebi, O., Amair‐Pinedo, F., Tsurumi, T., Vives, F. L., Serikawa, T., Sotelo, C., Guénet, J., & Rosa, J. L. (2009) · PLoS Genetics · doi:10.1371/journal.pgen.1000784 · Cited by 69
“Because processes such as growth, autophagy and neuronal plasticity are known to be regulated, at least in part, through the mTOR pathway [14,15] and because Herc1/Herc1 mice show features related to these processes (neuronal degeneration and smaller size), we hypothesized that a mutant HERC1 protein might affect some…”
BackgroundLong‐term cognitive outcomes in tuberous sclerosis complex
Tye, C., McEwen, F. S., Liang, H., Underwood, L., Woodhouse, E., Barker, E. D., Sheerin, F., Yates, J. R. W., Bolton, P., & Tuberous Sclerosis 2000 Study Group (2019) · Developmental Medicine & Child Neurology · doi:10.1111/dmcn.14356 · Cited by 68
“The TSC proteins hamartin and tuberin form a heterodimeric complex involved in intracellular signalling and the activation of mammalian target of rapamycin complex 1, which plays an important role in the regulation of cell proliferation and differentiation.(1) In addition to the primary mutation event, stochastic seco…”
BackgroundImplications of Nonphysiological Ovarian Primordial Follicle Activation for Fertility Preservation
Grosbois, J., Devos, M., & Demeestere, I. (2020) · Endocrine Reviews · doi:10.1210/endrev/bnaa020 · Cited by 68
Hedayati, N., Safari, M. H., Milasi, Y. E., Kahkesh, S., Farahani, N., Khoshnazar, S. M., Dorostgou, Z., Alaei, E., Alimohammadi, M., Rahimzadeh, P., et al. (2025) · Discover Oncology · doi:10.1007/s12672-025-02471-w · Cited by 75
“AKT activates the mTOR pathway by inhibiting the TSC1/TSC2 complex, thereby influencing cell proliferation [99].”
Characterization of the Intrinsic and TSC2-GAP–Regulated GTPase Activity of Rheb by Real-Time NMR
Marshall, C. B., Ho, J., Buerger, C., Plevin, M. J., Li, G., Li, Z., Ikura, M., & Stambolic, V. (2009) · Science Signaling · doi:10.1126/scisignal.2000029 · Cited by 70
“Mutations in these genes are associated with tuberous sclerosis, a disorder characterized by benign tumors (hamartomas) that affect the brain, kidneys, skin, heart, and lungs (9, 10).”
BackgroundPema, M., Drusian, L., Chiaravalli, M., Castelli, M., Yao, Q., Ricciardi, S., Somlo, S., Qian, F., Biffo, S., & Boletta, A. (2016) · Nature Communications · doi:10.1038/ncomms10786 · Cited by 70
Kathage, B., Gehlert, S., Ulbricht, A., Lüdecke, L., Tapia, V., Orfanos, Z., Wenzel, D., Bloch, W., Volkmer, R., Fleischmann, B. K., et al. (2016) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2016.10.007 · Cited by 68
Zhang, Z., Zhang, X., Zhao, D., Liu, B., Wang, B., Yu, W., Li, J., Yu, X., Cao, F., Zheng, G., et al. (2019) · Molecular Medicine Reports · doi:10.3892/mmr.2019.10051 · Cited by 66
“Activated AKT directly phosphorylates the Ser2448 site of mTOR (56); S6K1 is one of the main targets downstream of mTOR that is induced following the activation of mTOR (57).”
BackgroundXie, J., & Herbert, T. P. (2011) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-011-0874-4 · Cited by 69
“b Sites of phosphorylation on TSC2 and their respective kinases, adapted from [73].”
BackgroundEmerging Treatments in the Management of Tuberous Sclerosis Complex
Kohrman, M. H. (2012) · Pediatric Neurology · doi:10.1016/j.pediatrneurol.2012.02.015 · Cited by 66
“Early studies in Drosophila revealed the growthinhibitory properties of the hamartin and tuberin complex, and were corroborated by studies using rodent and human models of tuberous sclerosis complex [38].”
BackgroundResultZhou, J., Lal, H., Chen, X., Shang, X., Song, J., Li, Y., Kerkelä, R., Doble, B. W., MacAulay, K., DeCaul, M., et al. (2010) · Journal of Clinical Investigation · doi:10.1172/jci41407 · Cited by 67
“This is surprising, since the few studies done to date have focused on GSK-3β and its role in regulating mTORC1 downstream of Wnt signaling (30, 31).”
BackgroundRab-Family GTPase Regulates TOR Complex 2 Signaling in Fission Yeast
Tatebe, H., Morigasaki, S., Murayama, S., Zeng, C. J. T., & Shiozaki, K. (2010) · Current Biology · doi:10.1016/j.cub.2010.10.026 · Cited by 66
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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