Tuberous Sclerosis Complex and the Mammalian Target of Rapamycin Pathways


Tuberous sclerosis complex (TSC) is an autosomal dominant disease in which the mammalian target of rapamycin complex 1 (mTORC1) is hyperactivated. Lymphangioleiomyomatosis (LAM) is the pulmonary manifestation of TSC which occurs primarily in women. The TSC proteins tuberin and hamartin regulate the small guanosine triphophatase (GTPase) Rheb (Ras homologue enriched in brain), a direct activator of mTORC1. Activation of mTORC1 has been observed in TSC tumours and other human tumours, and mTORC1 inhibitors have been tested for the treatment of TSC and for malignancies including renal cancer. In this article, we discuss diagnostic features, updated molecular basis, evidences of mTORC1 activation, preclinical models and completed clinical trials of mTORC1 inhibitors in TSC. We also review the evidence of mTORC1‐independent functions of the TSC proteins, and discuss future therapeutic perspectives combining mTORC1 inhibitors with agents targeting other cellular pathways.

Key Concepts:

  • Tuberous sclerosis complex (TSC) is a hereditary disease characterised by the development of seizures, mental retardation, autism and hamartomas in multiple organs including the brain, retina, kidney, heart and skin.

  • Lymphangioleiomyomatosis (LAM) is the metastatic pulmonary manifestation of TSC occurring almost exclusively in women, in whom the lungs are infiltrated with abnormal smooth muscle‐like cells and there is degeneration of lung parenchyma.

  • Metastasis is the multistep process in which tumour cells at the primary site spread to distant tissues/organs to proliferate.

  • Loss of heterozygosity refers to the loss of a normal allele on a chromosome while the other allele has a genetic alteration or mutation.

  • Mammalian target of rapamycin (mTOR) refers to the FRAP1 gene product, a serine/threonine protein kinase that controls ribosome biogenesis, protein translation, cell growth and metabolism.

Keywords: tuberous sclerosis complex; lymphangioleiomyomatosis; Rheb; MTORC1; rapamycin; angiomyolipomas; metastasis; tumour suppressor; differentiation; signal transduction

Figure 1.

Evidences support that LAM is a metastatic disease. (a) Same somatic mutation in TSC2 was found in angiomyolipomas and LAM lung, but not in normal kidney or peripheral blood (Carsillo et al., ). (b) Oestrogen promotes the lung colonisation of Tsc2‐null ELT3 cells. Female ovariectomised CB17– (SCID) mice were implanted with estradiol (E2) (n=3) or placebo (n=3) pellets 1 week before cell injection. 2×105 ELT3luciferase cells were injected intravenously. Lung colonisation was measured using bioluminescence at 1, 3 and 24 h after injection. Representative images are shown (Yu et al., ). Reproduced with permission from Proceedings of the National Academy of Sciences of the USA.

Figure 2.

Tuberin and hamartin mediate signalling transduction to regulate cellular events. Tumour suppressor proteins tuberin (TSC2) and hamartin (TSC1) form a complex to suppress ciliary development and to inhibit the active form of the small GTPase Rheb (Rheb‐GTP). GTP‐bound Rheb activates mTOR complex 1 (mTORC1) which consists of mTOR, mLST8, Raptor, PRAS40 and Deptor; promotes ribosome biogenesis, protein translation, cell growth, metabolism and notch activation; and inhibits autophagy. Rheb also activates cell fate decision via notch, Hes‐1 and Hey‐1, and inhibits B‐Raf and C‐Raf activities. Hamartin is inactivated via phosphorylation by CDK1 and IKKβ. Tuberin is activated via phosphorylation by AMPK, and inactivated via phosphorylation by Akt, DAPK, ERK2, GSK3, MK2 and RSK1.



Astrinidis A, Senapedis W, Coleman TR et al. (2003) Cell cycle‐regulated phosphorylation of hamartin, the product of the tuberous sclerosis complex 1 gene, by cyclin‐dependent kinase 1/cyclin B. The Journal of Biological Chemistry 278: 51372–51379.

Bissler JJ, McCormack FX, Young LR et al. (2008) Sirolimus for angiomyolipoma in tuberous sclerosis complex or lymphangioleiomyomatosis. The New England Journal of Medicine 358: 140–151.

Bittmann I, Rolf B, Amann G et al. (2003) Recurrence of lymphangioleiomyomatosis after single lung transplantation: new insights into pathogenesis. Human Pathology 34: 95–98.

Brugarolas JB, Vazquez F, Reddy A et al. (2003) TSC2 regulates VEGF through mTOR‐dependent and ‐independent pathways. Cancer Cell 4: 147–158.

Carsillo T, Astrinidis A and Henske EP (2000) Mutations in the tuberous sclerosis complex gene TSC2 are a cause of sporadic pulmonary lymphangioleiomyomatosis. Proceedings of the National Academy of Sciences of the USA 97: 6085–6090.

Castro M, Shepherd CW, Gomez MR et al. (1995) Pulmonary tuberous sclerosis. Chest 107: 189–195.

Chan JA, Zhang H, Roberts PS et al. (2004) Pathogenesis of tuberous sclerosis subependymal giant cell astrocytomas: biallelic inactivation of TSC1 or TSC2 leads to mTOR activation. Journal of Neuropathology and Experimental Neurology 63: 1236–1242.

Crabtree JS, Jelinsky SA, Harris HA et al. (2009) Comparison of human and rat uterine leiomyomata: identification of a dysregulated mammalian target of rapamycin pathway. Cancer Research 69: 6171–6178.

Dan HC, Sun M, Yang L et al. (2002) Phosphatidylinositol 3‐kinase/Akt pathway regulates tuberous sclerosis tumor suppressor complex by phosphorylation of tuberin. The Journal of Biological Chemistry 277: 35364–35370.

Davies DM, Johnson SR, Tattersfield AE et al. (2008) Sirolimus therapy in tuberous sclerosis or sporadic lymphangioleiomyomatosis. The New England Journal of Medicine 358: 200–203.

Ehninger D, Han S, Shilyansky C et al. (2008) Reversal of learning deficits in a Tsc2+/− mouse model of tuberous sclerosis. Nature Medicine 14: 843–848.

El‐Hashemite N, Walker V, Zhang H et al. (2003a) Loss of Tsc1 or Tsc2 induces vascular endothelial growth factor production through mammalian target of rapamycin. Cancer Research 63: 5173–5177.

El‐Hashemite N, Zhang H, Henske EP et al. (2003b) Mutation in TSC2 and activation of mammalian target of rapamycin signalling pathway in renal angiomyolipoma. Lancet 361: 1348–1349.

Franz DN, Leonard J, Tudor C et al. (2006) Rapamycin causes regression of astrocytomas in tuberous sclerosis complex. Annals of Neurology 59: 490–498.

Garami A, Zwartkruis FJ, Nobukuni T et al. (2003) Insulin activation of Rheb, a mediator of mTOR/S6K/4E‐BP signaling, is inhibited by TSC1 and 2. Molecular Cell 11: 1457–1466.

Gau CL, Kato‐Stankiewicz J, Jiang C et al. (2005) Farnesyltransferase inhibitors reverse altered growth and distribution of actin filaments in Tsc‐deficient cells via inhibition of both rapamycin‐sensitive and ‐insensitive pathways. Molecular Cancer Therapeutics 4: 918–926.

Goncharova EA, Goncharov DA, Eszterhas A et al. (2002) Tuberin regulates p70 S6 kinase activation and ribosomal protein S6 phosphorylation: a role for the TSC2 tumor suppressor gene in pulmonary lymphangioleiomyomatosis (LAM). The Journal of Biological Chemistry 277: 30958–30967.

Hartman TR, Liu D, Zilfou JT et al. (2009) The tuberous sclerosis proteins regulate formation of the primary cilium via a rapamycin‐insensitive and polycystin 1‐independent pathway. Human Molecular Genetics 18: 151–163.

Huang J, Dibble CC, Matsuzaki M et al. (2008) The TSC1–TSC2 complex is required for proper activation of mTOR complex 2. Molecular and Cellular Biology 28: 4104–4115.

Inoki K, Li Y, Zhu T et al. (2002) TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nature Cell Biology 4: 648–657.

Inoki K, Ouyang H, Zhu T et al. (2006) TSC2 integrates Wnt and energy signals via a coordinated phosphorylation by AMPK and GSK3 to regulate cell growth. Cell 126: 955–968.

Karbowniczek M, Astrinidis A, Balsara BR et al. (2003a) Recurrent lymphangiomyomatosis after transplantation: genetic analyses reveal a metastatic mechanism. American Journal of Respiratory and Critical Care Medicine 167: 976–982.

Karbowniczek M, Cash T, Cheung M et al. (2004) Regulation of B‐Raf kinase activity by tuberin and Rheb is mammalian target of rapamycin (mTOR)‐independent. The Journal of Biological Chemistry 279: 29930–29937.

Karbowniczek M, Robertson GP and Henske EP (2006) Rheb inhibits C‐raf activity and B‐raf/C‐raf heterodimerization. The Journal of Biological Chemistry 281: 25447–25456.

Karbowniczek M, Yu J and Henske EP (2003b) Renal angiomyolipomas from patients with sporadic lymphangiomyomatosis contain both neoplastic and non‐neoplastic vascular structures. The American Journal of Pathology 162: 491–500.

Karbowniczek M, Zitserman D, Khabibullin D et al. (2010) The evolutionarily conserved TSC/Rheb pathway activates Notch in tuberous sclerosis complex and Drosophila external sensory organ development. The Journal of Clinical Investigation 120: 93–102.

Kenerson H, Dundon TA and Yeung RS (2005) Effects of rapamycin in the Eker rat model of tuberous sclerosis complex. Pediatric Research 57: 67–75.

Kenerson HL, Aicher LD, True LD et al. (2002) Activated mammalian target of rapamycin pathway in the pathogenesis of tuberous sclerosis complex renal tumors. Cancer Research 62: 5645–5650.

Kwiatkowski DJ, Zhang H, Bandura JL et al. (2002) A mouse model of TSC1 reveals sex‐dependent lethality from liver hemangiomas, and up‐regulation of p70S6 kinase activity in Tsc1 null cells. Human Molecular Genetics 11: 525–534.

Lee DF, Kuo HP, Chen CT et al. (2007) IKK beta suppression of TSC1 links inflammation and tumor angiogenesis via the mTOR pathway. Cell 130: 440–455.

Lee PS, Tsang SW, Moses MA et al. (2010) Rapamycin‐insensitive up‐regulation of MMP2 and other genes in TSC2‐deficient LAM‐like cells. American Journal of Respiratory Cell and Molecular Biology 42(2): 227.

Li Y, Inoki K, Vacratsis P et al. (2003) The p38 and MK2 kinase cascade phosphorylates tuberin, the tuberous sclerosis 2 gene product, and enhances its interaction with 14‐3‐3. The Journal of Biological Chemistry 278: 13663–13671.

Ma L, Chen Z, Erdjument‐Bromage H et al. (2005) Phosphorylation and functional inactivation of TSC2 by Erk implications for tuberous sclerosis and cancer pathogenesis. Cell 121: 179–193.

Manning BD, Tee AR, Logsdon MN et al. (2002) Identification of the tuberous sclerosis complex‐2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3‐kinase/akt pathway. Molecular Cell Biology 10: 151–162.

Meikle L, Pollizzi K, Egnor A et al. (2008) Response of a neuronal model of tuberous sclerosis to mammalian target of rapamycin (mTOR) inhibitors: effects on mTORC1 and Akt signaling lead to improved survival and function. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience 28: 5422–5432.

Meikle L, Talos DM, Onda H et al. (2007) A mouse model of tuberous sclerosis: neuronal loss of Tsc1 causes dysplastic and ectopic neurons, reduced myelination, seizure activity, and limited survival. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience 27: 5546–5558.

Onda H, Lueck A, Marks PW et al. (1999) Tsc2(+/−) mice develop tumors in multiple sites that express gelsolin and are influenced by genetic background. The Journal of Clinical Investigation 104: 687–695.

Orlova KA and Crino PB (2010) The tuberous sclerosis complex. Annals of the New York Academy of Sciences 1184: 87–105.

Potter CJ, Pedraza LG and Xu T (2002) Akt regulates growth by directly phosphorylating Tsc2. Nature Cell Biology 4: 658–665.

Roux PP, Ballif BA, Anjum R et al. (2004) Tumor‐promoting phorbol esters and activated Ras inactivate the tuberous sclerosis tumor suppressor complex via p90 ribosomal S6 kinase. Proceedings of the National Academy of Sciences of the USA 101: 13489–13494.

Sato T, Seyama K, Fujii H et al. (2002) Mutation analysis of the TSC1 and TSC2 genes in Japanese patients with pulmonary lymphangioleiomyomatosis. Journal of Human Genetics 47: 20–28.

Stevens C, Lin Y, Harrison B et al. (2009) Peptide combinatorial libraries identify TSC2 as a death‐associated protein kinase (DAPK) death domain‐binding protein and reveal a stimulatory role for DAPK in mTORC1 signaling. The Journal of Biological Chemistry 284: 334–344.

Thoreen CC, Kang SA, Chang JW et al. (2009) An ATP‐competitive mammalian target of rapamycin inhibitor reveals rapamycin‐resistant functions of mTORC1. The Journal of Biological Chemistry 284: 8023–8032.

Uhlmann EJ, Wong M, Baldwin RL et al. (2002) Astrocyte‐specific TSC1 conditional knockout mice exhibit abnormal neuronal organization and seizures. Annals of Neurology 52: 285–296.

Wilson C, Bonnet C, Guy C et al. (2006) Tsc1 haploinsufficiency without mammalian target of rapamycin activation is sufficient for renal cyst formation in Tsc1+/− mice. Cancer Research 66: 7934–7938.

Woodrum C, Nobil A and Dabora SL (2010) 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. Journal of Translational Medicine 8: 14.

Yu J, Astrinidis A, Howard S et al. (2004) Estradiol and tamoxifen stimulate lymphangiomyomatosis‐associated angiomyolipoma cell growth and activate both genomic and non‐genomic signaling pathways. American Journal of Physiology. Lung Cellular and Molecular Physiology 286(4): L694–L700.

Yu JJ, Robb VA, Morrison TA et al. (2009) Estrogen promotes the survival and pulmonary metastasis of tuberin‐null cells. Proceedings of the National Academy of Sciences of the USA 106: 2635–2640.

Zeng LH, Xu L, Gutmann DH et al. (2008) Rapamycin prevents epilepsy in a mouse model of tuberous sclerosis complex. Annals of Neurology 63: 444–453.

Zhou X, Ikenoue T, Chen X et al. (2009) Rheb controls misfolded protein metabolism by inhibiting aggresome formation and autophagy. Proceedings of the National Academy of Sciences of the USA 106: 8923–8928.

Further Reading

Astrinidis A, Senapedis W and Henske EP (2006) Hamartin, the tuberous sclerosis complex 1 gene product, interacts with polo‐like kinase 1 in a phosphorylation‐dependent manner. Human Molecular Genetics 15: 287–297.

Crino PB, Nathanson KL and Henske EP (2006) The tuberous sclerosis complex. The New England Journal of Medicine 355: 1345–1356.

Ehninger D, de Vries PJ and Silva AJ (2009) From mTOR to cognition: molecular and cellular mechanisms of cognitive impairments in tuberous sclerosis. Journal of Intellectual Disability Research 53(10): 838–851.

Inoki K, Zhu T and Guan KL (2003) TSC2 mediates cellular energy response to control cell growth and survival. Cell 115: 577–590.

Huang J and Manning BD (2009) A complex interplay between Akt, TSC2 and the two mTOR complexes. Biochemical Society Transactions 37(1): 217–222.

McCormack FX (2008) Lymphangioleiomyomatosis: a clinical update. Chest 133: 507–516.

Napolioni V, Moavero R and Curatolo P (2009) Recent advances in neurobiology of tuberous sclerosis complex. Brain & Development 31(2): 104–113.

Sampson JR (2009) Therapeutic targeting of mTOR in tuberous sclerosis. Biochemical Society Transactions 37(1): 259–264.

Yu J and Henske EP (2010a) Dysregulation of TOR signaling in tuberous sclerosis and lymphangioleiomyomotosis. The Enzymes, vol. 27, chap. 16. Burlington: Academic Press.

Yu J and Henske EP (2010b) mTOR activation, lymphangiogenesis, and estrogen‐mediated cell survival: the “perfect storm” of pro‐metastatic factors in LAM pathogenesis. Lymphatic Research and Biology 8(1): 43–49.

Yu J, Parkhitko A and Henske EP (2010) Mammalian target of rapamycin signaling and autophagy: roles in lymphangioleiomyomatosis. Proceedings of the American Thoracic Society 7: 48–53.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Yu, Jane(Sep 2010) Tuberous Sclerosis Complex and the Mammalian Target of Rapamycin Pathways. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0022388]