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Reliable, easy-to-read patient information on common medical conditions β€” written in plain language, free of jargon, and grounded in current evidence. Browse the most frequent diagnoses, understand what they mean for everyday life, and learn which steps and questions help you have a focused conversation with your doctor.

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Tuberous sclerosis protein

Introduction

Tuberous sclerosis proteins 1 and 2, also known as TSC1 (hamartin) and TSC2 (tuberin), form a protein-complex. The encoding two genes are TSC1 and TSC2. The complex is known as a tumor suppressor. Mutations in these genes can cause tuberous sclerosis complex. Depending on the grade of the disease, mental retardation, epilepsy and tumors of the skin, retina, heart, kidney and the central nervous system can be symptoms.

Physiological roles

Physiological roles

The TSC1/TSC2-complex integrates environmental signals such as stress and energy status in yeast and stress, energy status and growth factors in mammals into TOR signalling. In the case of stress (DNA damage, hypoxia) or low energy availability, it is activated and regulates protein synthesis down. Growth factors lead to an inhibition of the complex and have a positive effect on protein synthesis. Defects in its genes result in less control of cell growth and may cause tuberous sclerosis or tuberous sclerosis complex (TSC).[1] TSC is a rare genetic disease causing benign tumours to grow in the brain and on other vital organs. A combination of symptoms may include seizures, developmental delay, behavioural problems, skin abnormalities, lung and kidney disease.

Regulation

Regulation

The TSC1 and TSC2 proteins form a heterodimeric complex which acts as an important integrator of different signaling pathways controlling mTOR signaling, by regulating especially mTORC1 activity.[2] TSC2 contains a GTPase Activating Protein (GAP) domain which has been shown to stimulate (down regulate) the GTPase activity of the small GTPase Rheb,[3] which is – in its GTP bound form – an activator of mTORC1. TSC1 does not have a GAP domain but it acts as a stabilizer of TSC2 by protecting it from degradation.[4] The activity of the TSC1-TSC2 complex is regulated by phosphorylation of different Ser and Thr sites mediated by the following Pathways:

  • PI3K-AKT signalling: AKT inhibits TSC1-TSC2 by phosphorylating TSC2 on 2-5 sites. However the molecular mechanism is yet unknown since the GAP activity of TSC2 is not remarkably influenced by these phosphorylation events.[5][6]
  • Low energy levels and stress: The AMP-dependent protein kinase AMPK phosphorylates and thereby activates TSC1-TSC2 by phosphorylating at least 2 residues of TSC2.[7]
  • Hypoxia: The Hypoxia-inducible factor Ξ± HIFΞ± induces REDD1 at low oxygen levels. REDD1 has been shown to activate TSC1-TSC2 by neutralisation of AKT dependent inhibition.[8]
  • ERK-RSK signalling: When it is activated by ERK, RSK phosphorylates and inhibits TSC1-TSC2. TSC2 has 3 phosphorylation sites for RSK. Two of them are also substrates of AKT.[9]
Gene

Gene

The TSC1 gene is located on chromosome 9q34 and encodes the 130 kDa protein hamartin containing 1163 amino acids. The TSC2 gene is located on chromosome 16p13.3 and codes for the 200 kDa protein tuberin containing 1807 amino acids.

Protein structure

Protein structure

The following functions of tuberin have been identified:

  • GTPase-accelerating protein (GAP) function for the Rap1a GTPase.[10]
  • C-terminal transcriptional activation domains.[11]
  • Selective modulation of transcription mediated by members of the steroid receptor superfamily.[12]
References

References

  1. ↑ Inoki K, Ouyang H, Zhu T, Lindvall C, Wang Y, Zhang X, Yang Q, Bennett C, Harada Y, Stankunas K, Wang CY, He X, MacDougald OA, You M, Williams BO, Guan KL (September 2006). “TSC2 integrates Wnt and energy signals via a coordinated phosphorylation by AMPK and GSK3 to regulate cell growth”. Cell. 126 (5): 955–68. doi:10.1016/j.cell.2006.06.055. PMIDΒ 16959574.
  2. ↑ Huang J, Manning BD (February 2009). “A complex interplay between Akt, TSC2 and the two mTOR complexes”. Biochem. Soc. Trans. 37 (Pt 1): 217–22. doi:10.1042/BST0370217. PMCΒ 2778026. PMIDΒ 19143635.
  3. ↑ Inoki K, Li Y, Xu T, Guan KL (August 2003). “Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling”. Genes Dev. 17 (15): 1829–34. doi:10.1101/gad.1110003. PMCΒ 196227. PMIDΒ 12869586.
  4. ↑ Benvenuto G, Li S, Brown SJ, Braverman R, Vass WC, Cheadle JP, Halley DJ, Sampson JR, Wienecke R, DeClue JE (December 2000). “The tuberous sclerosis-1 (TSC1) gene product hamartin suppresses cell growth and augments the expression of the TSC2 product tuberin by inhibiting its ubiquitination”. Oncogene. 19 (54): 6306–16. doi:10.1038/sj.onc.1204009. PMIDΒ 11175345.
  5. ↑ Manning BD, Tee AR, Logsdon MN, Blenis J, Cantley LC (July 2002). “Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathway”. Mol. Cell. 10 (1): 151–62. doi:10.1016/S1097-2765(02)00568-3. PMIDΒ 12150915.
  6. ↑ Huang J, Manning BD (June 2008). “The TSC1-TSC2 complex: a molecular switchboard controlling cell growth”. Biochem. J. 412 (2): 179–90. doi:10.1042/BJ20080281. PMCΒ 2735030. PMIDΒ 18466115.
  7. ↑ Inoki K, Zhu T, Guan KL (November 2003). “TSC2 mediates cellular energy response to control cell growth and survival”. Cell. 115 (5): 577–90. doi:10.1016/S0092-8674(03)00929-2. PMIDΒ 14651849.
  8. ↑ DeYoung MP, Horak P, Sofer A, Sgroi D, Ellisen LW (January 2008). “Hypoxia regulates TSC1/2-mTOR signaling and tumor suppression through REDD1-mediated 14-3-3 shuttling”. Genes Dev. 22 (2): 239–51. doi:10.1101/gad.1617608. PMCΒ 2192757. PMIDΒ 18198340.
  9. ↑ Roux PP, Ballif BA, Anjum R, Gygi SP, Blenis J (September 2004). “Tumor-promoting phorbol esters and activated Ras inactivate the tuberous sclerosis tumor suppressor complex via p90 ribosomal S6 kinase”. Proc. Natl. Acad. Sci. U.S.A. 101 (37): 13489–94. doi:10.1073/pnas.0405659101. PMCΒ 518784. PMIDΒ 15342917.
  10. ↑ Wienecke R, KΓΆnig A, DeClue JE (July 1995). “Identification of tuberin, the tuberous sclerosis-2 product. Tuberin possesses specific Rap1GAP activity”. J. Biol. Chem. 270 (27): 16409–14. doi:10.1074/jbc.270.27.16409. PMIDΒ 7608212.
  11. ↑ Tsuchiya H, Orimoto K, Kobayashi K, Hino O (February 1996). “Presence of potent transcriptional activation domains in the predisposing tuberous sclerosis (Tsc2) gene product of the Eker rat model”. Cancer Res. 56 (3): 429–33. PMIDΒ 8564946.
  12. ↑ Henry KW, Yuan X, Koszewski NJ, Onda H, Kwiatkowski DJ, Noonan DJ (August 1998). “Tuberous sclerosis gene 2 product modulates transcription mediated by steroid hormone receptor family members”. J. Biol. Chem. 273 (32): 20535–9. doi:10.1074/jbc.273.32.20535. PMIDΒ 9685410.
Further reading

Further reading

  • van Slegtenhorst M, Nellist M, Nagelkerken B, Cheadle J, Snell R, van den Ouweland A, Reuser A, Sampson J, Halley D, van der Sluijs P (June 1998). “Interaction between hamartin and tuberin, the TSC1 and TSC2 gene products”. Hum. Mol. Genet. 7 (6): 1053–7. doi:10.1093/hmg/7.6.1053. PMIDΒ 9580671.