Tuberous sclerosis protein
|tuberous sclerosis 1|
|Locus||Chr. 9 q34|
|tuberous sclerosis 2|
|Locus||Chr. 16 p13.3|
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.
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). 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.
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. TSC2 contains a GTPase Activating Protein (GAP) domain which has been shown to stimulate the GTPase activity of the small GTPase Rheb, 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. 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.
- 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.
- Hypoxia: The Hypoxia-inducible factor α HIFα induces REDD1 at low oxygen levels. REDD1 has been shown to activate TSC1-TSC2 by neutralisation of AKT dependent inhibition.
- 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.
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.
The following functions of tuberin have been identified:
- GTPase-accelerating protein (GAP) function for the Rap1a GTPase.
- C-terminal transcriptional activation domains.
- Selective modulation of transcription mediated by members of the steroid receptor superfamily.
- 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. PMID 16959574.
- 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. PMC . PMID 19143635.
- 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. PMC . PMID 12869586.
- 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. PMID 11175345.
- 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. PMID 12150915.
- 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. PMC . PMID 18466115.
- 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. PMID 14651849.
- 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. PMC . PMID 18198340.
- 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. PMC . PMID 15342917.
- Wienecke R, König 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. PMID 7608212.
- 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. PMID 8564946.
- 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. PMID 9685410.