Biology:Tuberous sclerosis protein
| tuberous sclerosis 1 | |
|---|---|
| Identifiers | |
| Symbol | TSC1 |
| Alt. symbols | TSC |
| NCBI gene | 7248 |
| HGNC | 12362 |
| OMIM | 605284 |
| RefSeq | NM_000368 |
| UniProt | Q92574 |
| Other data | |
| Locus | Chr. 9 q34 |
| tuberous sclerosis 2 | |
|---|---|
| Identifiers | |
| Symbol | TSC2 |
| Alt. symbols | TSC4 |
| NCBI gene | 7249 |
| HGNC | 12363 |
| OMIM | 191092 |
| RefSeq | NM_000548 |
| UniProt | P49815 |
| Other data | |
| 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, intellectual disability, epilepsy and tumors of the skin, retina, heart, kidney and the central nervous system can be symptoms.
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
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 α HIFα 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
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
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
- ↑ "TSC2 integrates Wnt and energy signals via a coordinated phosphorylation by AMPK and GSK3 to regulate cell growth". Cell 126 (5): 955–68. September 2006. doi:10.1016/j.cell.2006.06.055. PMID 16959574.
- ↑ "A complex interplay between Akt, TSC2 and the two mTOR complexes". Biochem. Soc. Trans. 37 (Pt 1): 217–22. February 2009. doi:10.1042/BST0370217. PMID 19143635.
- ↑ "Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling". Genes Dev. 17 (15): 1829–34. August 2003. doi:10.1101/gad.1110003. PMID 12869586.
- ↑ "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. December 2000. doi:10.1038/sj.onc.1204009. PMID 11175345.
- ↑ "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. July 2002. doi:10.1016/S1097-2765(02)00568-3. PMID 12150915.
- ↑ "The TSC1-TSC2 complex: a molecular switchboard controlling cell growth". Biochem. J. 412 (2): 179–90. June 2008. doi:10.1042/BJ20080281. PMID 18466115.
- ↑ "TSC2 mediates cellular energy response to control cell growth and survival". Cell 115 (5): 577–90. November 2003. doi:10.1016/S0092-8674(03)00929-2. PMID 14651849.
- ↑ "Hypoxia regulates TSC1/2-mTOR signaling and tumor suppression through REDD1-mediated 14-3-3 shuttling". Genes Dev. 22 (2): 239–51. January 2008. doi:10.1101/gad.1617608. PMID 18198340.
- ↑ "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. September 2004. doi:10.1073/pnas.0405659101. PMID 15342917. Bibcode: 2004PNAS..10113489R.
- ↑ "Identification of tuberin, the tuberous sclerosis-2 product. Tuberin possesses specific Rap1GAP activity". J. Biol. Chem. 270 (27): 16409–14. July 1995. doi:10.1074/jbc.270.27.16409. PMID 7608212.
- ↑ "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. February 1996. PMID 8564946.
- ↑ "Tuberous sclerosis gene 2 product modulates transcription mediated by steroid hormone receptor family members". J. Biol. Chem. 273 (32): 20535–9. August 1998. doi:10.1074/jbc.273.32.20535. PMID 9685410.
Further reading
- "Interaction between hamartin and tuberin, the TSC1 and TSC2 gene products". Hum. Mol. Genet. 7 (6): 1053–7. June 1998. doi:10.1093/hmg/7.6.1053. PMID 9580671.
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