Tuberous sclerosis protein
Chr. 9 q34 | |||||||
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Chr. 16 p13.3 | |||||||
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Tuberous sclerosis proteins 1 and 2, also known as
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
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
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:
- 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]
- 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
amino acids. The TSC2 gene is located on chromosome 16p
13.3 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
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. PMID 9580671.