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 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 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. TSC2 contains a GTPase Activating Protein 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 kinaseAMPK phosphorylates and thereby activates TSC1-TSC2 by phosphorylating at least 2 residues of TSC2.
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.
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:
