TSC1; Tuberous sclerosis complex 1


One of the two tumor suppressor proteins (the other is called tuberin or TSC2) forming an intracellular heterodimeric complex is called tuberous sclerosis complex (TSC). Both proteins are needed for the normal activity of TSC. Mutation of the hamartin gene with the consequence of altered protein leads to the development of a neurological disorder tuberous sclerosis, associated with the formation of usually benign tumors, or hamartomas, in different organ systems.


TSC is responsible for the inhibition of mammalian target of rapamycin (mTOR) kinase, whose pathway is involved in numerous cell processes linked to cell growth control, like cell cycle progression, transcription, and translation control as well as nutrient uptake. mTOR detects signals of nutrient availability, hypoxia, or growth factor stimulation and, in favorable environmental conditions, its activity leads to phosphorylation of eIF4E-binding protein 1 (4E-BP1, PHAS-I) and ribosomal p70 S6 kinase (S6K1), having direct effect on mRNA translation efficiency. Thus, mTOR controls cell growth through general protein biogenesis. When TSC complex is not functional, mTOR is hyperactive and leads to potentiation of cell growth and formation of hamartomas.

The TSC complex does not act directly on mTOR, but inhibits a G protein, Ras homologue enriched in brain (Rheb). Rheb is a member of the Ras superfamily of GTPases, sharing the highest homology with Ras and Rap. GTPase-activating protein (GAP) region inhibiting Ras-related family of small G proteins, such as Rap1, Rab5, and Rheb, has been found in tuberin, thus explaining the link between tuberin mutations and strong phosphorylation of mTOR target proteins (S6K1 and 4E-BP1).

Although the GAP domain is only found in tuberin, mutations of hamartin result in the same clinical presentation of tuberous sclerosis, although in this case the severity of the disease may be slightly lower. Thus, although the specific activity is exerted by tuberin, hamartin can also influence signal transduction from Rheb to mTOR.

The TSC1 gene is located on chromosome 9q34. It has 23 exons and an 8.6 kb mRNA transcript. Protein product, hamartin, is an 1164-amino-acid/130 kDa protein expressed in most human tissues, including the brain, kidney, heart, liver, small and large intestine, prostate, or testes. The protein is hydrophilic and has a single transmembrane domain at amino acids 127–144, and a predicted coiled-coil region at residues 719–998.

Cytosolic hamartin forms homomeric complexes. Whether this interaction is important for the proper formation of the TSC complex or for the development of the disease is not clear. It seems, however, that tuberin acts as a chaperone, preventing formation of homomeric hamartin complexes. It is postulated that hamartin inhibits tumor formation by regulating actin dynamics and cellular adhesion through the actinbinding proteins of the ezrin-radixin-moiesin (ERM) family as well as the small G protein Rho. Importantly, interaction of hamartin with the ERM proteins is required for the activation of Rho by serum or lysophosphatidic acid. Moreover, hamartin was found to bind neurofilament-light chain (NF-L) and colocalize with NF-L and ERM proteins in neuronal growth cones of primary cortical neurons. The binding of NF-L and ERM proteins by hamartin may play an important role in neuronal migration which could explain disturbances of this process that are often postulated to underlie characteristic brain lesions found in tuberous sclerosis, sometimes defined as “neuronal migration disorder.”

Hamartin can be phosphorylated by cyclin-dependent kinase 1 (CDK1 or cdc2), activated in late cell cycle phases, at three residues: T417, S584, and T1047, one of which lies in the hamartin/tuberin interaction domain. It seems that complexing with tuberin protects hamartin from being phosphorylated, although on the other hand, such a phosphorylation does not influence the interaction with tuberin. Hamartin phosphorylation by CDK1 activates TSC, which strongly suggests specific regulation of this complex during cell cycle progression.


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