TSC2

Mutations in this gene lead to tuberous sclerosis. Its gene product is believed to be a tumor suppressor and is able to stimulate specific GTPases. Hamartin coded by the gene TSC1 functions as a facilitator of Hsp90 in chaperoning of tuberin, therefore preventing its ubiquitination and degradation in the proteasome.^[5] Alternative splicing results in multiple transcript variants encoding different isoforms of the protein.^[6] Mutations in TSC2 can cause lymphangioleiomyomatosis, a disease caused by the enlargement of tissue in the lungs, creating cysts and tumours and causing difficulty breathing. Because tuberin regulates cell size, along with the protein hamartin, mutations to TSC1 and TSC2 genes may prevent the control of cell growth in the lungs of individuals.^[5]

Cells from individuals with pathogenic mutations in the TSC2 gene display depletion of lysosomes, impairment of autophagy, and abnormal accumulation of glycogen. Defects in the autophagy-lysosome pathway are associated with excessive ubiquitination and degradation of LC3 and LAMP1/2 proteins.^[7]

Pharmacological inhibition of ERK1/2 restores GSK3β activity and protein synthesis levels in a model of tuberous sclerosis.^[8]

The defective degradation of glycogen by the autophagy-lysosome pathway is, at least in part, independent of impaired regulation of mTORC1 and is restored by the combined use of PKB/Akt and mTORC1 pharmacological inhibitors.^[7]

TSC2 functions within a multi-protein complex known as the TSC complex which consists of the core proteins TSC2, TSC1,^[9][10] and TBC1D7.

TSC2 has been reported to interact with several other proteins that are not a part of the TSC complex including:

• Tuberous sclerosis protein