Tuberous sclerosis complex 2 (TSC2), also known as tuberin, is a protein that in humans is encoded by the TSC2 gene.
Function edit
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]
Cell pathology edit
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]
Signaling pathways edit
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]
Interactions edit
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:
See also edit
References edit
Further reading edit
- Jones AC, Shyamsundar MM, Thomas MW, Maynard J, Idziaszczyk S, Tomkins S, Sampson JR, Cheadle JP (May 1999). "Comprehensive mutation analysis of TSC1 and TSC2-and phenotypic correlations in 150 families with tuberous sclerosis". American Journal of Human Genetics. 64 (5): 1305–15. doi:10.1086/302381. PMC 1377866. PMID 10205261.
- Hengstschläger M (August 2001). "Tuberous sclerosis complex genes: from flies to human genetics". Archives of Dermatological Research. 293 (8): 383–6. doi:10.1007/s004030100250. PMID 11686512. S2CID 35702323.
- Hockenbery DM (February 2003). "Nailing down a link between tuberin and renal cysts". The American Journal of Pathology. 162 (2): 369–71. doi:10.1016/S0002-9440(10)63831-X. PMC 1851147. PMID 12547695.
- Ramesh V (June 2003). "Aspects of tuberous sclerosis complex (TSC) protein function in the brain". Biochemical Society Transactions. 31 (Pt 3): 579–83. doi:10.1042/BST0310579. PMID 12773159.
- Knowles MA, Hornigold N, Pitt E (June 2003). "Tuberous sclerosis complex (TSC) gene involvement in sporadic tumours". Biochemical Society Transactions. 31 (Pt 3): 597–602. doi:10.1042/BST0310597. PMID 12773163.
- Ellisen LW (November 2005). "Growth control under stress: mTOR regulation through the REDD1-TSC pathway". Cell Cycle. 4 (11): 1500–02. doi:10.4161/cc.4.11.2139. PMID 16258273.
- Jozwiak J, Jozwiak S (March 2007). "Giant cells: contradiction to two-hit model of tuber formation?". Cellular and Molecular Neurobiology. 27 (2): 251–61. doi:10.1007/s10571-006-9106-0. PMID 16897363. S2CID 31624726.
- Cai SL, Walker CL (January 2006). "TSC2, a key player in tumor suppression and cystic kidney disease". Nephrologie & Therapeutique. 2 (Suppl 2): S119-22. PMID 17373211.
- Urban T (June 2007). "[Pulmonary lymphangioleiomyomatosis with or without tuberous sclerosis]". Revue des Maladies Respiratoires. 24 (6): 725–40. doi:10.1016/S0761-8425(07)91147-X. PMID 17632432.