Tuberous sclerosis complex 2 (TSC2), also known as tuberin, is a protein that in humans is encoded by the TSC2 gene.
Tuberous sclerosis complex 2 (TSC2), also known as tuberin, is a protein that in humans is encoded by the TSC2 gene.
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 complex (TSC) is a rare multisystem autosomal dominant genetic disease that causes non-cancerous tumours to grow in the brain and on other vital organs such as the kidneys, heart, liver, eyes, lungs and skin. A combination of symptoms may include seizures, intellectual disability, developmental delay, behavioral problems, skin abnormalities, lung disease, and kidney disease.
Lymphangioleiomyomatosis (LAM) is a rare, progressive and systemic disease that typically results in cystic lung destruction. It predominantly affects women, especially during childbearing years. The term sporadic LAM is used for patients with LAM not associated with tuberous sclerosis complex (TSC), while TSC-LAM refers to LAM that is associated with TSC.
Tuberous sclerosis complex (TSC) tumor suppressors form the TSC1-TSC2 molecular complex. Under poor growth conditions the TSC1-TSC2 complex limits cell growth. A key promoter of cell growth, mTORC1, is inhibited by the tuberous sclerosis complex. Insulin activates mTORC1 and causes dissociation of TSC from the surface of lysosomes.
The history of tuberous sclerosis (TSC) research spans less than 200 years. TSC is a rare, multi-system genetic disease that can cause benign tumours to grow on the brain or other vital organs such as the kidneys, heart, eyes, lungs, and skin. A combination of symptoms may include seizures, developmental delay, behavioural problems and skin abnormalities, as well as lung and kidney disease. TSC is caused by mutations on either of two genes, TSC1 and TSC2, which encode for the proteins hamartin and tuberin respectively. These proteins act as tumour growth suppressors and regulate cell proliferation and differentiation. Originally regarded as a rare pathological curiosity, it is now an important focus of research into tumour formation and suppression.
Tuberous sclerosis 1 (TSC1), also known as hamartin, is a protein that in humans is encoded by the TSC1 gene.
RAC(Rho family)-alpha serine/threonine-protein kinase is an enzyme that in humans is encoded by the AKT1 gene. This enzyme belongs to the AKT subfamily of serine/threonine kinases that contain SH2 protein domains. It is commonly referred to as PKB, or by both names as "Akt/PKB".
Glycogen synthase kinase-3 beta, (GSK-3 beta), is an enzyme that in humans is encoded by the GSK3B gene. In mice, the enzyme is encoded by the Gsk3b gene. Abnormal regulation and expression of GSK-3 beta is associated with an increased susceptibility towards bipolar disorder.
Serine/threonine-protein kinase PLK1, also known as polo-like kinase 1 (PLK-1) or serine/threonine-protein kinase 13 (STPK13), is an enzyme that in humans is encoded by the PLK1 gene.
Axin-1 is a protein that in humans is encoded by the AXIN1 gene.
Ras-related protein Rap-1A is a protein that in humans is encoded by the RAP1A gene.
RHEB also known as Ras homolog enriched in brain (RHEB) is a GTP-binding protein that is ubiquitously expressed in humans and other mammals. The protein is largely involved in the mTOR pathway and the regulation of the cell cycle.
Ribosomal protein S6 kinase alpha-1 is an enzyme that in humans is encoded by the RPS6KA1 gene.
Inhibitor of growth protein 1 is a protein that in humans is encoded by the ING1 gene.
DNA-damage-inducible transcript 4 (DDIT4) protein also known as protein regulated in development and DNA damage response 1 (REDD1) is a protein that in humans is encoded by the DDIT4 gene.
STE20-related kinase adapter protein beta is an enzyme that in humans is encoded by the STRADB gene.
Dedicator of cytokinesis protein (Dock7) is a large protein encoded in the human by the DOCK7 gene, involved in intracellular signalling networks. It is a member of the DOCK-C subfamily of the DOCK family of guanine nucleotide exchange factors (GEFs) which function as activators of small G-proteins. Dock7 activates isoforms of the small G protein Rac.
Tuberous sclerosis proteins 1 and 2, also known as TSC1 (hamartin) and TSC2 (tuberin), form a protein-complex. The encoding two genes are TSC1 and TSC2. The complex is known as a tumor suppressor. Mutations in these genes can cause tuberous sclerosis complex. Depending on the grade of the disease, intellectual disability, epilepsy and tumors of the skin, retina, heart, kidney and the central nervous system can be symptoms.
Lewis C. Cantley is an American cell biologist and biochemist who has made significant advances to the understanding of cancer metabolism. Among his most notable contributions are the discovery and study of the enzyme PI-3-kinase, now known to be important to understanding cancer and diabetes mellitus. He is currently Meyer Director and Professor of Cancer Biology at the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine in New York City. He was formerly a professor in the Departments of Systems Biology and Medicine at Harvard Medical School, and the Director of Cancer Research at the Beth Israel Deaconess Medical Center, in Boston, Massachusetts. In 2016, he was elected Chairman of the Board for the Hope Funds for Cancer Research.
mTORC1, also known as mammalian target of rapamycin complex 1 or mechanistic target of rapamycin complex 1, is a protein complex that functions as a nutrient/energy/redox sensor and controls protein synthesis.
Duojia Pan is a Chinese-American developmental biologist at the University of Texas Southwestern Medical Center, where he is Fouad A. and Val Imm Bashour Distinguished Professor of Physiology, chairman of the department of physiology, and investigator of the Howard Hughes Medical Institute (HHMI). His research is focused on molecular mechanisms of growth control and tissue homeostasis and their implications in human disease.