Tuberous sclerosis protein

tuberous sclerosis 2
tuberous sclerosis 2
Identifiers
Symbol	TSC2
Alt. symbols	TSC4
NCBI gene	7249
HGNC	12363
OMIM	191092
RefSeq	NM_000548
UniProt	P49815
Other data
Locus	Chr. 16 p13.3
Structures
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Structures	Swiss-model
Domains	InterPro

Search for
Structures	Swiss-model
Domains	InterPro

tuberous sclerosis 1
tuberous sclerosis 1
Identifiers
Symbol	TSC1
Alt. symbols	TSC
NCBI gene	7248
HGNC	12362
OMIM	605284
RefSeq	NM_000368
UniProt	Q92574
Other data
Locus	Chr. 9 q34
Structures
Search for
Structures	Swiss-model
Domains	InterPro

Last updated December 11, 2023

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.

Physiological roles

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 (DNA damage, hypoxia) 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).^[1] 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.^[2] TSC2 contains a GTPase Activating Protein (GAP) domain which has been shown to stimulate (down regulate) the GTPase activity of the small GTPase Rheb,^[3] 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.^[4] 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.^[5]^[6]
Low energy levels and stress: The AMP-dependent protein kinase AMPK phosphorylates and thereby activates TSC1-TSC2 by phosphorylating at least 2 residues of TSC2.^[7]
Hypoxia: The Hypoxia-inducible factor α HIFα induces REDD1 at low oxygen levels. REDD1 has been shown to activate TSC1-TSC2 by neutralisation of AKT dependent inhibition.^[8]
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.^[9]

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:

GTPase-accelerating protein (GAP) function for the Rap1a GTPase.^[10]
C-terminal transcriptional activation domains.^[11]
Selective modulation of transcription mediated by members of the steroid receptor superfamily.^[12]

Related Research Articles

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.

<span class="mw-page-title-main">Lymphangioleiomyomatosis</span> Medical condition

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.

Protein kinase B (PKB), also known as Akt, is the collective name of a set of three serine/threonine-specific protein kinases that play key roles in multiple cellular processes such as glucose metabolism, apoptosis, cell proliferation, transcription, and cell migration.

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.

Tuberous sclerosis 1 (TSC1), also known as hamartin, is a protein that in humans is encoded by the TSC1 gene.

The tumor suppressor gene FLCN encodes the protein folliculin, also known as Birt–Hogg–Dubé syndrome protein, which functions as an inhibitor of Lactate Dehydrogenase-A and a regulator of the Warburg effect. Folliculin (FLCN) is also associated with Birt–Hogg–Dubé syndrome, which is an autosomal dominant inherited cancer syndrome in which affected individuals are at risk for the development of benign cutaneous tumors (folliculomas), pulmonary cysts, and kidney tumors.

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".

Mitogen-activated protein kinase 3, also known as p44MAPK and ERK1, is an enzyme that in humans is encoded by the MAPK3 gene.

Tuberous Sclerosis Complex 2 (TSC2), also known as Tuberin, is a protein that in humans is encoded by the TSC2 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.

5'-AMP-activated protein kinase catalytic subunit alpha-1 is an enzyme that in humans is encoded by the PRKAA1 gene.

Ribosomal protein S6 kinase alpha-2 is an enzyme that in humans is encoded by the RPS6KA2 gene.

Regulatory-associated protein of mTOR also known as raptor or KIAA1303 is an adapter protein that is encoded in humans by the RPTOR gene. Two mRNAs from the gene have been identified that encode proteins of 1335 and 1177 amino acids long.

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.

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.

Kun-Liang Guan, is a Chinese and American biochemist. He won the MacArthur Award in 1998.

The Akt signaling pathway or PI3K-Akt signaling pathway is a signal transduction pathway that promotes survival and growth in response to extracellular signals. Key proteins involved are PI3K and Akt.

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.

References

↑ Inoki K, Ouyang H, Zhu T, Lindvall C, Wang Y, Zhang X, Yang Q, Bennett C, Harada Y, Stankunas K, Wang CY, He X, MacDougald OA, You M, Williams BO, Guan KL (September 2006). "TSC2 integrates Wnt and energy signals via a coordinated phosphorylation by AMPK and GSK3 to regulate cell growth". Cell. 126 (5): 955–68. doi: 10.1016/j.cell.2006.06.055 . PMID 16959574. S2CID 16047397.
↑ Huang J, Manning BD (February 2009). "A complex interplay between Akt, TSC2 and the two mTOR complexes". Biochem. Soc. Trans. 37 (Pt 1): 217–22. doi:10.1042/BST0370217. PMC 2778026 . PMID 19143635.
↑ Inoki K, Li Y, Xu T, Guan KL (August 2003). "Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling". Genes Dev. 17 (15): 1829–34. doi:10.1101/gad.1110003. PMC 196227 . PMID 12869586.
↑ Benvenuto G, Li S, Brown SJ, Braverman R, Vass WC, Cheadle JP, Halley DJ, Sampson JR, Wienecke R, DeClue JE (December 2000). "The tuberous sclerosis-1 (TSC1) gene product hamartin suppresses cell growth and augments the expression of the TSC2 product tuberin by inhibiting its ubiquitination". Oncogene. 19 (54): 6306–16. doi:10.1038/sj.onc.1204009. PMID 11175345. S2CID 21879707.
↑ Manning BD, Tee AR, Logsdon MN, Blenis J, Cantley LC (July 2002). "Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathway". Mol. Cell. 10 (1): 151–62. doi: 10.1016/S1097-2765(02)00568-3 . PMID 12150915.
↑ Huang J, Manning BD (June 2008). "The TSC1-TSC2 complex: a molecular switchboard controlling cell growth". Biochem. J. 412 (2): 179–90. doi:10.1042/BJ20080281. PMC 2735030 . PMID 18466115.
↑ Inoki K, Zhu T, Guan KL (November 2003). "TSC2 mediates cellular energy response to control cell growth and survival". Cell. 115 (5): 577–90. doi: 10.1016/S0092-8674(03)00929-2 . PMID 14651849. S2CID 18173817.
↑ DeYoung MP, Horak P, Sofer A, Sgroi D, Ellisen LW (January 2008). "Hypoxia regulates TSC1/2-mTOR signaling and tumor suppression through REDD1-mediated 14-3-3 shuttling". Genes Dev. 22 (2): 239–51. doi:10.1101/gad.1617608. PMC 2192757 . PMID 18198340.
↑ Roux PP, Ballif BA, Anjum R, Gygi SP, Blenis J (September 2004). "Tumor-promoting phorbol esters and activated Ras inactivate the tuberous sclerosis tumor suppressor complex via p90 ribosomal S6 kinase". Proc. Natl. Acad. Sci. U.S.A. 101 (37): 13489–94. Bibcode:2004PNAS..10113489R. doi: 10.1073/pnas.0405659101 . PMC 518784 . PMID 15342917.
↑ Wienecke R, König A, DeClue JE (July 1995). "Identification of tuberin, the tuberous sclerosis-2 product. Tuberin possesses specific Rap1GAP activity". J. Biol. Chem. 270 (27): 16409–14. doi: 10.1074/jbc.270.27.16409 . PMID 7608212.
↑ Tsuchiya H, Orimoto K, Kobayashi K, Hino O (February 1996). "Presence of potent transcriptional activation domains in the predisposing tuberous sclerosis (Tsc2) gene product of the Eker rat model". Cancer Res. 56 (3): 429–33. PMID 8564946.
↑ Henry KW, Yuan X, Koszewski NJ, Onda H, Kwiatkowski DJ, Noonan DJ (August 1998). "Tuberous sclerosis gene 2 product modulates transcription mediated by steroid hormone receptor family members". J. Biol. Chem. 273 (32): 20535–9. doi: 10.1074/jbc.273.32.20535 . PMID 9685410.