TSC2

TSC2
Identifiers
Aliases	TSC2, LAM, PPP1R160, TSC4, tuberous sclerosis 2
External IDs	MGI: 102548 HomoloGene: 462 GeneCards: TSC2
Genetically Related Diseases
obesity[1]
Gene ontology Molecular function • phosphatase binding • protein homodimerization activity • GTPase activator activity • small GTPase binding • protein binding Cellular component • cytoplasm • cytosol • Golgi apparatus • membrane • TSC1-TSC2 complex • perinuclear region of cytoplasm • lysosome • nucleus Biological process • regulation of endocytosis • protein localization • insulin-like growth factor receptor signaling pathway • negative regulation of protein kinase B signaling • endocytosis • protein kinase B signaling • protein import into nucleus • negative regulation of protein kinase activity • negative regulation of Wnt signaling pathway • negative regulation of phosphatidylinositol 3-kinase signaling • regulation of cell cycle • heart development • negative regulation of TOR signaling • positive regulation of GTPase activity • neural tube closure • negative regulation of insulin receptor signaling pathway • cell cycle arrest • positive chemotaxis • viral process • regulation of small GTPase mediated signal transduction • vesicle-mediated transport • negative regulation of cell proliferation • regulation of insulin receptor signaling pathway Sources:Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	7249	22084
Ensembl	ENSG00000103197	ENSMUSG00000002496
UniProt	P49815	Q61037
RefSeq (mRNA)	NM_000548 NM_001077183 NM_001114382 NM_021055 NM_021056 NM_001318827 NM_001318829 NM_001318831 NM_001318832	NM_001039363 NM_001286713 NM_001286714 NM_001286716 NM_001286718 NM_001286720 NM_011647
RefSeq (protein)	NP_000539.2 NP_001070651.1 NP_001107854.1 NP_001305756.1 NP_001305758.1 NP_001305760.1 NP_001305761.1	n/a
Location (UCSC)	Chr 16: 2.05 – 2.09 Mb	Chr 17: 24.6 – 24.63 Mb
PubMed search	[2]	[3]
Wikidata

View/Edit Human

View/Edit Mouse

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

Function

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. The protein associates with hamartin in a cytosolic complex, possibly acting as a chaperone for hamartin. Alternative splicing results in multiple transcript variants encoding different isoforms of the protein.^[4] Together with tuberous sclerosis, 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 coded by the gene TSC1, mutations to these genes may prevent the control of cell growth in the lungs of individuals.^[5]

Interactions

TSC2 functions within a multi-protein complex knowns as the TSC complex which consists of the core proteins TSC2, TSC1,^[6][7] and TBC1D7.

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

• AKT1,^[8][9]
• AXIN1,^[10]
• FOXO1,^[11]
• GSK3B,^[10][12]
• MAPK1,^[13]
• PTK2,^[14]
• PAM,^[15]
• PRKAA1,^[16][17]
• RAP1A,^[18][19]
• RHEB,^{[11][18][20][21][22][23]}
• RPS6KA1,^[9][24]
• UBE3A^[25][26] and
• YWHAZ.^[27]

See also

• Tuberous sclerosis protein

References

1. "Diseases that are genetically associated with TSC2 view/edit references on wikidata".
2. "Human PubMed Reference:".
3. "Mouse PubMed Reference:".
4. "Entrez Gene: TSC2 tuberous sclerosis 2".
5. "Lymphangioleiomyomatosis". Genetics Home Reference. Retrieved 28 September 2015.
6. Orlova KA, Crino PB (2010). "The tuberous sclerosis complex". Ann. N. Y. Acad. Sci. 1184: 87–105. doi:10.1111/j.1749-6632.2009.05117.x. PMC 2892799. PMID 20146692.
7. Li Y, Inoki K, Guan KL (2004). "Biochemical and functional characterizations of small GTPase Rheb and TSC2 GAP activity". Mol. Cell. Biol. 24 (18): 7965–75. doi:10.1128/MCB.24.18.7965-7975.2004. PMC 515062. PMID 15340059.
8. Dan HC, Sun M, Yang L, Feldman RI, Sui XM, Ou CC, Nellist M, Yeung RS, Halley DJ, Nicosia SV, Pledger WJ, Cheng JQ (2002). "Phosphatidylinositol 3-kinase/Akt pathway regulates tuberous sclerosis tumor suppressor complex by phosphorylation of tuberin". J. Biol. Chem. 277 (38): 35364–70. doi:10.1074/jbc.M205838200. PMID 12167664.
9. Roux PP, Ballif BA, Anjum R, Gygi SP, Blenis J (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. doi:10.1073/pnas.0405659101. PMC 518784. PMID 15342917.
10. Mak BC, Takemaru K, Kenerson HL, Moon RT, Yeung RS (2003). "The tuberin-hamartin complex negatively regulates beta-catenin signaling activity". J. Biol. Chem. 278 (8): 5947–51. doi:10.1074/jbc.C200473200. PMID 12511557.
11. Cao Y, Kamioka Y, Yokoi N, Kobayashi T, Hino O, Onodera M, Mochizuki N, Nakae J (2006). "Interaction of FoxO1 and TSC2 induces insulin resistance through activation of the mammalian target of rapamycin/p70 S6K pathway". J. Biol. Chem. 281 (52): 40242–51. doi:10.1074/jbc.M608116200. PMID 17077083.
12. 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 (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.
13. Ma L, Chen Z, Erdjument-Bromage H, Tempst P, Pandolfi PP (2005). "Phosphorylation and functional inactivation of TSC2 by Erk implications for tuberous sclerosis and cancer pathogenesis". Cell. 121 (2): 179–93. doi:10.1016/j.cell.2005.02.031. PMID 15851026.
14. Gan B, Yoo Y, Guan JL (2006). "Association of focal adhesion kinase with tuberous sclerosis complex 2 in the regulation of s6 kinase activation and cell growth". J. Biol. Chem. 281 (49): 37321–9. doi:10.1074/jbc.M605241200. PMID 17043358.
15. Murthy V, Han S, Beauchamp RL, Smith N, Haddad LA, Ito N, Ramesh V (2004). "Pam and its ortholog highwire interact with and may negatively regulate the TSC1.TSC2 complex". J. Biol. Chem. 279 (2): 1351–8. doi:10.1074/jbc.M310208200. PMID 14559897.
16. Inoki K, Zhu T, Guan KL (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.
17. Shaw RJ, Bardeesy N, Manning BD, Lopez L, Kosmatka M, DePinho RA, Cantley LC (2004). "The LKB1 tumor suppressor negatively regulates mTOR signaling". Cancer Cell. 6 (1): 91–9. doi:10.1016/j.ccr.2004.06.007. PMID 15261145.
18. Castro AF, Rebhun JF, Clark GJ, Quilliam LA (2003). "Rheb binds tuberous sclerosis complex 2 (TSC2) and promotes S6 kinase activation in a rapamycin- and farnesylation-dependent manner". J. Biol. Chem. 278 (35): 32493–6. doi:10.1074/jbc.C300226200. PMID 12842888.
19. Yamamoto Y, Jones KA, Mak BC, Muehlenbachs A, Yeung RS (2002). "Multicompartmental distribution of the tuberous sclerosis gene products, hamartin and tuberin". Arch. Biochem. Biophys. 404 (2): 210–7. doi:10.1016/S0003-9861(02)00300-4. PMID 12147258.
20. Inoki K, Li Y, Xu T, Guan KL (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.
21. Garami A, Zwartkruis FJ, Nobukuni T, Joaquin M, Roccio M, Stocker H, Kozma SC, Hafen E, Bos JL, Thomas G (2003). "Insulin activation of Rheb, a mediator of mTOR/S6K/4E-BP signaling, is inhibited by TSC1 and 2". Mol. Cell. 11 (6): 1457–66. doi:10.1016/S1097-2765(03)00220-X. PMID 12820960.
22. Zhang Y, Gao X, Saucedo LJ, Ru B, Edgar BA, Pan D (2003). "Rheb is a direct target of the tuberous sclerosis tumour suppressor proteins". Nat. Cell Biol. 5 (6): 578–81. doi:10.1038/ncb999. PMID 12771962.
23. Long X, Lin Y, Ortiz-Vega S, Yonezawa K, Avruch J (2005). "Rheb binds and regulates the mTOR kinase". Curr. Biol. 15 (8): 702–13. doi:10.1016/j.cub.2005.02.053. PMID 15854902.
24. Rolfe M, McLeod LE, Pratt PF, Proud CG (2005). "Activation of protein synthesis in cardiomyocytes by the hypertrophic agent phenylephrine requires the activation of ERK and involves phosphorylation of tuberous sclerosis complex 2 (TSC2)". Biochem. J. 388 (Pt 3): 973–84. doi:10.1042/BJ20041888. PMC 1183479. PMID 15757502.
25. Lu Z, Hu X, Li Y, Zheng L, Zhou Y, Jiang H, Ning T, Basang Z, Zhang C, Ke Y (2004). "Human papillomavirus 16 E6 oncoprotein interferences with insulin signaling pathway by binding to tuberin". J. Biol. Chem. 279 (34): 35664–70. doi:10.1074/jbc.M403385200. PMID 15175323.
26. Zheng L, Ding H, Lu Z, Li Y, Pan Y, Ning T, Ke Y (2008). "E3 ubiquitin ligase E6AP-mediated TSC2 turnover in the presence and absence of HPV16 E6". Genes Cells. 13 (3): 285–94. doi:10.1111/j.1365-2443.2008.01162.x. PMID 18298802.
27. Nellist M, Goedbloed MA, de Winter C, Verhaaf B, Jankie A, Reuser AJ, van den Ouweland AM, van der Sluijs P, Halley DJ (2002). "Identification and characterization of the interaction between tuberin and 14-3-3zeta". J. Biol. Chem. 277 (42): 39417–24. doi:10.1074/jbc.M204802200. PMID 12176984.

Further reading

• Jones AC, Shyamsundar MM, Thomas MW, et al. (1999). "Comprehensive mutation analysis of TSC1 and TSC2-and phenotypic correlations in 150 families with tuberous sclerosis.". Am. J. Hum. Genet. 64 (5): 1305–15. doi:10.1086/302381. PMC 1377866. PMID 10205261.
• Hengstschläger M (2002). "Tuberous sclerosis complex genes: from flies to human genetics.". Arch. Dermatol. Res. 293 (8): 383–6. doi:10.1007/s004030100250. PMID 11686512.
• Hockenbery DM (2003). "Nailing down a link between tuberin and renal cysts.". Am. J. Pathol. 162 (2): 369–71. doi:10.1016/S0002-9440(10)63831-X. PMC 1851147. PMID 12547695.
• Ramesh V (2004). "Aspects of tuberous sclerosis complex (TSC) protein function in the brain.". Biochem. Soc. Trans. 31 (Pt 3): 579–83. doi:10.1042/BST0310579. PMID 12773159.
• Knowles MA, Hornigold N, Pitt E (2004). "Tuberous sclerosis complex (TSC) gene involvement in sporadic tumours.". Biochem. Soc. Trans. 31 (Pt 3): 597–602. doi:10.1042/BST0310597. PMID 12773163.
• Ellisen LW (2007). "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 (2007). "Giant cells: contradiction to two-hit model of tuber formation?". Cell. Mol. Neurobiol. 27 (2): 251–61. doi:10.1007/s10571-006-9106-0. PMID 16897363.
• Cai SL, Walker CL (2007). "TSC2, a key player in tumor suppression and cystic kidney disease.". Nephrol. Ther. 2 Suppl 2: S119–22. PMID 17373211.
• Urban T (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.

External links

• GeneReviews/NIH/NCBI/UW entry on Tuberous Sclerosis Complex or Bourneville Disease