TSC2

TSC2
Identifiers
AliasesTSC2, LAM, PPP1R160, TSC4, tuberous sclerosis 2, TSC complex subunit 2
External IDsMGI: 102548 HomoloGene: 462 GeneCards: TSC2
Gene location (Human)
Chr.Chromosome 16 (human)[1]
Band16p13.3Start2,047,465 bp[1]
End2,089,487 bp[1]
RNA expression pattern
More reference expression data
Orthologs
SpeciesHumanMouse
Entrez

7249

22084

Ensembl

ENSG00000103197

ENSMUSG00000002496

UniProt

P49815

Q61037

RefSeq (mRNA)
RefSeq (protein)

n/a

Location (UCSC)Chr 16: 2.05 – 2.09 MbChr 17: 24.6 – 24.63 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/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. 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]

Signaling Pathways

Pharmacological inhibition of ERK1/2 restores GSK3β activity and protein synthesis levels in a model of tuberous sclerosis.[7]

Interactions

TSC2 functions within a multi-protein complex knowns as the TSC complex which consists of the core proteins TSC2, TSC1,[8][9] and TBC1D7.

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

See also

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000103197 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000002496 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:".
  4. ↑ "Mouse PubMed Reference:".
  5. 1 2 3 4 Woodford MR, Sager RA, Marris E, Dunn DM, Blanden AR, Murphy RL, Rensing N, Shapiro O, Panaretou B, Prodromou C, Loh SN, Gutmann DH, Bourboulia D, Bratslavsky G, Wong M, Mollapour M (December 2017). "Tumor suppressor Tsc1 is a new Hsp90 co-chaperone that facilitates folding of kinase and non-kinase clients". The EMBO Journal. 36 (24): 3650–3665. doi:10.15252/embj.201796700. PMC 5730846. PMID 29127155.
  6. ↑ "Entrez Gene: TSC2 tuberous sclerosis 2".
  7. ↑ Pal R, Bondar VV, Adamski CJ, Rodney GG, Sardiello M (June 2017). "Inhibition of ERK1/2 Restores GSK3β Activity and Protein Synthesis Levels in a Model of Tuberous Sclerosis". Scientific Reports. 7 (1): 4174. doi:10.1038/s41598-017-04528-5. PMC 5482840. PMID 28646232.
  8. ↑ Orlova KA, Crino PB (January 2010). "The tuberous sclerosis complex". Annals of the New York Academy of Sciences. 1184: 87–105. doi:10.1111/j.1749-6632.2009.05117.x. PMC 2892799. PMID 20146692.
  9. ↑ Li Y, Inoki K, Guan KL (September 2004). "Biochemical and functional characterizations of small GTPase Rheb and TSC2 GAP activity". Molecular and Cellular Biology. 24 (18): 7965–75. doi:10.1128/MCB.24.18.7965-7975.2004. PMC 515062. PMID 15340059.
  10. ↑ Dan HC, Sun M, Yang L, Feldman RI, Sui XM, Ou CC, Nellist M, Yeung RS, Halley DJ, Nicosia SV, Pledger WJ, Cheng JQ (September 2002). "Phosphatidylinositol 3-kinase/Akt pathway regulates tuberous sclerosis tumor suppressor complex by phosphorylation of tuberin". The Journal of Biological Chemistry. 277 (38): 35364–70. doi:10.1074/jbc.M205838200. PMID 12167664.
  11. 1 2 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". Proceedings of the National Academy of Sciences of the United States of America. 101 (37): 13489–94. doi:10.1073/pnas.0405659101. PMC 518784. PMID 15342917.
  12. 1 2 Mak BC, Takemaru K, Kenerson HL, Moon RT, Yeung RS (February 2003). "The tuberin-hamartin complex negatively regulates beta-catenin signaling activity". The Journal of Biological Chemistry. 278 (8): 5947–51. doi:10.1074/jbc.C200473200. PMID 12511557.
  13. 1 2 Cao Y, Kamioka Y, Yokoi N, Kobayashi T, Hino O, Onodera M, Mochizuki N, Nakae J (December 2006). "Interaction of FoxO1 and TSC2 induces insulin resistance through activation of the mammalian target of rapamycin/p70 S6K pathway". The Journal of Biological Chemistry. 281 (52): 40242–51. doi:10.1074/jbc.M608116200. PMID 17077083.
  14. ↑ 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.
  15. ↑ Ma L, Chen Z, Erdjument-Bromage H, Tempst P, Pandolfi PP (April 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.
  16. ↑ Gan B, Yoo Y, Guan JL (December 2006). "Association of focal adhesion kinase with tuberous sclerosis complex 2 in the regulation of s6 kinase activation and cell growth". The Journal of Biological Chemistry. 281 (49): 37321–9. doi:10.1074/jbc.M605241200. PMID 17043358.
  17. ↑ Murthy V, Han S, Beauchamp RL, Smith N, Haddad LA, Ito N, Ramesh V (January 2004). "Pam and its ortholog highwire interact with and may negatively regulate the TSC1.TSC2 complex". The Journal of Biological Chemistry. 279 (2): 1351–8. doi:10.1074/jbc.M310208200. PMID 14559897.
  18. ↑ 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.
  19. ↑ Shaw RJ, Bardeesy N, Manning BD, Lopez L, Kosmatka M, DePinho RA, Cantley LC (July 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.
  20. 1 2 Castro AF, Rebhun JF, Clark GJ, Quilliam LA (August 2003). "Rheb binds tuberous sclerosis complex 2 (TSC2) and promotes S6 kinase activation in a rapamycin- and farnesylation-dependent manner". The Journal of Biological Chemistry. 278 (35): 32493–6. doi:10.1074/jbc.C300226200. PMID 12842888.
  21. ↑ Yamamoto Y, Jones KA, Mak BC, Muehlenbachs A, Yeung RS (August 2002). "Multicompartmental distribution of the tuberous sclerosis gene products, hamartin and tuberin". Archives of Biochemistry and Biophysics. 404 (2): 210–7. doi:10.1016/S0003-9861(02)00300-4. PMID 12147258.
  22. ↑ 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 & Development. 17 (15): 1829–34. doi:10.1101/gad.1110003. PMC 196227. PMID 12869586.
  23. ↑ Garami A, Zwartkruis FJ, Nobukuni T, Joaquin M, Roccio M, Stocker H, Kozma SC, Hafen E, Bos JL, Thomas G (June 2003). "Insulin activation of Rheb, a mediator of mTOR/S6K/4E-BP signaling, is inhibited by TSC1 and 2". Molecular Cell. 11 (6): 1457–66. doi:10.1016/S1097-2765(03)00220-X. PMID 12820960.
  24. ↑ Zhang Y, Gao X, Saucedo LJ, Ru B, Edgar BA, Pan D (June 2003). "Rheb is a direct target of the tuberous sclerosis tumour suppressor proteins". Nature Cell Biology. 5 (6): 578–81. doi:10.1038/ncb999. PMID 12771962.
  25. ↑ Long X, Lin Y, Ortiz-Vega S, Yonezawa K, Avruch J (April 2005). "Rheb binds and regulates the mTOR kinase". Current Biology. 15 (8): 702–13. doi:10.1016/j.cub.2005.02.053. PMID 15854902.
  26. ↑ Rolfe M, McLeod LE, Pratt PF, Proud CG (June 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)". The Biochemical Journal. 388 (Pt 3): 973–84. doi:10.1042/BJ20041888. PMC 1183479. PMID 15757502.
  27. ↑ Lu Z, Hu X, Li Y, Zheng L, Zhou Y, Jiang H, Ning T, Basang Z, Zhang C, Ke Y (August 2004). "Human papillomavirus 16 E6 oncoprotein interferences with insulin signaling pathway by binding to tuberin". The Journal of Biological Chemistry. 279 (34): 35664–70. doi:10.1074/jbc.M403385200. PMID 15175323.
  28. ↑ Zheng L, Ding H, Lu Z, Li Y, Pan Y, Ning T, Ke Y (March 2008). "E3 ubiquitin ligase E6AP-mediated TSC2 turnover in the presence and absence of HPV16 E6". Genes to Cells. 13 (3): 285–94. doi:10.1111/j.1365-2443.2008.01162.x. PMID 18298802.
  29. ↑ Nellist M, Goedbloed MA, de Winter C, Verhaaf B, Jankie A, Reuser AJ, van den Ouweland AM, van der Sluijs P, Halley DJ (October 2002). "Identification and characterization of the interaction between tuberin and 14-3-3zeta". The Journal of Biological Chemistry. 277 (42): 39417–24. doi:10.1074/jbc.M204802200. PMID 12176984.

Further reading

  • 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.
  • 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.
  • 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.
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