TSC2

Tuberous sclerosis 2
Identifiers
Symbols TSC2; FLJ43106; LAM; TSC4
External IDs OMIM: 191092 MGI: 102548 HomoloGene: 462 GeneCards: TSC2 Gene
RNA expression pattern
More reference expression data
Orthologs
Species Human Mouse
Entrez 7249 22084
Ensembl ENSG00000103197 ENSMUSG00000002496
UniProt P49815 Q3TQ10
RefSeq (mRNA) NM_000548.3 NM_001039363
RefSeq (protein) NP_000539.2 NP_001034452
Location (UCSC) Chr 16:
2.1 – 2.14 Mb		 Chr 17:
24.73 – 24.77 Mb
PubMed search [1] [2]

Tuberous sclerosis protein 2, also known as TSC2 and Tuberin, is a human protein and 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. 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.[1]

Contents

Interactions

TSC2 has been shown to interact with FOXO1,[2] GSK3B,[3][4] Peptidylglycine alpha-amidating monooxygenase,[5] RAP1A,[6][7] MAPK1,[8] AKT1,[9][10] AXIN1,[3] TSC1,[2][3][8][9][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25] PTK2,[26] Protein kinase, AMP-activated, alpha 1,[17][27] YWHAZ,[14] RPS6KA1,[10][28] UBE3A[29][30] and RHEB.[2][6][31][32][33][34]

See also

References

  1. ^ "Entrez Gene: TSC2 tuberous sclerosis 2". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=7249. 
  2. ^ a b c Cao, Yongheng; Kamioka Yuji, Yokoi Norihide, Kobayashi Toshiyuki, Hino Okio, Onodera Masafumi, Mochizuki Naoki, Nakae Jun (Dec. 2006). "Interaction of FoxO1 and TSC2 induces insulin resistance through activation of the mammalian target of rapamycin/p70 S6K pathway". J. Biol. Chem. (United States) 281 (52): 40242–51. doi:10.1074/jbc.M608116200. ISSN 0021-9258. PMID 17077083. 
  3. ^ a b c Mak, Baldwin C; Takemaru Ken-Ichi, Kenerson Heidi L, Moon Randall T, Yeung Raymond S (Feb. 2003). "The tuberin-hamartin complex negatively regulates beta-catenin signaling activity". J. Biol. Chem. (United States) 278 (8): 5947–51. doi:10.1074/jbc.C200473200. ISSN 0021-9258. PMID 12511557. 
  4. ^ Inoki, Ken; Ouyang Hongjiao, Zhu Tianqing, Lindvall Charlotta, Wang Yian, Zhang Xiaojie, Yang Qian, Bennett Christina, Harada Yuko, Stankunas Kryn, Wang Cun-Yu, He Xi, MacDougald Ormond A, You Ming, Williams Bart O, Guan Kun-Liang (Sep. 2006). "TSC2 integrates Wnt and energy signals via a coordinated phosphorylation by AMPK and GSK3 to regulate cell growth". Cell (United States) 126 (5): 955–68. doi:10.1016/j.cell.2006.06.055. ISSN 0092-8674. PMID 16959574. 
  5. ^ Murthy, Vanishree; Han Sangyeul, Beauchamp Roberta L, Smith Nicole, Haddad Luciana A, Ito Naoto, Ramesh Vijaya (Jan. 2004). "Pam and its ortholog highwire interact with and may negatively regulate the TSC1.TSC2 complex". J. Biol. Chem. (United States) 279 (2): 1351–8. doi:10.1074/jbc.M310208200. ISSN 0021-9258. PMID 14559897. 
  6. ^ a b Castro, Ariel F; Rebhun John F, Clark Geoffrey J, Quilliam Lawrence A (Aug. 2003). "Rheb binds tuberous sclerosis complex 2 (TSC2) and promotes S6 kinase activation in a rapamycin- and farnesylation-dependent manner". J. Biol. Chem. (United States) 278 (35): 32493–6. doi:10.1074/jbc.C300226200. ISSN 0021-9258. PMID 12842888. 
  7. ^ Yamamoto, Yuji; Jones Kathryn A, Mak Baldwin C, Muehlenbachs Atis, Yeung Raymond S (Aug. 2002). "Multicompartmental distribution of the tuberous sclerosis gene products, hamartin and tuberin". Arch. Biochem. Biophys. (United States) 404 (2): 210–7. doi:10.1016/S0003-9861(02)00300-4. ISSN 0003-9861. PMID 12147258. 
  8. ^ a b Ma, Li; Chen Zhenbang, Erdjument-Bromage Hediye, Tempst Paul, Pandolfi Pier Paolo (Apr. 2005). "Phosphorylation and functional inactivation of TSC2 by Erk implications for tuberous sclerosis and cancer pathogenesis". Cell (United States) 121 (2): 179–93. doi:10.1016/j.cell.2005.02.031. ISSN 0092-8674. PMID 15851026. 
  9. ^ a b Dan, Han C; Sun Mei, Yang Lin, Feldman Richard I, Sui Xue-Mei, Ou Chien Chen, Nellist Mark, Yeung Raymond S, Halley Dicky J J, Nicosia Santo V, Pledger Warren J, Cheng Jin Q (Sep. 2002). "Phosphatidylinositol 3-kinase/Akt pathway regulates tuberous sclerosis tumor suppressor complex by phosphorylation of tuberin". J. Biol. Chem. (United States) 277 (38): 35364–70. doi:10.1074/jbc.M205838200. ISSN 0021-9258. PMID 12167664. 
  10. ^ a b Roux, Philippe P; Ballif Bryan A, Anjum Rana, Gygi Steven P, Blenis John (Sep. 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. (United States) 101 (37): 13489–94. doi:10.1073/pnas.0405659101. ISSN 0027-8424. PMC 518784. PMID 15342917. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=518784. 
  11. ^ Hodges, A K; Li S, Maynard J, Parry L, Braverman R, Cheadle J P, DeClue J E, Sampson J R (Dec. 2001). "Pathological mutations in TSC1 and TSC2 disrupt the interaction between hamartin and tuberin". Hum. Mol. Genet. (England) 10 (25): 2899–905. doi:10.1093/hmg/10.25.2899. ISSN 0964-6906. PMID 11741833. 
  12. ^ Aicher, L D; Campbell J S, Yeung R S (Jun. 2001). "Tuberin phosphorylation regulates its interaction with hamartin. Two proteins involved in tuberous sclerosis". J. Biol. Chem. (United States) 276 (24): 21017–21. doi:10.1074/jbc.C100136200. ISSN 0021-9258. PMID 11290735. 
  13. ^ van Slegtenhorst, M; Nellist M, Nagelkerken B, Cheadle J, Snell R, van den Ouweland A, Reuser A, Sampson J, Halley D, van der Sluijs P (Jun. 1998). "Interaction between hamartin and tuberin, the TSC1 and TSC2 gene products". Hum. Mol. Genet. (ENGLAND) 7 (6): 1053–7. doi:10.1093/hmg/7.6.1053. ISSN 0964-6906. PMID 9580671. 
  14. ^ a b Nellist, Mark; Goedbloed Miriam A, de Winter Christa, Verhaaf Brenda, Jankie Anita, Reuser Arnold J J, van den Ouweland Ans M W, van der Sluijs Peter, Halley Dicky J J (Oct. 2002). "Identification and characterization of the interaction between tuberin and 14-3-3zeta". J. Biol. Chem. (United States) 277 (42): 39417–24. doi:10.1074/jbc.M204802200. ISSN 0021-9258. PMID 12176984. 
  15. ^ Li, Yong; Inoki Ken, Guan Kun-Liang (Sep. 2004). "Biochemical and functional characterizations of small GTPase Rheb and TSC2 GAP activity". Mol. Cell. Biol. (United States) 24 (18): 7965–75. doi:10.1128/MCB.24.18.7965-7975.2004. ISSN 0270-7306. PMC 515062. PMID 15340059. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=515062. 
  16. ^ Cai, Sheng-Li; Tee Andrew R, Short John D, Bergeron Judith M, Kim Jinhee, Shen Jianjun, Guo Ruifeng, Johnson Charles L, Kiguchi Kaoru, Walker Cheryl Lyn (Apr. 2006). "Activity of TSC2 is inhibited by AKT-mediated phosphorylation and membrane partitioning". J. Cell Biol. (United States) 173 (2): 279–89. doi:10.1083/jcb.200507119. ISSN 0021-9525. PMC 2063818. PMID 16636147. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2063818. 
  17. ^ a b Inoki, Ken; Zhu Tianqing, Guan Kun-Liang (Nov. 2003). "TSC2 mediates cellular energy response to control cell growth and survival". Cell (United States) 115 (5): 577–90. doi:10.1016/S0092-8674(03)00929-2. ISSN 0092-8674. PMID 14651849. 
  18. ^ Nellist, Mark; Burgers Peter C, van den Ouweland Ans M W, Halley Dicky J J, Luider Theo M (Aug. 2005). "Phosphorylation and binding partner analysis of the TSC1-TSC2 complex". Biochem. Biophys. Res. Commun. (United States) 333 (3): 818–26. doi:10.1016/j.bbrc.2005.05.175. ISSN 0006-291X. PMID 15963462. 
  19. ^ Goncharova, Elena A; Goncharov Dmitriy A, Spaits Matthew, Noonan Daniel J, Talovskaya Ekaterina, Eszterhas Andrew, Krymskaya Vera P (May. 2006). "Abnormal growth of smooth muscle-like cells in lymphangioleiomyomatosis: Role for tumor suppressor TSC2". Am. J. Respir. Cell Mol. Biol. (United States) 34 (5): 561–72. doi:10.1165/rcmb.2005-0300OC. ISSN 1044-1549. PMC 2644221. PMID 16424383. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2644221. 
  20. ^ Astrinidis, Aristotelis; Senapedis William, Henske Elizabeth P (Jan. 2006). "Hamartin, the tuberous sclerosis complex 1 gene product, interacts with polo-like kinase 1 in a phosphorylation-dependent manner". Hum. Mol. Genet. (England) 15 (2): 287–97. doi:10.1093/hmg/ddi444. ISSN 0964-6906. PMID 16339216. 
  21. ^ Astrinidis, Aristotelis; Senapedis William, Coleman Thomas R, Henske Elizabeth Petri (Dec. 2003). "Cell cycle-regulated phosphorylation of hamartin, the product of the tuberous sclerosis complex 1 gene, by cyclin-dependent kinase 1/cyclin B". J. Biol. Chem. (United States) 278 (51): 51372–9. doi:10.1074/jbc.M303956200. ISSN 0021-9258. PMID 14551205. 
  22. ^ Nellist, M; Verhaaf B, Goedbloed M A, Reuser A J, van den Ouweland A M, Halley D J (Dec. 2001). "TSC2 missense mutations inhibit tuberin phosphorylation and prevent formation of the tuberin-hamartin complex". Hum. Mol. Genet. (England) 10 (25): 2889–98. doi:10.1093/hmg/10.25.2889. ISSN 0964-6906. PMID 11741832. 
  23. ^ Benvenuto, G; Li S, Brown S J, Braverman R, Vass W C, Cheadle J P, Halley D J, Sampson J R, Wienecke R, DeClue J E (Dec. 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 (England) 19 (54): 6306–16. doi:10.1038/sj.onc.1204009. ISSN 0950-9232. PMID 11175345. 
  24. ^ Murthy, V; Haddad L A, Smith N, Pinney D, Tyszkowski R, Brown D, Ramesh V (May. 2000). "Similarities and differences in the subcellular localization of hamartin and tuberin in the kidney". Am. J. Physiol. Renal Physiol. (United States) 278 (5): F737–46. ISSN 0363-6127. PMID 10807585. 
  25. ^ Miloloza, A; Rosner M, Nellist M, Halley D, Bernaschek G, Hengstschläger M (Jul. 2000). "The TSC1 gene product, hamartin, negatively regulates cell proliferation". Hum. Mol. Genet. (ENGLAND) 9 (12): 1721–7. doi:10.1093/hmg/9.12.1721. ISSN 0964-6906. PMID 10915759. 
  26. ^ Gan, Boyi; Yoo Youngdong, Guan Jun-Lin (Dec. 2006). "Association of focal adhesion kinase with tuberous sclerosis complex 2 in the regulation of s6 kinase activation and cell growth". J. Biol. Chem. (United States) 281 (49): 37321–9. doi:10.1074/jbc.M605241200. ISSN 0021-9258. PMID 17043358. 
  27. ^ Shaw, Reuben J; Bardeesy Nabeel, Manning Brendan D, Lopez Lyle, Kosmatka Monica, DePinho Ronald A, Cantley Lewis C (Jul. 2004). "The LKB1 tumor suppressor negatively regulates mTOR signaling". Cancer Cell (United States) 6 (1): 91–9. doi:10.1016/j.ccr.2004.06.007. ISSN 1535-6108. PMID 15261145. 
  28. ^ Rolfe, Mark; McLeod Laura E, Pratt Phillip F, Proud Christopher G (Jun. 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. (England) 388 (Pt 3): 973–84. doi:10.1042/BJ20041888. PMC 1183479. PMID 15757502. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1183479. 
  29. ^ Lu, Zheming; Hu Xiuhua, Li Yong, Zheng Li, Zhou Yue, Jiang Haidi, Ning Tao, Basang Zhuoma, Zhang Chunfeng, Ke Yang (Aug. 2004). "Human papillomavirus 16 E6 oncoprotein interferences with insulin signaling pathway by binding to tuberin". J. Biol. Chem. (United States) 279 (34): 35664–70. doi:10.1074/jbc.M403385200. ISSN 0021-9258. PMID 15175323. 
  30. ^ Zheng, Li; Ding Huirong, Lu Zheming, Li Yong, Pan Yaqi, Ning Tao, Ke Yang (Mar. 2008). "E3 ubiquitin ligase E6AP-mediated TSC2 turnover in the presence and absence of HPV16 E6". Genes Cells (England) 13 (3): 285–94. doi:10.1111/j.1365-2443.2008.01162.x. PMID 18298802. 
  31. ^ Inoki, Ken; Li Yong, Xu Tian, Guan Kun-Liang (Aug. 2003). "Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling". Genes Dev. (United States) 17 (15): 1829–34. doi:10.1101/gad.1110003. ISSN 0890-9369. PMC 196227. PMID 12869586. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=196227. 
  32. ^ Garami, Attila; Zwartkruis Fried J T, Nobukuni Takahiro, Joaquin Manel, Roccio Marta, Stocker Hugo, Kozma Sara C, Hafen Ernst, Bos Johannes L, Thomas George (Jun. 2003). "Insulin activation of Rheb, a mediator of mTOR/S6K/4E-BP signaling, is inhibited by TSC1 and 2". Mol. Cell (United States) 11 (6): 1457–66. doi:10.1016/S1097-2765(03)00220-X. ISSN 1097-2765. PMID 12820960. 
  33. ^ Zhang, Yong; Gao Xinsheng, Saucedo Leslie J, Ru Binggen, Edgar Bruce A, Pan Duojia (Jun. 2003). "Rheb is a direct target of the tuberous sclerosis tumour suppressor proteins". Nat. Cell Biol. (England) 5 (6): 578–81. doi:10.1038/ncb999. ISSN 1465-7392. PMID 12771962. 
  34. ^ Long, Xiaomeng; Lin Yenshou, Ortiz-Vega Sara, Yonezawa Kazuyoshi, Avruch Joseph (Apr. 2005). "Rheb binds and regulates the mTOR kinase". Curr. Biol. (England) 15 (8): 702–13. doi:10.1016/j.cub.2005.02.053. ISSN 0960-9822. PMID 15854902. 

External links

Further reading

GTPase activating protein
Monomeric
Heterotrimeric
Guanine nucleotide exchange factor
Other
B trdu: iter (nrpl/grfl/cytl/horl), csrc (lgic, enzr, gprc, igsr, intg, nrpr/grfr/cytr), itra (adap, gbpr, mapk), calc, lipd; path (hedp, wntp, tgfp+mapp, notp, jakp, fsap, hipp, tlrp)