TSC2

Tuberozna skleroza 2
Identifikatori
Simboli	TSC2; LAM; PPP1R160; TSC4
Vanjski ID	OMIM: 191092 MGI: 102548 HomoloGene: 462 GeneCards: TSC2 Gene
Ontologija gena
Molekulska funkcija	• Aktivnost GTPaznog aktivatora; • proteinsko vezivanje; • fosfatazno vezivanje;
Ćelijska komponenta	• nukleus; • citoplazma; • Goldžijev aparat;
Biološki proces	• respons na hipoksiju; • zatvaranje neuralnih tubula; • negativna regulacija dejstva proteinske kinaze;
Pregled RNK izražavanja
	podaci
Ortolozi

edit

Tuberozno sklerozni kompleks 2 (TSC2), takođe poznat kao Tuberin, je protein koji je kod ljudi kodiran TSC2 genom.

Funkcija

Mutacije ovog gena dovode do tuberozne skleroze. Smatra se da je njegov genski produkt tumorni supresor i da ima sposobnost stimulacije specifičnih GTPaza. Protein se asocira sa hamartinom u citozolni kompleks, za koji se smatra da deluje kao šaperon hamartina. Alternativno splajsovanje dovodi do višestrukih transkriptnih varijanti koje kodiraju različite izoforme proteina.^[1]

Interakcije

TSC2 funkcioniše unutar multi-proteinskog kompleksa poznatog kao TSC kompleks, koji se sastoji od sržnih proteina TSC2, TSC1,^[2]^[3] i TBC1D7.

Poznato je da TSC2 formira interakcije sa nekoliko drugih proteina:

Povezano

Tuberozno sklerozni protein

Reference

↑ „Entrez Gene: TSC2 tuberous sclerosis 2”.
↑ 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.
↑ 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.
↑ 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.
↑ ^5,0 ^5,1 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.
↑ ^6,0 ^6,1 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.
↑ ^7,0 ^7,1 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.
↑ 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.
↑ 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.
↑ 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.
↑ 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.
↑ 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.
↑ 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.
↑ ^14,0 ^14,1 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.
↑ 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.
↑ 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.
↑ 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.
↑ 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.
↑ 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.
↑ 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.
↑ 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.
↑ 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.
↑ 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.

Literatura

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.

Vanjske veze

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

[1] „Entrez Gene: TSC2 tuberous sclerosis 2”.

[pmid20146692-2] 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.

[pmid15340059-3] 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.

[pmid12167664-4] 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.

[pmid15342917-5] 5,0 ^5,1 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.

[pmid12511557-6] 6,0 ^6,1 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.

[pmid17077083-7] 7,0 ^7,1 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.

[pmid16959574-8] 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.

[pmid15851026-9] 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.

[pmid17043358-10] 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.

[pmid14559897-11] 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.

[pmid14651849-12] 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.

[pmid15261145-13] 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.

[pmid12842888-14] 14,0 ^14,1 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.

[pmid12147258-15] 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.

[pmid12869586-16] 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.

[pmid12820960-17] 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.

[pmid12771962-18] 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.

[pmid15854902-19] 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.

[pmid15757502-20] 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.

[pmid15175323-21] 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.

[pmid18298802-22] 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.

[pmid12176984-23] 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.

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