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== Function ==
== 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 [[GTPase]]s. 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 [[isoform]]s of the protein.<ref>{{cite web | title = Entrez Gene: TSC2 tuberous sclerosis 2| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=7249| accessdate = }}</ref>  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.<ref>{{cite web|title=Lymphangioleiomyomatosis|url=http://ghr.nlm.nih.gov/condition/lymphangioleiomyomatosis|website=Genetics Home Reference|accessdate=28 September 2015}}</ref>
Mutations in this gene lead to [[tuberous sclerosis]]. Its gene product is believed to be a [[tumor suppressor]] and is able to stimulate specific [[GTPase]]s. 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.<ref name=":0">{{cite journal | vauthors = 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 | title = Tumor suppressor Tsc1 is a new Hsp90 co-chaperone that facilitates folding of kinase and non-kinase clients | journal = The EMBO Journal | volume = 36 | issue = 24 | pages = 3650–3665 | date = December 2017 | pmid = 29127155 | pmc = 5730846 | doi = 10.15252/embj.201796700 }}</ref> [[Alternative splicing]] results in multiple transcript variants encoding different [[isoform]]s of the protein.<ref>{{cite web | title = Entrez Gene: TSC2 tuberous sclerosis 2| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=7249| access-date = }}</ref>  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.<ref name=":0" />


==Signaling Pathways==
==Signaling Pathways==


Pharmacological inhibition of [[MAPK3|ERK1/2]] restores [[GSK3β]] activity and protein synthesis levels in a model of tuberous sclerosis.<ref name="pmid28646232">{{cite journal | vauthors = Pal R, Bondar VV, Adamski CJ, Rodney GG, Sardiello M | title = Inhibition of ERK1/2 Restores GSK3β Activity and Protein Synthesis Levels in a Model of Tuberous Sclerosis | journal = Sci. Rep. | volume = 7 | issue = 1 | pages = 4174 | year = 2017 | pmid = 28646232 | doi = 10.1038/s41598-017-04528-5 }}</ref>
Pharmacological inhibition of [[MAPK3|ERK1/2]] restores [[GSK3β]] activity and protein synthesis levels in a model of tuberous sclerosis.<ref name="pmid28646232">{{cite journal | vauthors = Pal R, Bondar VV, Adamski CJ, Rodney GG, Sardiello M | title = Inhibition of ERK1/2 Restores GSK3β Activity and Protein Synthesis Levels in a Model of Tuberous Sclerosis | journal = Scientific Reports | volume = 7 | issue = 1 | pages = 4174 | date = June 2017 | pmid = 28646232 | pmc = 5482840 | doi = 10.1038/s41598-017-04528-5 }}</ref>


==Interactions==
== Interactions ==
TSC2 functions within a multi-protein complex knowns as the TSC complex which consists of the core proteins TSC2, TSC1,<ref name = "pmid20146692">{{cite journal | vauthors = Orlova KA, Crino PB | title = The tuberous sclerosis complex | journal = Ann. N. Y. Acad. Sci. | volume = 1184 | issue = | pages = 87–105 | year = 2010 | pmid = 20146692 | pmc = 2892799 | doi = 10.1111/j.1749-6632.2009.05117.x}}</ref><ref name = pmid15340059>{{cite journal | vauthors = Li Y, Inoki K, Guan KL | title = Biochemical and functional characterizations of small GTPase Rheb and TSC2 GAP activity | journal = Mol. Cell. Biol. | volume = 24 | issue = 18 | pages = 7965–75 | year = 2004 | pmid = 15340059 | pmc = 515062 | doi = 10.1128/MCB.24.18.7965-7975.2004 }}</ref> and TBC1D7.
 
TSC2 functions within a multi-protein complex knowns as the TSC complex which consists of the core proteins TSC2, TSC1,<ref name = "pmid20146692">{{cite journal | vauthors = Orlova KA, Crino PB | title = The tuberous sclerosis complex | journal = Annals of the New York Academy of Sciences | volume = 1184 | issue = | pages = 87–105 | date = January 2010 | pmid = 20146692 | pmc = 2892799 | doi = 10.1111/j.1749-6632.2009.05117.x }}</ref><ref name = pmid15340059>{{cite journal | vauthors = Li Y, Inoki K, Guan KL | title = Biochemical and functional characterizations of small GTPase Rheb and TSC2 GAP activity | journal = Molecular and Cellular Biology | volume = 24 | issue = 18 | pages = 7965–75 | date = September 2004 | pmid = 15340059 | pmc = 515062 | doi = 10.1128/MCB.24.18.7965-7975.2004 }}</ref> and TBC1D7.


TSC2 has been reported to [[Protein-protein interaction|interact]] with several other proteins that are not a part of the TSC complex including:
TSC2 has been reported to [[Protein-protein interaction|interact]] with several other proteins that are not a part of the TSC complex including:
{{div col|colwidth=20em}}
{{div col|colwidth=20em}}
* [[AKT1]],<ref name = pmid12167664>{{cite journal | vauthors = Dan HC, Sun M, Yang L, Feldman RI, Sui XM, Ou CC, Nellist M, Yeung RS, Halley DJ, Nicosia SV, Pledger WJ, Cheng JQ | title = Phosphatidylinositol 3-kinase/Akt pathway regulates tuberous sclerosis tumor suppressor complex by phosphorylation of tuberin | journal = J. Biol. Chem. | volume = 277 | issue = 38 | pages = 35364–70 | year = 2002 | pmid = 12167664 | doi = 10.1074/jbc.M205838200 }}</ref><ref name = pmid15342917>{{cite journal | vauthors = Roux PP, Ballif BA, Anjum R, Gygi SP, Blenis J | title = Tumor-promoting phorbol esters and activated Ras inactivate the tuberous sclerosis tumor suppressor complex via p90 ribosomal S6 kinase | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 101 | issue = 37 | pages = 13489–94 | year = 2004 | pmid = 15342917 | pmc = 518784 | doi = 10.1073/pnas.0405659101 }}</ref>  
* [[AKT1]],<ref name = pmid12167664>{{cite journal | vauthors = Dan HC, Sun M, Yang L, Feldman RI, Sui XM, Ou CC, Nellist M, Yeung RS, Halley DJ, Nicosia SV, Pledger WJ, Cheng JQ | title = Phosphatidylinositol 3-kinase/Akt pathway regulates tuberous sclerosis tumor suppressor complex by phosphorylation of tuberin | journal = The Journal of Biological Chemistry | volume = 277 | issue = 38 | pages = 35364–70 | date = September 2002 | pmid = 12167664 | doi = 10.1074/jbc.M205838200 }}</ref><ref name = pmid15342917>{{cite journal | vauthors = Roux PP, Ballif BA, Anjum R, Gygi SP, Blenis J | title = Tumor-promoting phorbol esters and activated Ras inactivate the tuberous sclerosis tumor suppressor complex via p90 ribosomal S6 kinase | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 101 | issue = 37 | pages = 13489–94 | date = September 2004 | pmid = 15342917 | pmc = 518784 | doi = 10.1073/pnas.0405659101 }}</ref>  
* [[AXIN1]],<ref name = pmid12511557/>  
* [[AXIN1]],<ref name = pmid12511557/>  
* [[FOXO1]],<ref name = pmid17077083>{{cite journal | vauthors = Cao Y, Kamioka Y, Yokoi N, Kobayashi T, Hino O, Onodera M, Mochizuki N, Nakae J | title = Interaction of FoxO1 and TSC2 induces insulin resistance through activation of the mammalian target of rapamycin/p70 S6K pathway | journal = J. Biol. Chem. | volume = 281 | issue = 52 | pages = 40242–51 | year = 2006 | pmid = 17077083 | doi = 10.1074/jbc.M608116200 }}</ref>  
* [[FOXO1]],<ref name = pmid17077083>{{cite journal | vauthors = Cao Y, Kamioka Y, Yokoi N, Kobayashi T, Hino O, Onodera M, Mochizuki N, Nakae J | title = Interaction of FoxO1 and TSC2 induces insulin resistance through activation of the mammalian target of rapamycin/p70 S6K pathway | journal = The Journal of Biological Chemistry | volume = 281 | issue = 52 | pages = 40242–51 | date = December 2006 | pmid = 17077083 | doi = 10.1074/jbc.M608116200 }}</ref>  
* [[GSK3B]],<ref name = pmid12511557>{{cite journal | vauthors = Mak BC, Takemaru K, Kenerson HL, Moon RT, Yeung RS | title = The tuberin-hamartin complex negatively regulates beta-catenin signaling activity | journal = J. Biol. Chem. | volume = 278 | issue = 8 | pages = 5947–51 | year = 2003 | pmid = 12511557 | doi = 10.1074/jbc.C200473200 }}</ref><ref name = pmid16959574>{{cite journal | vauthors = 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 | title = TSC2 integrates Wnt and energy signals via a coordinated phosphorylation by AMPK and GSK3 to regulate cell growth | journal = Cell | volume = 126 | issue = 5 | pages = 955–68 | year = 2006 | pmid = 16959574 | doi = 10.1016/j.cell.2006.06.055 }}</ref>  
* [[GSK3B]],<ref name = pmid12511557>{{cite journal | vauthors = Mak BC, Takemaru K, Kenerson HL, Moon RT, Yeung RS | title = The tuberin-hamartin complex negatively regulates beta-catenin signaling activity | journal = The Journal of Biological Chemistry | volume = 278 | issue = 8 | pages = 5947–51 | date = February 2003 | pmid = 12511557 | doi = 10.1074/jbc.C200473200 }}</ref><ref name = pmid16959574>{{cite journal | vauthors = 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 | title = TSC2 integrates Wnt and energy signals via a coordinated phosphorylation by AMPK and GSK3 to regulate cell growth | journal = Cell | volume = 126 | issue = 5 | pages = 955–68 | date = September 2006 | pmid = 16959574 | doi = 10.1016/j.cell.2006.06.055 }}</ref>  
* [[MAPK1]],<ref name = pmid15851026>{{cite journal | vauthors = Ma L, Chen Z, Erdjument-Bromage H, Tempst P, Pandolfi PP | title = Phosphorylation and functional inactivation of TSC2 by Erk implications for tuberous sclerosis and cancer pathogenesis | journal = Cell | volume = 121 | issue = 2 | pages = 179–93 | year = 2005 | pmid = 15851026 | doi = 10.1016/j.cell.2005.02.031 }}</ref>  
* [[HSP70|Hsp70]]<ref name=":0"/>  
* [[PTK2]],<ref name = pmid17043358>{{cite journal | vauthors = Gan B, Yoo Y, Guan JL | title = Association of focal adhesion kinase with tuberous sclerosis complex 2 in the regulation of s6 kinase activation and cell growth | journal = J. Biol. Chem. | volume = 281 | issue = 49 | pages = 37321–9 | year = 2006 | pmid = 17043358 | doi = 10.1074/jbc.M605241200 }}</ref>  
* [[HSP90|Hsp90]]<ref name=":0"/>
* [[Peptidylglycine alpha-amidating monooxygenase|PAM]],<ref name = pmid14559897>{{cite journal | vauthors = Murthy V, Han S, Beauchamp RL, Smith N, Haddad LA, Ito N, Ramesh V | title = Pam and its ortholog highwire interact with and may negatively regulate the TSC1.TSC2 complex | journal = J. Biol. Chem. | volume = 279 | issue = 2 | pages = 1351–8 | year = 2004 | pmid = 14559897 | doi = 10.1074/jbc.M310208200 }}</ref>  
* [[MAPK1]],<ref name = pmid15851026>{{cite journal | vauthors = Ma L, Chen Z, Erdjument-Bromage H, Tempst P, Pandolfi PP | title = Phosphorylation and functional inactivation of TSC2 by Erk implications for tuberous sclerosis and cancer pathogenesis | journal = Cell | volume = 121 | issue = 2 | pages = 179–93 | date = April 2005 | pmid = 15851026 | doi = 10.1016/j.cell.2005.02.031 }}</ref>  
* [[Protein kinase, AMP-activated, alpha 1|PRKAA1]],<ref name = pmid14651849>{{cite journal | vauthors = Inoki K, Zhu T, Guan KL | title = TSC2 mediates cellular energy response to control cell growth and survival | journal = Cell | volume = 115 | issue = 5 | pages = 577–90 | year = 2003 | pmid = 14651849 | doi = 10.1016/S0092-8674(03)00929-2}}</ref><ref name = pmid15261145>{{cite journal | vauthors = Shaw RJ, Bardeesy N, Manning BD, Lopez L, Kosmatka M, DePinho RA, Cantley LC | title = The LKB1 tumor suppressor negatively regulates mTOR signaling | journal = Cancer Cell | volume = 6 | issue = 1 | pages = 91–9 | year = 2004 | pmid = 15261145 | doi = 10.1016/j.ccr.2004.06.007 }}</ref>  
* [[PTK2]],<ref name = pmid17043358>{{cite journal | vauthors = Gan B, Yoo Y, Guan JL | title = Association of focal adhesion kinase with tuberous sclerosis complex 2 in the regulation of s6 kinase activation and cell growth | journal = The Journal of Biological Chemistry | volume = 281 | issue = 49 | pages = 37321–9 | date = December 2006 | pmid = 17043358 | doi = 10.1074/jbc.M605241200 }}</ref>  
* [[RAP1A]],<ref name = pmid12842888>{{cite journal | vauthors = Castro AF, Rebhun JF, Clark GJ, Quilliam LA | title = Rheb binds tuberous sclerosis complex 2 (TSC2) and promotes S6 kinase activation in a rapamycin- and farnesylation-dependent manner | journal = J. Biol. Chem. | volume = 278 | issue = 35 | pages = 32493–6 | year = 2003 | pmid = 12842888 | doi = 10.1074/jbc.C300226200 }}</ref><ref name = pmid12147258>{{cite journal | vauthors = Yamamoto Y, Jones KA, Mak BC, Muehlenbachs A, Yeung RS | title = Multicompartmental distribution of the tuberous sclerosis gene products, hamartin and tuberin | journal = Arch. Biochem. Biophys. | volume = 404 | issue = 2 | pages = 210–7 | year = 2002 | pmid = 12147258 | doi = 10.1016/S0003-9861(02)00300-4}}</ref>  
* [[Peptidylglycine alpha-amidating monooxygenase|PAM]],<ref name = pmid14559897>{{cite journal | vauthors = Murthy V, Han S, Beauchamp RL, Smith N, Haddad LA, Ito N, Ramesh V | title = Pam and its ortholog highwire interact with and may negatively regulate the TSC1.TSC2 complex | journal = The Journal of Biological Chemistry | volume = 279 | issue = 2 | pages = 1351–8 | date = January 2004 | pmid = 14559897 | doi = 10.1074/jbc.M310208200 }}</ref>  
* [[RHEB]],<ref name = pmid17077083/><ref name = pmid12842888/><ref name = pmid12869586>{{cite journal | vauthors = Inoki K, Li Y, Xu T, Guan KL | title = Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling | journal = Genes Dev. | volume = 17 | issue = 15 | pages = 1829–34 | year = 2003 | pmid = 12869586 | pmc = 196227 | doi = 10.1101/gad.1110003 }}</ref><ref name = pmid12820960>{{cite journal | vauthors = Garami A, Zwartkruis FJ, Nobukuni T, Joaquin M, Roccio M, Stocker H, Kozma SC, Hafen E, Bos JL, Thomas G | title = Insulin activation of Rheb, a mediator of mTOR/S6K/4E-BP signaling, is inhibited by TSC1 and 2 | journal = Mol. Cell | volume = 11 | issue = 6 | pages = 1457–66 | year = 2003 | pmid = 12820960 | doi = 10.1016/S1097-2765(03)00220-X}}</ref><ref name = pmid12771962>{{cite journal | vauthors = Zhang Y, Gao X, Saucedo LJ, Ru B, Edgar BA, Pan D | title = Rheb is a direct target of the tuberous sclerosis tumour suppressor proteins | journal = Nat. Cell Biol. | volume = 5 | issue = 6 | pages = 578–81 | year = 2003 | pmid = 12771962 | doi = 10.1038/ncb999 }}</ref><ref name = pmid15854902>{{cite journal | vauthors = Long X, Lin Y, Ortiz-Vega S, Yonezawa K, Avruch J | title = Rheb binds and regulates the mTOR kinase | journal = Curr. Biol. | volume = 15 | issue = 8 | pages = 702–13 | year = 2005 | pmid = 15854902 | doi = 10.1016/j.cub.2005.02.053 }}</ref>
* [[Protein kinase, AMP-activated, alpha 1|PRKAA1]],<ref name = pmid14651849>{{cite journal | vauthors = Inoki K, Zhu T, Guan KL | title = TSC2 mediates cellular energy response to control cell growth and survival | journal = Cell | volume = 115 | issue = 5 | pages = 577–90 | date = November 2003 | pmid = 14651849 | doi = 10.1016/S0092-8674(03)00929-2 }}</ref><ref name = pmid15261145>{{cite journal | vauthors = Shaw RJ, Bardeesy N, Manning BD, Lopez L, Kosmatka M, DePinho RA, Cantley LC | title = The LKB1 tumor suppressor negatively regulates mTOR signaling | journal = Cancer Cell | volume = 6 | issue = 1 | pages = 91–9 | date = July 2004 | pmid = 15261145 | doi = 10.1016/j.ccr.2004.06.007 }}</ref>  
* [[RPS6KA1]],<ref name = pmid15342917/><ref name = pmid15757502>{{cite journal | vauthors = Rolfe M, McLeod LE, Pratt PF, Proud CG | title = 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) | journal = Biochem. J. | volume = 388 | issue = Pt 3 | pages = 973–84 | year = 2005 | pmid = 15757502 | pmc = 1183479 | doi = 10.1042/BJ20041888 }}</ref>  
* [[RAP1A]],<ref name = pmid12842888>{{cite journal | vauthors = Castro AF, Rebhun JF, Clark GJ, Quilliam LA | title = Rheb binds tuberous sclerosis complex 2 (TSC2) and promotes S6 kinase activation in a rapamycin- and farnesylation-dependent manner | journal = The Journal of Biological Chemistry | volume = 278 | issue = 35 | pages = 32493–6 | date = August 2003 | pmid = 12842888 | doi = 10.1074/jbc.C300226200 }}</ref><ref name = pmid12147258>{{cite journal | vauthors = Yamamoto Y, Jones KA, Mak BC, Muehlenbachs A, Yeung RS | title = Multicompartmental distribution of the tuberous sclerosis gene products, hamartin and tuberin | journal = Archives of Biochemistry and Biophysics | volume = 404 | issue = 2 | pages = 210–7 | date = August 2002 | pmid = 12147258 | doi = 10.1016/S0003-9861(02)00300-4 }}</ref>  
* [[UBE3A]]<ref name = pmid15175323>{{cite journal | vauthors = Lu Z, Hu X, Li Y, Zheng L, Zhou Y, Jiang H, Ning T, Basang Z, Zhang C, Ke Y | title = Human papillomavirus 16 E6 oncoprotein interferences with insulin signaling pathway by binding to tuberin | journal = J. Biol. Chem. | volume = 279 | issue = 34 | pages = 35664–70 | year = 2004 | pmid = 15175323 | doi = 10.1074/jbc.M403385200 }}</ref><ref name = pmid18298802>{{cite journal | vauthors = Zheng L, Ding H, Lu Z, Li Y, Pan Y, Ning T, Ke Y | title = E3 ubiquitin ligase E6AP-mediated TSC2 turnover in the presence and absence of HPV16 E6 | journal = Genes Cells | volume = 13 | issue = 3 | pages = 285–94 | year = 2008 | pmid = 18298802 | doi = 10.1111/j.1365-2443.2008.01162.x }}</ref>  and
* [[RHEB]],<ref name = pmid17077083/><ref name = pmid12842888/><ref name = pmid12869586>{{cite journal | vauthors = Inoki K, Li Y, Xu T, Guan KL | title = Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling | journal = Genes & Development | volume = 17 | issue = 15 | pages = 1829–34 | date = August 2003 | pmid = 12869586 | pmc = 196227 | doi = 10.1101/gad.1110003 }}</ref><ref name = pmid12820960>{{cite journal | vauthors = Garami A, Zwartkruis FJ, Nobukuni T, Joaquin M, Roccio M, Stocker H, Kozma SC, Hafen E, Bos JL, Thomas G | title = Insulin activation of Rheb, a mediator of mTOR/S6K/4E-BP signaling, is inhibited by TSC1 and 2 | journal = Molecular Cell | volume = 11 | issue = 6 | pages = 1457–66 | date = June 2003 | pmid = 12820960 | doi = 10.1016/S1097-2765(03)00220-X }}</ref><ref name = pmid12771962>{{cite journal | vauthors = Zhang Y, Gao X, Saucedo LJ, Ru B, Edgar BA, Pan D | title = Rheb is a direct target of the tuberous sclerosis tumour suppressor proteins | journal = Nature Cell Biology | volume = 5 | issue = 6 | pages = 578–81 | date = June 2003 | pmid = 12771962 | doi = 10.1038/ncb999 }}</ref><ref name = pmid15854902>{{cite journal | vauthors = Long X, Lin Y, Ortiz-Vega S, Yonezawa K, Avruch J | title = Rheb binds and regulates the mTOR kinase | journal = Current Biology | volume = 15 | issue = 8 | pages = 702–13 | date = April 2005 | pmid = 15854902 | doi = 10.1016/j.cub.2005.02.053 }}</ref>
* [[YWHAZ]].<ref name = pmid12176984>{{cite journal | vauthors = Nellist M, Goedbloed MA, de Winter C, Verhaaf B, Jankie A, Reuser AJ, van den Ouweland AM, van der Sluijs P, Halley DJ | title = Identification and characterization of the interaction between tuberin and 14-3-3zeta | journal = J. Biol. Chem. | volume = 277 | issue = 42 | pages = 39417–24 | year = 2002 | pmid = 12176984 | doi = 10.1074/jbc.M204802200 }}</ref>  
* [[RPS6KA1]],<ref name = pmid15342917/><ref name = pmid15757502>{{cite journal | vauthors = Rolfe M, McLeod LE, Pratt PF, Proud CG | title = 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) | journal = The Biochemical Journal | volume = 388 | issue = Pt 3 | pages = 973–84 | date = June 2005 | pmid = 15757502 | pmc = 1183479 | doi = 10.1042/BJ20041888 }}</ref>  
* [[UBE3A]]<ref name = pmid15175323>{{cite journal | vauthors = Lu Z, Hu X, Li Y, Zheng L, Zhou Y, Jiang H, Ning T, Basang Z, Zhang C, Ke Y | title = Human papillomavirus 16 E6 oncoprotein interferences with insulin signaling pathway by binding to tuberin | journal = The Journal of Biological Chemistry | volume = 279 | issue = 34 | pages = 35664–70 | date = August 2004 | pmid = 15175323 | doi = 10.1074/jbc.M403385200 }}</ref><ref name = pmid18298802>{{cite journal | vauthors = Zheng L, Ding H, Lu Z, Li Y, Pan Y, Ning T, Ke Y | title = E3 ubiquitin ligase E6AP-mediated TSC2 turnover in the presence and absence of HPV16 E6 | journal = Genes to Cells | volume = 13 | issue = 3 | pages = 285–94 | date = March 2008 | pmid = 18298802 | doi = 10.1111/j.1365-2443.2008.01162.x }}</ref>  and
* [[YWHAZ]].<ref name = pmid12176984>{{cite journal | vauthors = Nellist M, Goedbloed MA, de Winter C, Verhaaf B, Jankie A, Reuser AJ, van den Ouweland AM, van der Sluijs P, Halley DJ | title = Identification and characterization of the interaction between tuberin and 14-3-3zeta | journal = The Journal of Biological Chemistry | volume = 277 | issue = 42 | pages = 39417–24 | date = October 2002 | pmid = 12176984 | doi = 10.1074/jbc.M204802200 }}</ref>  
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==References==
== References ==
{{Reflist|35em}}
{{Reflist|32em}}


==Further reading==
== Further reading ==
{{Refbegin|35em}}
{{Refbegin|32em}}
*{{cite journal   |vauthors=Jones AC, Shyamsundar MM, Thomas MW, etal |title=Comprehensive mutation analysis of TSC1 and TSC2-and phenotypic correlations in 150 families with tuberous sclerosis. |journal=Am. J. Hum. Genet. |volume=64 |issue= 5 |pages= 1305–15 |year= 1999 |pmid= 10205261 |doi=10.1086/302381 | pmc=1377866  }}
* {{cite journal | vauthors = Jones AC, Shyamsundar MM, Thomas MW, Maynard J, Idziaszczyk S, Tomkins S, Sampson JR, Cheadle JP | title = Comprehensive mutation analysis of TSC1 and TSC2-and phenotypic correlations in 150 families with tuberous sclerosis | journal = American Journal of Human Genetics | volume = 64 | issue = 5 | pages = 1305–15 | date = May 1999 | pmid = 10205261 | pmc = 1377866 | doi = 10.1086/302381 }}
*{{cite journal | author=Hengstschläger M |title=Tuberous sclerosis complex genes: from flies to human genetics. |journal=Arch. Dermatol. Res. |volume=293 |issue= 8 |pages= 383–6 |year= 2002 |pmid= 11686512 |doi=10.1007/s004030100250 }}
* {{cite journal | vauthors = Hengstschläger M | title = Tuberous sclerosis complex genes: from flies to human genetics | journal = Archives of Dermatological Research | volume = 293 | issue = 8 | pages = 383–6 | date = August 2001 | pmid = 11686512 | doi = 10.1007/s004030100250 }}
*{{cite journal | author=Hockenbery DM |title=Nailing down a link between tuberin and renal cysts. |journal=Am. J. Pathol. |volume=162 |issue= 2 |pages= 369–71 |year= 2003 |pmid= 12547695 |doi= 10.1016/S0002-9440(10)63831-X| pmc=1851147  }}
* {{cite journal | vauthors = Hockenbery DM | title = Nailing down a link between tuberin and renal cysts | journal = The American Journal of Pathology | volume = 162 | issue = 2 | pages = 369–71 | date = February 2003 | pmid = 12547695 | pmc = 1851147 | doi = 10.1016/S0002-9440(10)63831-X }}
*{{cite journal | author=Ramesh V |title=Aspects of tuberous sclerosis complex (TSC) protein function in the brain. |journal=Biochem. Soc. Trans. |volume=31 |issue= Pt 3 |pages= 579–83 |year= 2004 |pmid= 12773159 |doi=10.1042/BST0310579 }}
* {{cite journal | vauthors = Ramesh V | title = Aspects of tuberous sclerosis complex (TSC) protein function in the brain | journal = Biochemical Society Transactions | volume = 31 | issue = Pt 3 | pages = 579–83 | date = June 2003 | pmid = 12773159 | doi = 10.1042/BST0310579 }}
*{{cite journal | vauthors=Knowles MA, Hornigold N, Pitt E |title=Tuberous sclerosis complex (TSC) gene involvement in sporadic tumours. |journal=Biochem. Soc. Trans. |volume=31 |issue= Pt 3 |pages= 597–602 |year= 2004 |pmid= 12773163 |doi=10.1042/BST0310597 }}
* {{cite journal | vauthors = Knowles MA, Hornigold N, Pitt E | title = Tuberous sclerosis complex (TSC) gene involvement in sporadic tumours | journal = Biochemical Society Transactions | volume = 31 | issue = Pt 3 | pages = 597–602 | date = June 2003 | pmid = 12773163 | doi = 10.1042/BST0310597 }}
*{{cite journal | author=Ellisen LW |title=Growth control under stress: mTOR regulation through the REDD1-TSC pathway. |journal=Cell Cycle |volume=4 |issue= 11 |pages= 1500–02 |year= 2007 |pmid= 16258273 |doi=10.4161/cc.4.11.2139 }}
* {{cite journal | vauthors = Ellisen LW | title = Growth control under stress: mTOR regulation through the REDD1-TSC pathway | journal = Cell Cycle | volume = 4 | issue = 11 | pages = 1500–02 | date = November 2005 | pmid = 16258273 | doi = 10.4161/cc.4.11.2139 }}
*{{cite journal | vauthors=Jozwiak J, Jozwiak S |title=Giant cells: contradiction to two-hit model of tuber formation? |journal=Cell. Mol. Neurobiol. |volume=27 |issue= 2 |pages= 251–61 |year= 2007 |pmid= 16897363 |doi= 10.1007/s10571-006-9106-0 }}
* {{cite journal | vauthors = Jozwiak J, Jozwiak S | title = Giant cells: contradiction to two-hit model of tuber formation? | journal = Cellular and Molecular Neurobiology | volume = 27 | issue = 2 | pages = 251–61 | date = March 2007 | pmid = 16897363 | doi = 10.1007/s10571-006-9106-0 }}
*{{cite journal | vauthors=Cai SL, Walker CL |title=TSC2, a key player in tumor suppression and cystic kidney disease. |journal=Nephrol. Ther. |volume=2 Suppl 2 |issue=  |pages= S119–22 |year= 2007 |pmid= 17373211 |doi=  }}
* {{cite journal | vauthors = Cai SL, Walker CL | title = TSC2, a key player in tumor suppression and cystic kidney disease | journal = Nephrologie & Therapeutique | volume = 2 Suppl 2 | issue =  | pages = S119-22 | date = January 2006 | pmid = 17373211 | doi =  }}
*{{cite journal | author=Urban T |title=[Pulmonary lymphangioleiomyomatosis with or without tuberous sclerosis] |journal=Revue des maladies respiratoires |volume=24 |issue= 6 |pages= 725–40 |year= 2007 |pmid= 17632432 |doi=10.1016/S0761-8425(07)91147-X }}
* {{cite journal | vauthors = Urban T | title = [Pulmonary lymphangioleiomyomatosis with or without tuberous sclerosis] | journal = Revue Des Maladies Respiratoires | volume = 24 | issue = 6 | pages = 725–40 | date = June 2007 | pmid = 17632432 | doi = 10.1016/S0761-8425(07)91147-X }}
{{Refend}}
{{Refend}}


==External links==
== External links ==
* [https://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=tuberous-sclerosis  GeneReviews/NIH/NCBI/UW entry on Tuberous Sclerosis Complex or Bourneville Disease]
* [https://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=tuberous-sclerosis  GeneReviews/NIH/NCBI/UW entry on Tuberous Sclerosis Complex or Bourneville Disease]


{{GTP-binding protein regulators}}
{{GTP-binding protein regulators}}

Latest revision as of 09:26, 10 January 2019

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Identifiers
Aliases
External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
Entrez

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Ensembl

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UniProt

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RefSeq (mRNA)

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RefSeq (protein)

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Location (UCSC)n/an/a
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Wikidata
View/Edit Human

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.[1] Alternative splicing results in multiple transcript variants encoding different isoforms of the protein.[2] 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.[1]

Signaling Pathways

Pharmacological inhibition of ERK1/2 restores GSK3β activity and protein synthesis levels in a model of tuberous sclerosis.[3]

Interactions

TSC2 functions within a multi-protein complex knowns as the TSC complex which consists of the core proteins TSC2, TSC1,[4][5] 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. ↑ 1.0 1.1 1.2 1.3 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.
  2. ↑ "Entrez Gene: TSC2 tuberous sclerosis 2".
  3. ↑ 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.
  4. ↑ 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.
  5. ↑ 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.
  6. ↑ 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.
  7. ↑ 7.0 7.1 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.
  8. ↑ 8.0 8.1 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.
  9. ↑ 9.0 9.1 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.
  10. ↑ 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.
  11. ↑ 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.
  12. ↑ 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.
  13. ↑ 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.
  14. ↑ 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.
  15. ↑ 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.
  16. ↑ 16.0 16.1 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.
  17. ↑ 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.
  18. ↑ 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.
  19. ↑ 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.
  20. ↑ 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.
  21. ↑ 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.
  22. ↑ 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.
  23. ↑ 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.
  24. ↑ 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.
  25. ↑ 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

External links

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