TSC2

TSC2
識別子
記号	TSC2, LAM, PPP1R160, TSC4, tuberous sclerosis 2, TSC complex subunit 2
外部ID	OMIM: 191092 MGI: 102548 HomoloGene: 462 GeneCards: TSC2
遺伝子の位置 (ヒト)
染色体	16番染色体 (ヒト)
終点	2,089,491 bp
遺伝子の位置 (マウス)
染色体	17番染色体 (マウス)
終点	24,851,604 bp
RNA発現パターン
	さらなる参照発現データ
遺伝子オントロジー
分子機能	• phosphatase binding; • protein homodimerization activity; • GTPase activator activity; • small GTPase binding; • 血漿タンパク結合; • Hsp90タンパク質結合;
細胞の構成要素	• 細胞質; • 細胞質基質; • ゴルジ体; • 膜; • TSC1-TSC2 complex; • perinuclear region of cytoplasm; • リソソーム; • 細胞核; • シナプス後肥厚;
生物学的プロセス	• regulation of endocytosis; • タンパク質局在化; • insulin-like growth factor receptor signaling pathway; • negative regulation of protein kinase B signaling; • エンドサイトーシス; • 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; • 心臓発生; • positive regulation of GTPase activity; • neural tube closure; • negative regulation of insulin receptor signaling pathway; • positive chemotaxis; • viral process; • regulation of small GTPase mediated signal transduction; • vesicle-mediated transport; • negative regulation of cell population proliferation; • regulation of insulin receptor signaling pathway; • positive regulation of macroautophagy; • アノイキス; • negative regulation of mitophagy; • negative regulation of TOR signaling; • Akt/PKBシグナル経路;
	出典:Amigo / QuickGO
オルソログ
	7249
	22084
	ENSG00000103197
	ENSMUSG00000002496
	P49815,I3L3B1
	Q61037
NM_000548; NM_001077183; NM_001114382; NM_021055; NM_021056;
	NM_001318827; NM_001318829; NM_001318831; NM_001318832; NM_001363528; NM_001370404; NM_001370405
NM_001039363; NM_001286713; NM_001286714; NM_001286716; NM_001286718;
	NM_001286720; NM_011647
NP_000539; NP_001070651; NP_001107854; NP_001305756; NP_001305758;
	NP_001305760; NP_001305761; NP_066399; NP_001350457; NP_001357333; NP_001357334
	n/a
	ウィキデータ
閲覧/編集ヒト	閲覧/編集マウス

TSC2（tuberous sclerosis complex 2）は、ヒトではTSC2遺伝子によってコードされるタンパク質である。ツベリン（チュベリン、tuberin）としても知られる。

機能

TSC2遺伝子の変異は結節性硬化症の原因となる。TSC2はがん抑制因子であると考えられており、特定のGTPアーゼを刺激することができる。TSC1（英語版）遺伝子にコードされるTSC1（ハマルチン）は、Hsp90のTSC2に対するシャペロン活性の促進因子として機能し、TSC2のユビキチン化とプロテアソームによる分解を防ぐ^[5]。TSC2遺伝子からは、選択的スプライシングによって異なるアイソフォームをコードする複数の転写産物が産生される^[6]。TSC2の変異はリンパ脈管筋腫症の原因となる場合がある。この疾患は肺の組織の肥大によって引き起こされ、嚢胞や腫瘍が形成されて呼吸困難が生じる。TSC2はTSC1とともに細胞のサイズを調節するため、TSC1やTSC2の変異によって肺での細胞増殖の制御が阻害される可能性がある^[5]。

細胞病理学

TSC2遺伝子の病原性変異を持つ患者の細胞では、リソソームの枯渇、オートファジーの機能不全、グリコーゲンの異常な蓄積が観察される。オートファジー-リソソーム経路の欠陥は、LC3（英語版）、LAMP1（英語版）/2（英語版）タンパク質の過剰なユビキチン化と分解と関係している^[7]。

シグナル伝達経路

Tsc2を欠損した結節性硬化症モデルでは、ERK1（英語版）/2の薬理的阻害によってGSK3βの活性とタンパク質合成レベルが回復する^[8]。

オートファジー-リソソーム経路によるグリコーゲン分解の欠陥は、少なくともその一部はmTORC1の調節異常とは無関係であり、PKB/AktとmTORC1の阻害剤を併用することで回復する^[7]。

相互作用

TSC2はTSC複合体（英語版）と呼ばれる多タンパク質複合体内で機能し、この複合体にはコアタンパク質としてTSC2、TSC1^[9]^[10]、TBC1D7^[11]が含まれる。

TSC2は、次に挙げるTSC複合体以外のタンパク質との相互作用も報告されている。

出典

^ ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000103197 - Ensembl, May 2017
^ ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000002496 - Ensembl, May 2017
^ Human PubMed Reference:
^ Mouse PubMed Reference:
^ ^a ^b ^c ^d “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. (December 2017). doi:10.15252/embj.201796700. PMC 5730846. PMID 29127155.
^ “Entrez Gene: TSC2 tuberous sclerosis 2”. 2022年1月9日閲覧。
^ ^a ^b “Abnormal glycogen storage in tuberous sclerosis complex caused by impairment of mTORC1-dependent and -independent signaling pathways.”. Proc Natl Acad Sci U S A 116 (8): 2977–2986. (February 2019). doi:10.1073/pnas.1812943116. PMC 6386676. PMID 30728291.
^ “Inhibition of ERK1/2 Restores GSK3β Activity and Protein Synthesis Levels in a Model of Tuberous Sclerosis”. Scientific Reports 7 (1): 4174. (June 2017). doi:10.1038/s41598-017-04528-5. PMC 5482840. PMID 28646232.
^ “The tuberous sclerosis complex”. Annals of the New York Academy of Sciences 1184: 87–105. (January 2010). doi:10.1111/j.1749-6632.2009.05117.x. PMC 2892799. PMID 20146692.
^ “Biochemical and functional characterizations of small GTPase Rheb and TSC2 GAP activity”. Molecular and Cellular Biology 24 (18): 7965–75. (September 2004). doi:10.1128/MCB.24.18.7965-7975.2004. PMC 515062. PMID 15340059.
^ Dibble, Christian C.; Elis, Winfried; Menon, Suchithra; Qin, Wei; Klekota, Justin; Asara, John M.; Finan, Peter M.; Kwiatkowski, David J. et al. (2012-08-24). “TBC1D7 is a third subunit of the TSC1-TSC2 complex upstream of mTORC1”. Molecular Cell 47 (4): 535–546. doi:10.1016/j.molcel.2012.06.009. ISSN 1097-4164. PMC 3693578. PMID 22795129.
^ “Phosphatidylinositol 3-kinase/Akt pathway regulates tuberous sclerosis tumor suppressor complex by phosphorylation of tuberin”. The Journal of Biological Chemistry 277 (38): 35364–70. (September 2002). doi:10.1074/jbc.M205838200. PMID 12167664.
^ ^a ^b “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. (September 2004). doi:10.1073/pnas.0405659101. PMC 518784. PMID 15342917.
^ ^a ^b “The tuberin-hamartin complex negatively regulates beta-catenin signaling activity”. The Journal of Biological Chemistry 278 (8): 5947–51. (February 2003). doi:10.1074/jbc.C200473200. PMID 12511557.
^ ^a ^b “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. (December 2006). doi:10.1074/jbc.M608116200. PMID 17077083.
^ “TSC2 integrates Wnt and energy signals via a coordinated phosphorylation by AMPK and GSK3 to regulate cell growth”. Cell 126 (5): 955–68. (September 2006). doi:10.1016/j.cell.2006.06.055. PMID 16959574.
^ “Phosphorylation and functional inactivation of TSC2 by Erk implications for tuberous sclerosis and cancer pathogenesis”. Cell 121 (2): 179–93. (April 2005). doi:10.1016/j.cell.2005.02.031. PMID 15851026.
^ “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. (December 2006). doi:10.1074/jbc.M605241200. PMID 17043358.
^ “Pam and its ortholog highwire interact with and may negatively regulate the TSC1.TSC2 complex”. The Journal of Biological Chemistry 279 (2): 1351–8. (January 2004). doi:10.1074/jbc.M310208200. PMID 14559897.
^ “TSC2 mediates cellular energy response to control cell growth and survival”. Cell 115 (5): 577–90. (November 2003). doi:10.1016/S0092-8674(03)00929-2. PMID 14651849.
^ “The LKB1 tumor suppressor negatively regulates mTOR signaling”. Cancer Cell 6 (1): 91–9. (July 2004). doi:10.1016/j.ccr.2004.06.007. PMID 15261145.
^ ^a ^b “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. (August 2003). doi:10.1074/jbc.C300226200. PMID 12842888.
^ “Multicompartmental distribution of the tuberous sclerosis gene products, hamartin and tuberin”. Archives of Biochemistry and Biophysics 404 (2): 210–7. (August 2002). doi:10.1016/S0003-9861(02)00300-4. PMID 12147258.
^ “Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling”. Genes & Development 17 (15): 1829–34. (August 2003). doi:10.1101/gad.1110003. PMC 196227. PMID 12869586.
^ “Insulin activation of Rheb, a mediator of mTOR/S6K/4E-BP signaling, is inhibited by TSC1 and 2”. Molecular Cell 11 (6): 1457–66. (June 2003). doi:10.1016/S1097-2765(03)00220-X. PMID 12820960.
^ “Rheb is a direct target of the tuberous sclerosis tumour suppressor proteins”. Nature Cell Biology 5 (6): 578–81. (June 2003). doi:10.1038/ncb999. PMID 12771962.
^ “Rheb binds and regulates the mTOR kinase”. Current Biology 15 (8): 702–13. (April 2005). doi:10.1016/j.cub.2005.02.053. PMID 15854902.
^ “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. (June 2005). doi:10.1042/BJ20041888. PMC 1183479. PMID 15757502.
^ “Human papillomavirus 16 E6 oncoprotein interferences with insulin signaling pathway by binding to tuberin”. The Journal of Biological Chemistry 279 (34): 35664–70. (August 2004). doi:10.1074/jbc.M403385200. PMID 15175323.
^ “E3 ubiquitin ligase E6AP-mediated TSC2 turnover in the presence and absence of HPV16 E6”. Genes to Cells 13 (3): 285–94. (March 2008). doi:10.1111/j.1365-2443.2008.01162.x. PMID 18298802.
^ “Identification and characterization of the interaction between tuberin and 14-3-3zeta”. The Journal of Biological Chemistry 277 (42): 39417–24. (October 2002). doi:10.1074/jbc.M204802200. PMID 12176984.

外部リンク

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

[refGRCh38Ensembl-1] GRCh38: Ensembl release 89: ENSG00000103197 - Ensembl, May 2017

[refGRCm38Ensembl-2] GRCm38: Ensembl release 89: ENSMUSG00000002496 - Ensembl, May 2017

[3] Human PubMed Reference:

[4] Mouse PubMed Reference:

[:0-5] “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. (December 2017). doi:10.15252/embj.201796700. PMC 5730846. PMID 29127155.

[:1-6] “Entrez Gene: TSC2 tuberous sclerosis 2”. 2022年1月9日閲覧。

[pmid30728291-7] “Abnormal glycogen storage in tuberous sclerosis complex caused by impairment of mTORC1-dependent and -independent signaling pathways.”. Proc Natl Acad Sci U S A 116 (8): 2977–2986. (February 2019). doi:10.1073/pnas.1812943116. PMC 6386676. PMID 30728291.

[pmid28646232-8] “Inhibition of ERK1/2 Restores GSK3β Activity and Protein Synthesis Levels in a Model of Tuberous Sclerosis”. Scientific Reports 7 (1): 4174. (June 2017). doi:10.1038/s41598-017-04528-5. PMC 5482840. PMID 28646232.

[pmid20146692-9] “The tuberous sclerosis complex”. Annals of the New York Academy of Sciences 1184: 87–105. (January 2010). doi:10.1111/j.1749-6632.2009.05117.x. PMC 2892799. PMID 20146692.

[pmid15340059-10] “Biochemical and functional characterizations of small GTPase Rheb and TSC2 GAP activity”. Molecular and Cellular Biology 24 (18): 7965–75. (September 2004). doi:10.1128/MCB.24.18.7965-7975.2004. PMC 515062. PMID 15340059.

[11] Dibble, Christian C.; Elis, Winfried; Menon, Suchithra; Qin, Wei; Klekota, Justin; Asara, John M.; Finan, Peter M.; Kwiatkowski, David J. et al. (2012-08-24). “TBC1D7 is a third subunit of the TSC1-TSC2 complex upstream of mTORC1”. Molecular Cell 47 (4): 535–546. doi:10.1016/j.molcel.2012.06.009. ISSN 1097-4164. PMC 3693578. PMID 22795129.

[pmid12167664-12] “Phosphatidylinositol 3-kinase/Akt pathway regulates tuberous sclerosis tumor suppressor complex by phosphorylation of tuberin”. The Journal of Biological Chemistry 277 (38): 35364–70. (September 2002). doi:10.1074/jbc.M205838200. PMID 12167664.

[pmid15342917-13] “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. (September 2004). doi:10.1073/pnas.0405659101. PMC 518784. PMID 15342917.

[pmid12511557-14] “The tuberin-hamartin complex negatively regulates beta-catenin signaling activity”. The Journal of Biological Chemistry 278 (8): 5947–51. (February 2003). doi:10.1074/jbc.C200473200. PMID 12511557.

[pmid17077083-15] “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. (December 2006). doi:10.1074/jbc.M608116200. PMID 17077083.

[pmid16959574-16] “TSC2 integrates Wnt and energy signals via a coordinated phosphorylation by AMPK and GSK3 to regulate cell growth”. Cell 126 (5): 955–68. (September 2006). doi:10.1016/j.cell.2006.06.055. PMID 16959574.

[pmid15851026-17] “Phosphorylation and functional inactivation of TSC2 by Erk implications for tuberous sclerosis and cancer pathogenesis”. Cell 121 (2): 179–93. (April 2005). doi:10.1016/j.cell.2005.02.031. PMID 15851026.

[pmid17043358-18] “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. (December 2006). doi:10.1074/jbc.M605241200. PMID 17043358.

[pmid14559897-19] “Pam and its ortholog highwire interact with and may negatively regulate the TSC1.TSC2 complex”. The Journal of Biological Chemistry 279 (2): 1351–8. (January 2004). doi:10.1074/jbc.M310208200. PMID 14559897.

[pmid14651849-20] “TSC2 mediates cellular energy response to control cell growth and survival”. Cell 115 (5): 577–90. (November 2003). doi:10.1016/S0092-8674(03)00929-2. PMID 14651849.

[pmid15261145-21] “The LKB1 tumor suppressor negatively regulates mTOR signaling”. Cancer Cell 6 (1): 91–9. (July 2004). doi:10.1016/j.ccr.2004.06.007. PMID 15261145.

[pmid12842888-22] “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. (August 2003). doi:10.1074/jbc.C300226200. PMID 12842888.

[pmid12147258-23] “Multicompartmental distribution of the tuberous sclerosis gene products, hamartin and tuberin”. Archives of Biochemistry and Biophysics 404 (2): 210–7. (August 2002). doi:10.1016/S0003-9861(02)00300-4. PMID 12147258.

[pmid12869586-24] “Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling”. Genes & Development 17 (15): 1829–34. (August 2003). doi:10.1101/gad.1110003. PMC 196227. PMID 12869586.

[pmid12820960-25] “Insulin activation of Rheb, a mediator of mTOR/S6K/4E-BP signaling, is inhibited by TSC1 and 2”. Molecular Cell 11 (6): 1457–66. (June 2003). doi:10.1016/S1097-2765(03)00220-X. PMID 12820960.

[pmid12771962-26] “Rheb is a direct target of the tuberous sclerosis tumour suppressor proteins”. Nature Cell Biology 5 (6): 578–81. (June 2003). doi:10.1038/ncb999. PMID 12771962.

[pmid15854902-27] “Rheb binds and regulates the mTOR kinase”. Current Biology 15 (8): 702–13. (April 2005). doi:10.1016/j.cub.2005.02.053. PMID 15854902.

[pmid15757502-28] “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. (June 2005). doi:10.1042/BJ20041888. PMC 1183479. PMID 15757502.

[pmid15175323-29] “Human papillomavirus 16 E6 oncoprotein interferences with insulin signaling pathway by binding to tuberin”. The Journal of Biological Chemistry 279 (34): 35664–70. (August 2004). doi:10.1074/jbc.M403385200. PMID 15175323.

[pmid18298802-30] “E3 ubiquitin ligase E6AP-mediated TSC2 turnover in the presence and absence of HPV16 E6”. Genes to Cells 13 (3): 285–94. (March 2008). doi:10.1111/j.1365-2443.2008.01162.x. PMID 18298802.

[pmid12176984-31] “Identification and characterization of the interaction between tuberin and 14-3-3zeta”. The Journal of Biological Chemistry 277 (42): 39417–24. (October 2002). doi:10.1074/jbc.M204802200. PMID 12176984.

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TSC2

機能

細胞病理学

シグナル伝達経路

相互作用

出典

関連文献

関連項目

外部リンク