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Gene Review

TSC2  -  tuberous sclerosis 2

Homo sapiens

Synonyms: LAM, PPP1R160, TSC4, Tuberin, Tuberous sclerosis 2 protein, ...
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Disease relevance of TSC2


Psychiatry related information on TSC2


High impact information on TSC2


Chemical compound and disease context of TSC2


Biological context of TSC2


Anatomical context of TSC2


Associations of TSC2 with chemical compounds

  • In addition, we identified asparagine residues essential for TSC2 GAP activity [17].
  • Tuberin, the product of TSC2, appears to be localized to the Golgi apparatus and may have a function in vesicular transport [25].
  • Here we show that serum and anisomycin enhance the interaction between TSC2 and 14-3-3 by stimulating phosphorylation of Ser(1210) [26].
  • We have reported previously that phosphorylation of serine 1210 (Ser(1210)) in TSC2 is essential for 14-3-3 binding [26].
  • Earlier studies from our laboratory (1) linked TSC2 with steroid/nuclear receptor signaling [27].

Physical interactions of TSC2


Enzymatic interactions of TSC2

  • The PI3K effector Akt/protein kinase B has been found to directly phosphorylate tuberin and is thereby thought to activate mTOR through inhibition of the tuberin-hamartin complex [30].

Regulatory relationships of TSC2

  • Such a modification of tuberin influences its activity within the complex with hamartin and positively or negatively modulates mTOR-regulated protein translation and cellular proliferation [31].
  • Third, hamartin and tuberin blocked the ability of amino acids to activate S6K1 within nutrient-deprived cells, a process that is dependent on mTOR [32].
  • TSC1 stabilizes TSC2 by inhibiting the interaction between TSC2 and the HERC1 ubiquitin ligase [33].
  • Interaction of FoxO1 and TSC2 Induces Insulin Resistance through Activation of the Mammalian Target of Rapamycin/p70 S6K Pathway [34].
  • Pretreatment of cells with pertussis toxin or PI3K inhibitor wortmannin blocked the opioid-stimulated tuberin phosphorylation, implicating the possible involvement of the G(i/o) proteins and the phosphatidylinositol-3 kinase/Akt pathway in opioid-induced tuberin phosphorylation [35].

Other interactions of TSC2


Analytical, diagnostic and therapeutic context of TSC2


  1. Mutation in TSC2 and activation of mammalian target of rapamycin signalling pathway in renal angiomyolipoma. El-Hashemite, N., Zhang, H., Henske, E.P., Kwiatkowski, D.J. Lancet (2003) [Pubmed]
  2. Germ-line mutational analysis of the TSC2 gene in 90 tuberous-sclerosis patients. Au, K.S., Rodriguez, J.A., Finch, J.L., Volcik, K.A., Roach, E.S., Delgado, M.R., Rodriguez, E., Northrup, H. Am. J. Hum. Genet. (1998) [Pubmed]
  3. The TSC1 gene product, hamartin, negatively regulates cell proliferation. Miloloza, A., Rosner, M., Nellist, M., Halley, D., Bernaschek, G., Hengstschläger, M. Hum. Mol. Genet. (2000) [Pubmed]
  4. Phosphorylation of tuberin as a novel mechanism for somatic inactivation of the tuberous sclerosis complex proteins in brain lesions. Han, S., Santos, T.M., Puga, A., Roy, J., Thiele, E.A., McCollin, M., Stemmer-Rachamimov, A., Ramesh, V. Cancer Res. (2004) [Pubmed]
  5. Pathogenesis of tuberous sclerosis subependymal giant cell astrocytomas: biallelic inactivation of TSC1 or TSC2 leads to mTOR activation. Chan, J.A., Zhang, H., Roberts, P.S., Jozwiak, S., Wieslawa, G., Lewin-Kowalik, J., Kotulska, K., Kwiatkowski, D.J. J. Neuropathol. Exp. Neurol. (2004) [Pubmed]
  6. The mTOR/S6K signalling pathway: the role of the TSC1/2 tumour suppressor complex and the proto-oncogene Rheb. Nobukini, T., Thomas, G. Novartis Found. Symp. (2004) [Pubmed]
  7. Association of INPP1, PIK3CG, and TSC2 gene variants with autistic disorder: implications for phosphatidylinositol signalling in autism. Serajee, F.J., Nabi, R., Zhong, H., Mahbubul Huq, A.H. J. Med. Genet. (2003) [Pubmed]
  8. Tuberin--a new molecular target in Alzheimer's disease? Ferrando-Miguel, R., Rosner, M., Freilinger, A., Lubec, G., Hengstschläger, M. Neurochem. Res. (2005) [Pubmed]
  9. Mind the GAP: Wnt Steps onto the mTORC1 Train. Choo, A.Y., Roux, P.P., Blenis, J. Cell (2006) [Pubmed]
  10. Phosphorylation and functional inactivation of TSC2 by Erk implications for tuberous sclerosis and cancer pathogenesis. Ma, L., Chen, Z., Erdjument-Bromage, H., Tempst, P., Pandolfi, P.P. Cell (2005) [Pubmed]
  11. TSC2 mediates cellular energy response to control cell growth and survival. Inoki, K., Zhu, T., Guan, K.L. Cell (2003) [Pubmed]
  12. 14-3-3beta binds to and negatively regulates the tuberous sclerosis complex 2 (TSC2) tumor suppressor gene product, tuberin. Shumway, S.D., Li, Y., Xiong, Y. J. Biol. Chem. (2003) [Pubmed]
  13. AKT-independent Phosphorylation of TSC2 and Activation of mTOR and Ribosomal Protein S6 Kinase Signaling by Prostaglandin F2{alpha}. Arvisais, E.W., Romanelli, A., Hou, X., Davis, J.S. J. Biol. Chem. (2006) [Pubmed]
  14. 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). Rolfe, M., McLeod, L.E., Pratt, P.F., Proud, C.G. Biochem. J. (2005) [Pubmed]
  15. Prostaglandin E2 mediates phosphorylation and down-regulation of the tuberous sclerosis-2 tumor suppressor (tuberin) in human endometrial adenocarcinoma cells via the Akt signaling pathway. Sales, K.J., Battersby, S., Williams, A.R., Anderson, R.A., Jabbour, H.N. J. Clin. Endocrinol. Metab. (2004) [Pubmed]
  16. Estradiol and tamoxifen stimulate LAM-associated angiomyolipoma cell growth and activate both genomic and nongenomic signaling pathways. Yu, J., Astrinidis, A., Howard, S., Henske, E.P. Am. J. Physiol. Lung Cell Mol. Physiol. (2004) [Pubmed]
  17. Biochemical and functional characterizations of small GTPase Rheb and TSC2 GAP activity. Li, Y., Inoki, K., Guan, K.L. Mol. Cell. Biol. (2004) [Pubmed]
  18. Hamartin, the tuberous sclerosis complex 1 gene product, interacts with polo-like kinase 1 in a phosphorylation-dependent manner. Astrinidis, A., Senapedis, W., Henske, E.P. Hum. Mol. Genet. (2006) [Pubmed]
  19. TSC2 missense mutations inhibit tuberin phosphorylation and prevent formation of the tuberin-hamartin complex. Nellist, M., Verhaaf, B., Goedbloed, M.A., Reuser, A.J., van den Ouweland, A.M., Halley, D.J. Hum. Mol. Genet. (2001) [Pubmed]
  20. Tuberin phosphorylation regulates its interaction with hamartin. Two proteins involved in tuberous sclerosis. Aicher, L.D., Campbell, J.S., Yeung, R.S. J. Biol. Chem. (2001) [Pubmed]
  21. Evidence for a molecular link between the tuberous sclerosis complex and the Crumbs complex. Massey-Harroche, D., Delgrossi, M.H., Lane-Guermonprez, L., Arsanto, J.P., Borg, J.P., Billaud, M., Le Bivic, A. Hum. Mol. Genet. (2007) [Pubmed]
  22. Role of the tuberous sclerosis gene-2 product in cell cycle control. Loss of the tuberous sclerosis gene-2 induces quiescent cells to enter S phase. Soucek, T., Pusch, O., Wienecke, R., DeClue, J.E., Hengstschläger, M. J. Biol. Chem. (1997) [Pubmed]
  23. Subcellular distribution of the TSC2 gene product tuberin in human airway smooth muscle cells is driven by multiple localization sequences and is cell-cycle dependent. Clements, D., Mayer, R.J., Johnson, S.R. Am. J. Physiol. Lung Cell Mol. Physiol. (2007) [Pubmed]
  24. The tuberous sclerosis genes, TSC1 and TSC2, trigger different gene expression responses. Rosner, M., Freilinger, A., Lubec, G., Hengstschläger, M. Int. J. Oncol. (2005) [Pubmed]
  25. Hamartin, the product of the tuberous sclerosis 1 (TSC1) gene, interacts with tuberin and appears to be localized to cytoplasmic vesicles. Plank, T.L., Yeung, R.S., Henske, E.P. Cancer Res. (1998) [Pubmed]
  26. The p38 and MK2 kinase cascade phosphorylates tuberin, the tuberous sclerosis 2 gene product, and enhances its interaction with 14-3-3. Li, Y., Inoki, K., Vacratsis, P., Guan, K.L. J. Biol. Chem. (2003) [Pubmed]
  27. A calmodulin binding site in the tuberous sclerosis 2 gene product is essential for regulation of transcription events and is altered by mutations linked to tuberous sclerosis and lymphangioleiomyomatosis. Noonan, D.J., Lou, D., Griffith, N., Vanaman, T.C. Arch. Biochem. Biophys. (2002) [Pubmed]
  28. Inactivation of the tuberous sclerosis complex-1 and -2 gene products occurs by phosphoinositide 3-kinase/Akt-dependent and -independent phosphorylation of tuberin. Tee, A.R., Anjum, R., Blenis, J. J. Biol. Chem. (2003) [Pubmed]
  29. Rheb binds tuberous sclerosis complex 2 (TSC2) and promotes S6 kinase activation in a rapamycin- and farnesylation-dependent manner. Castro, A.F., Rebhun, J.F., Clark, G.J., Quilliam, L.A. J. Biol. Chem. (2003) [Pubmed]
  30. United at last: the tuberous sclerosis complex gene products connect the phosphoinositide 3-kinase/Akt pathway to mammalian target of rapamycin (mTOR) signalling. Manning, B.D., Cantley, L.C. Biochem. Soc. Trans. (2003) [Pubmed]
  31. Hamartin and tuberin: working together for tumour suppression. Jozwiak, J. Int. J. Cancer (2006) [Pubmed]
  32. Tuberous sclerosis complex-1 and -2 gene products function together to inhibit mammalian target of rapamycin (mTOR)-mediated downstream signaling. Tee, A.R., Fingar, D.C., Manning, B.D., Kwiatkowski, D.J., Cantley, L.C., Blenis, J. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  33. TSC1 stabilizes TSC2 by inhibiting the interaction between TSC2 and the HERC1 ubiquitin ligase. Chong-Kopera, H., Inoki, K., Li, Y., Zhu, T., Garcia-Gonzalo, F.R., Rosa, J.L., Guan, K.L. J. Biol. Chem. (2006) [Pubmed]
  34. Interaction of FoxO1 and TSC2 Induces Insulin Resistance through Activation of the Mammalian Target of Rapamycin/p70 S6K Pathway. Cao, Y., Kamioka, Y., Yokoi, N., Kobayashi, T., Hino, O., Onodera, M., Mochizuki, N., Nakae, J. J. Biol. Chem. (2006) [Pubmed]
  35. Activation of delta-, kappa-, and mu-opioid receptors induces phosphorylation of tuberin in transfected HEK 293 cells and native cells. Wu, E.H., Wong, Y.H. Biochem. Biophys. Res. Commun. (2005) [Pubmed]
  36. Tuberin-dependent membrane localization of polycystin-1: a functional link between polycystic kidney disease and the TSC2 tumor suppressor gene. Kleymenova, E., Ibraghimov-Beskrovnaya, O., Kugoh, H., Everitt, J., Xu, H., Kiguchi, K., Landes, G., Harris, P., Walker, C. Mol. Cell (2001) [Pubmed]
  37. Tumor-promoting phorbol esters and activated Ras inactivate the tuberous sclerosis tumor suppressor complex via p90 ribosomal S6 kinase. Roux, P.P., Ballif, B.A., Anjum, R., Gygi, S.P., Blenis, J. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  38. Hamartin and tuberin interaction with the G2/M cyclin-dependent kinase CDK1 and its regulatory cyclins A and B. Catania, M.G., Mischel, P.S., Vinters, H.V. J. Neuropathol. Exp. Neurol. (2001) [Pubmed]
  39. Genomic structure and sequence of a human homologue (NTHL1/NTH1) of Escherichia coli endonuclease III with those of the adjacent parts of TSC2 and SLC9A3R2 genes. Imai, K., Sarker, A.H., Akiyama, K., Ikeda, S., Yao, M., Tsutsui, K., Shohmori, T., Seki, S. Gene (1998) [Pubmed]
  40. Tuberous sclerosis genes regulate cellular 14-3-3 protein levels. Hengstschläger, M., Rosner, M., Fountoulakis, M., Lubec, G. Biochem. Biophys. Res. Commun. (2003) [Pubmed]
  41. Regulation of PCNA and CAF-1 expression by the two tuberous sclerosis gene products. Hengstschläger, M., Rosner, M., Fountoulakis, M., Lubec, G. Biochem. Biophys. Res. Commun. (2003) [Pubmed]
  42. Tuberous sclerosis as an underlying basis for infantile spasm. Yeung, R.S. Int. Rev. Neurobiol. (2002) [Pubmed]
  43. Identification of tuberin, the tuberous sclerosis-2 product. Tuberin possesses specific Rap1GAP activity. Wienecke, R., König, A., DeClue, J.E. J. Biol. Chem. (1995) [Pubmed]
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