TSC2

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.{{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 }} Alternative splicing results in multiple transcript variants encoding different isoforms of the protein.{{cite web | title = Entrez Gene: TSC2 tuberous sclerosis 2| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=7249}} 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.

Cell pathology

Cells from individuals with pathogenic mutations in the TSC2 gene display depletion of lysosomes, impairment of autophagy, and abnormal accumulation of glycogen. Defects in the autophagy-lysosome pathway are associated with excessive ubiquitination and degradation of LC3 and LAMP1/2 proteins.{{cite journal | vauthors = Pal R, Xiong Y, Sardiello M | title = Abnormal glycogen storage in tuberous sclerosis complex caused by impairment of mTORC1-dependent and -independent signaling pathways. | journal = Proc Natl Acad Sci U S A | date = February 2019 | pmid = 30728291 | doi = 10.1073/pnas.1812943116 | volume=116 | issue = 8 | pmc=6386676 | pages=2977–2986| doi-access = free }}

Signaling pathways

Pharmacological inhibition of ERK1/2 restores GSK3β activity and protein synthesis levels in a model of tuberous sclerosis.{{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 | bibcode = 2017NatSR...7.4174P }}

The defective degradation of glycogen by the autophagy-lysosome pathway is, at least in part, independent of impaired regulation of mTORC1 and is restored by the combined use of PKB/Akt and mTORC1 pharmacological inhibitors.

Interactions

TSC2 functions within a multi-protein complex known as the TSC complex which consists of the core proteins TSC2, TSC1,{{cite journal | vauthors = Orlova KA, Crino PB | title = The tuberous sclerosis complex | journal = Annals of the New York Academy of Sciences | volume = 1184 | pages = 87–105 | date = January 2010 | pmid = 20146692 | pmc = 2892799 | doi = 10.1111/j.1749-6632.2009.05117.x }}{{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 }} and TBC1D7.

TSC2 has been reported to interact with several other proteins that are not a part of the TSC complex including:

AKT1,{{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 | bibcode = 2004PNAS..10113489R | doi-access = free }}
AXIN1,
FOXO1,{{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 | doi-access = free }}
GSK3B,{{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 | doi-access = free }}{{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 | s2cid = 16047397 | doi-access = free }}
Hsp70
Hsp90
MAPK1,{{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 | s2cid = 18663447 | doi-access = free }}
PTK2,{{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 | doi-access = free }}
PAM,{{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 | doi-access = free }}
PRKAA1,{{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 | s2cid = 18173817 | doi-access = free }}{{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 | doi-access = free }}
RAP1A,{{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 | doi-access = free }}{{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 }}
RHEB,{{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 }}{{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 | url = https://www.zora.uzh.ch/id/eprint/658/1/GaramiV.pdf }}{{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 | s2cid = 13451385 }}{{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 | s2cid = 3078706 | doi-access = free }}
RPS6KA1,{{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 }}
UBE3A{{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 | doi-access = free }}{{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 | s2cid = 25851829 | doi-access = free }} and
YWHAZ.{{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 | doi-access = free }}

References

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]