TSC1 |
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Available structures |
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PDB | Ortholog search: PDBe RCSB |
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List of PDB id codes |
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5EJC, 4Z6Y |
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Identifiers |
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Aliases | TSC1, LAM, TSC, tuberous sclerosis 1, TSC complex subunit 1 |
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External IDs | OMIM: 605284; MGI: 1929183; HomoloGene: 314; GeneCards: TSC1; OMA:TSC1 - orthologs |
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Gene location (Human) |
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![Chromosome 9 (human)](//upload.wikimedia.org/wikipedia/commons/thumb/d/de/Ideogram_human_chromosome_9.svg/300px-Ideogram_human_chromosome_9.svg.png) | Chr. | Chromosome 9 (human)[1] |
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| Band | 9q34.13 | Start | 132,891,348 bp[1] |
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End | 132,946,874 bp[1] |
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Gene location (Mouse) |
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![Chromosome 2 (mouse)](//upload.wikimedia.org/wikipedia/commons/thumb/b/bb/Ideogram_house_mouse_chromosome_2.svg/260px-Ideogram_house_mouse_chromosome_2.svg.png) | Chr. | Chromosome 2 (mouse)[2] |
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| Band | 2|2 A3 | Start | 28,531,240 bp[2] |
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End | 28,581,179 bp[2] |
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RNA expression pattern |
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Bgee | Human | Mouse (ortholog) |
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Top expressed in | - Pars compacta
- glutes
- external globus pallidus
- Region I of hippocampus proper
- pars reticulata
- lateral nuclear group of thalamus
- dorsal motor nucleus of vagus nerve
- inferior olivary nucleus
- superior vestibular nucleus
- middle temporal gyrus
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| Top expressed in | - ventromedial nucleus
- lateral hypothalamus
- lateral septal nucleus
- anterior amygdaloid area
- supraoptic nucleus
- Rostral migratory stream
- paraventricular nucleus of hypothalamus
- substantia nigra
- mammillary body
- arcuate nucleus
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| More reference expression data |
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BioGPS | ![](//upload.wikimedia.org/wikipedia/commons/thumb/a/a7/PBB_GE_TSC1_209390_at_fs.png/250px-PBB_GE_TSC1_209390_at_fs.png) | More reference expression data |
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Gene ontology |
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Molecular function | - chaperone binding
- protein binding
- protein N-terminus binding
- Hsp70 protein binding
- ATPase inhibitor activity
- Hsp90 protein binding
- GTPase activating protein binding
| Cellular component | - cytoplasm
- cell cortex
- growth cone
- intracellular membrane-bounded organelle
- lamellipodium
- membrane
- actin filament
- TSC1-TSC2 complex
- cytoskeleton
- cytosol
- nucleus
- perinuclear region of cytoplasm
- lipid droplet
- plasma membrane
- cell projection
- protein-containing complex
- chaperone complex
- postsynaptic density
| Biological process | - rRNA export from nucleus
- regulation of cell cycle
- neural tube closure
- cerebral cortex development
- memory T cell differentiation
- regulation of protein kinase activity
- positive regulation of focal adhesion assembly
- myelination
- negative regulation of insulin receptor signaling pathway
- synapse organization
- regulation of translation
- hippocampus development
- regulation of phosphoprotein phosphatase activity
- cell-matrix adhesion
- potassium ion transport
- adaptive immune response
- protein heterooligomerization
- kidney development
- nervous system development
- cell projection organization
- activation of GTPase activity
- regulation of focal adhesion assembly
- glucose import
- regulation of cell-matrix adhesion
- negative regulation of cell size
- response to insulin
- cardiac muscle cell differentiation
- negative regulation of translation
- negative regulation of cell population proliferation
- cellular response to oxygen-glucose deprivation
- adult locomotory behavior
- negative regulation of TOR signaling
- regulation of neuron death
- negative regulation of macroautophagy
- negative regulation of neuron projection development
- positive regulation of macroautophagy
- negative regulation of GTPase activity
- regulation of stress fiber assembly
- positive regulation of stress fiber assembly
- negative regulation of oxidative stress-induced neuron death
- negative regulation of ATP-dependent activity
- protein stabilization
| Sources:Amigo / QuickGO |
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Orthologs |
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Species | Human | Mouse |
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Entrez | | |
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Ensembl | | |
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UniProt | | |
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RefSeq (mRNA) | |
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NM_000368 NM_001008567 NM_001162426 NM_001162427 NM_001362177 |
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NM_022887 NM_001289575 NM_001289576 |
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RefSeq (protein) | |
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NP_000359 NP_001155898 NP_001155899 NP_001349106 |
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NP_001276504 NP_001276505 NP_075025 |
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Location (UCSC) | Chr 9: 132.89 – 132.95 Mb | Chr 2: 28.53 – 28.58 Mb |
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PubMed search | [3] | [4] |
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Wikidata |
View/Edit Human | View/Edit Mouse |
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Tuberous sclerosis 1 (TSC1), also known as hamartin, is a protein that in humans is encoded by the TSC1 gene.[5]
Function
TSC1 functions as a co-chaperone which inhibits the ATPase activity of the chaperone Hsp90 (heat shock protein-90) and decelerates its chaperone cycle. TSC1 functions as a facilitator of Hsp90 in chaperoning the kinase and non-kinase clients including TSC2, therefore preventing their ubiquitination and degradation in the proteasome.[6] TSC1, TSC2 and TBC1D7 is a multi-protein complex also known as the TSC complex. This complex negatively regulates mTORC1 signaling by functioning as a GTPase-activating protein (GAP) for the small GTPase Rheb, an essential activator of mTORC1. The TSC complex has been implicated as a tumor suppressor.
Clinical significance
Defects in this gene can cause tuberous sclerosis, due to a functional impairment of the TSC complex.[citation needed] Defects in TSC1 may also be a cause of focal cortical dysplasia.[citation needed] TSC1 may be involved in protecting brain neurons in the CA3 region of the hippocampus from the effects of stroke.[7]
Interactions
TSC1 has been shown to interact with:
- AKT1,[8]
- HSP70[6]
- HSP90[6]
- NEFL,[9]
- PLK1,[10] and
- TSC2.[10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][excessive citations]
See also
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000165699 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000026812 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Entrez Gene: TSC1 tuberous sclerosis 1".
- ^ a b c 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.
- ^ Papadakis M, Hadley G, Xilouri M, Hoyte LC, Nagel S, McMenamin MM, Tsaknakis G, Watt SM, Drakesmith CW, Chen R, Wood MJ, Zhao Z, Kessler B, Vekrellis K, Buchan AM (March 2013). "Tsc1 (hamartin) confers neuroprotection against ischemia by inducing autophagy". Nature Medicine. 19 (3): 351–7. doi:10.1038/nm.3097. PMC 3744134. PMID 23435171.
- ^ 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. Bibcode:2004PNAS..10113489R. doi:10.1073/pnas.0405659101. PMC 518784. PMID 15342917.
- ^ Haddad LA, Smith N, Bowser M, Niida Y, Murthy V, Gonzalez-Agosti C, Ramesh V (November 2002). "The TSC1 tumor suppressor hamartin interacts with neurofilament-L and possibly functions as a novel integrator of the neuronal cytoskeleton". The Journal of Biological Chemistry. 277 (46): 44180–6. doi:10.1074/jbc.M207211200. PMID 12226091.
- ^ a b Astrinidis A, Senapedis W, Henske EP (January 2006). "Hamartin, the tuberous sclerosis complex 1 gene product, interacts with polo-like kinase 1 in a phosphorylation-dependent manner". Human Molecular Genetics. 15 (2): 287–97. doi:10.1093/hmg/ddi444. PMID 16339216.
- ^ Hodges AK, Li S, Maynard J, Parry L, Braverman R, Cheadle JP, DeClue JE, Sampson JR (December 2001). "Pathological mutations in TSC1 and TSC2 disrupt the interaction between hamartin and tuberin". Human Molecular Genetics. 10 (25): 2899–905. doi:10.1093/hmg/10.25.2899. PMID 11741833.
- ^ Aicher LD, Campbell JS, Yeung RS (June 2001). "Tuberin phosphorylation regulates its interaction with hamartin. Two proteins involved in tuberous sclerosis". The Journal of Biological Chemistry. 276 (24): 21017–21. doi:10.1074/jbc.C100136200. PMID 11290735.
- ^ van Slegtenhorst M, Nellist M, Nagelkerken B, Cheadle J, Snell R, van den Ouweland A, Reuser A, Sampson J, Halley D, van der Sluijs P (June 1998). "Interaction between hamartin and tuberin, the TSC1 and TSC2 gene products". Human Molecular Genetics. 7 (6): 1053–7. doi:10.1093/hmg/7.6.1053. hdl:1765/8818. PMID 9580671.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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. S2CID 18663447.
- ^ Cai SL, Tee AR, Short JD, Bergeron JM, Kim J, Shen J, Guo R, Johnson CL, Kiguchi K, Walker CL (April 2006). "Activity of TSC2 is inhibited by AKT-mediated phosphorylation and membrane partitioning". The Journal of Cell Biology. 173 (2): 279–89. doi:10.1083/jcb.200507119. PMC 2063818. PMID 16636147.
- ^ 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.
- ^ 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. S2CID 18173817.
- ^ Nellist M, Burgers PC, van den Ouweland AM, Halley DJ, Luider TM (August 2005). "Phosphorylation and binding partner analysis of the TSC1-TSC2 complex". Biochemical and Biophysical Research Communications. 333 (3): 818–26. doi:10.1016/j.bbrc.2005.05.175. PMID 15963462.
- ^ Goncharova EA, Goncharov DA, Spaits M, Noonan DJ, Talovskaya E, Eszterhas A, Krymskaya VP (May 2006). "Abnormal growth of smooth muscle-like cells in lymphangioleiomyomatosis: Role for tumor suppressor TSC2". American Journal of Respiratory Cell and Molecular Biology. 34 (5): 561–72. doi:10.1165/rcmb.2005-0300OC. PMC 2644221. PMID 16424383.
- ^ Astrinidis A, Senapedis W, Coleman TR, Henske EP (December 2003). "Cell cycle-regulated phosphorylation of hamartin, the product of the tuberous sclerosis complex 1 gene, by cyclin-dependent kinase 1/cyclin B". The Journal of Biological Chemistry. 278 (51): 51372–9. doi:10.1074/jbc.M303956200. PMID 14551205.
- ^ Nellist M, Verhaaf B, Goedbloed MA, Reuser AJ, van den Ouweland AM, Halley DJ (December 2001). "TSC2 missense mutations inhibit tuberin phosphorylation and prevent formation of the tuberin-hamartin complex". Human Molecular Genetics. 10 (25): 2889–98. doi:10.1093/hmg/10.25.2889. hdl:1765/9803. PMID 11741832.
- ^ Benvenuto G, Li S, Brown SJ, Braverman R, Vass WC, Cheadle JP, Halley DJ, Sampson JR, Wienecke R, DeClue JE (December 2000). "The tuberous sclerosis-1 (TSC1) gene product hamartin suppresses cell growth and augments the expression of the TSC2 product tuberin by inhibiting its ubiquitination". Oncogene. 19 (54): 6306–16. doi:10.1038/sj.onc.1204009. PMID 11175345.
- ^ Murthy V, Haddad LA, Smith N, Pinney D, Tyszkowski R, Brown D, Ramesh V (May 2000). "Similarities and differences in the subcellular localization of hamartin and tuberin in the kidney". American Journal of Physiology. Renal Physiology. 278 (5): F737–46. doi:10.1152/ajprenal.2000.278.5.F737. PMID 10807585. S2CID 13321027.
- ^ Miloloza A, Rosner M, Nellist M, Halley D, Bernaschek G, Hengstschläger M (July 2000). "The TSC1 gene product, hamartin, negatively regulates cell proliferation". Human Molecular Genetics. 9 (12): 1721–7. doi:10.1093/hmg/9.12.1721. PMID 10915759.
Further reading
- Hengstschläger M (August 2001). "Tuberous sclerosis complex genes: from flies to human genetics". Archives of Dermatological Research. 293 (8): 383–6. doi:10.1007/s004030100250. PMID 11686512. S2CID 35702323.
- Ramesh V (June 2003). "Aspects of tuberous sclerosis complex (TSC) protein function in the brain". Biochemical Society Transactions. 31 (Pt 3): 579–83. doi:10.1042/BST0310579. PMID 12773159.
- Knowles MA, Hornigold N, Pitt E (June 2003). "Tuberous sclerosis complex (TSC) gene involvement in sporadic tumours". Biochemical Society Transactions. 31 (Pt 3): 597–602. doi:10.1042/BST0310597. PMID 12773163.
- Ellisen LW (November 2005). "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 (March 2007). "Giant cells: contradiction to two-hit model of tuber formation?". Cellular and Molecular Neurobiology. 27 (2): 251–61. doi:10.1007/s10571-006-9106-0. PMID 16897363. S2CID 31624726.
- Nagase T, Seki N, Ishikawa K, Ohira M, Kawarabayasi Y, Ohara O, Tanaka A, Kotani H, Miyajima N, Nomura N (October 1996). "Prediction of the coding sequences of unidentified human genes. VI. The coding sequences of 80 new genes (KIAA0201-KIAA0280) deduced by analysis of cDNA clones from cell line KG-1 and brain". DNA Research. 3 (5): 321–9, 341–54. doi:10.1093/dnares/3.5.321. PMID 9039502.
- van Slegtenhorst M, de Hoogt R, Hermans C, Nellist M, Janssen B, Verhoef S, Lindhout D, van den Ouweland A, Halley D, Young J, Burley M, Jeremiah S, Woodward K, Nahmias J, Fox M, Ekong R, Osborne J, Wolfe J, Povey S, Snell RG, Cheadle JP, Jones AC, Tachataki M, Ravine D, Sampson JR, Reeve MP, Richardson P, Wilmer F, Munro C, Hawkins TL, Sepp T, Ali JB, Ward S, Green AJ, Yates JR, Kwiatkowska J, Henske EP, Short MP, Haines JH, Jozwiak S, Kwiatkowski DJ (August 1997). "Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34". Science. 277 (5327): 805–8. doi:10.1126/science.277.5327.805. PMID 9242607.
- Jones AC, Daniells CE, Snell RG, Tachataki M, Idziaszczyk SA, Krawczak M, Sampson JR, Cheadle JP (November 1997). "Molecular genetic and phenotypic analysis reveals differences between TSC1 and TSC2 associated familial and sporadic tuberous sclerosis". Human Molecular Genetics. 6 (12): 2155–61. doi:10.1093/hmg/6.12.2155. PMID 9328481.
- van Slegtenhorst M, Nellist M, Nagelkerken B, Cheadle J, Snell R, van den Ouweland A, Reuser A, Sampson J, Halley D, van der Sluijs P (June 1998). "Interaction between hamartin and tuberin, the TSC1 and TSC2 gene products". Human Molecular Genetics. 7 (6): 1053–7. doi:10.1093/hmg/7.6.1053. hdl:1765/8818. PMID 9580671.
- Plank TL, Yeung RS, Henske EP (November 1998). "Hamartin, the product of the tuberous sclerosis 1 (TSC1) gene, interacts with tuberin and appears to be localized to cytoplasmic vesicles". Cancer Research. 58 (21): 4766–70. PMID 9809973.
- Kwiatkowska J, Jozwiak S, Hall F, Henske EP, Haines JL, McNamara P, Braiser J, Wigowska-Sowinska J, Kasprzyk-Obara J, Short MP, Kwiatkowski DJ (July 1998). "Comprehensive mutational analysis of the TSC1 gene: observations on frequency of mutation, associated features, and nonpenetrance". Annals of Human Genetics. 62 (Pt 4): 277–85. doi:10.1046/j.1469-1809.1998.6240277.x. PMID 9924605. S2CID 12987381.
- van Slegtenhorst M, Verhoef S, Tempelaars A, Bakker L, Wang Q, Wessels M, Bakker R, Nellist M, Lindhout D, Halley D, van den Ouweland A (April 1999). "Mutational spectrum of the TSC1 gene in a cohort of 225 tuberous sclerosis complex patients: no evidence for genotype-phenotype correlation". Journal of Medical Genetics. 36 (4): 285–9. doi:10.1136/jmg.36.4.285. PMC 1734341. PMID 10227394.
- Niida Y, Lawrence-Smith N, Banwell A, Hammer E, Lewis J, Beauchamp RL, Sims K, Ramesh V, Ozelius L (2000). "Analysis of both TSC1 and TSC2 for germline mutations in 126 unrelated patients with tuberous sclerosis". Human Mutation. 14 (5): 412–22. doi:10.1002/(SICI)1098-1004(199911)14:5<412::AID-HUMU7>3.0.CO;2-K. PMID 10533067. S2CID 38335573.
- Zhang H, Nanba E, Yamamoto T, Ninomiya H, Ohno K, Mizuguchi M, Takeshita K (2000). "Mutational analysis of TSC1 and TSC2 genes in Japanese patients with tuberous sclerosis complex". Journal of Human Genetics. 44 (6): 391–6. doi:10.1007/s100380050185. PMID 10570911.
- Nellist M, van Slegtenhorst MA, Goedbloed M, van den Ouweland AM, Halley DJ, van der Sluijs P (December 1999). "Characterization of the cytosolic tuberin-hamartin complex. Tuberin is a cytosolic chaperone for hamartin". The Journal of Biological Chemistry. 274 (50): 35647–52. doi:10.1074/jbc.274.50.35647. PMID 10585443.
- Yamashita Y, Ono J, Okada S, Wataya-Kaneda M, Yoshikawa K, Nishizawa M, Hirayama Y, Kobayashi E, Seyama K, Hino O (January 2000). "Analysis of all exons of TSC1 and TSC2 genes for germline mutations in Japanese patients with tuberous sclerosis: report of 10 mutations". American Journal of Medical Genetics. 90 (2): 123–6. doi:10.1002/(SICI)1096-8628(20000117)90:2<123::AID-AJMG7>3.0.CO;2-L. PMID 10607950.
- Lamb RF, Roy C, Diefenbach TJ, Vinters HV, Johnson MW, Jay DG, Hall A (May 2000). "The TSC1 tumour suppressor hamartin regulates cell adhesion through ERM proteins and the GTPase Rho". Nature Cell Biology. 2 (5): 281–7. doi:10.1038/35010550. PMID 10806479. S2CID 25353057.
- Miloloza A, Rosner M, Nellist M, Halley D, Bernaschek G, Hengstschläger M (July 2000). "The TSC1 gene product, hamartin, negatively regulates cell proliferation". Human Molecular Genetics. 9 (12): 1721–7. doi:10.1093/hmg/9.12.1721. PMID 10915759.
- Murthy V, Stemmer-Rachamimov AO, Haddad LA, Roy JE, Cutone AN, Beauchamp RL, Smith N, Louis DN, Ramesh V (March 2001). "Developmental expression of the tuberous sclerosis proteins tuberin and hamartin". Acta Neuropathologica. 101 (3): 202–10. doi:10.1007/s004010000269. PMID 11307618. S2CID 8067136.
- Catania MG, Mischel PS, Vinters HV (July 2001). "Hamartin and tuberin interaction with the G2/M cyclin-dependent kinase CDK1 and its regulatory cyclins A and B". Journal of Neuropathology and Experimental Neurology. 60 (7): 711–23. doi:10.1093/jnen/60.7.711. PMID 11444800.
External links
- GeneReviews/NIH/NCBI/UW entry on Tuberous Sclerosis Complex or Bourneville Disease
- Overview of all the structural information available in the PDB for UniProt: Q92574 (Hamartin) at the PDBe-KB.