Home LiteratureArticle Details
PMID: 22795129 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

TBC1D7 is a third subunit of the TSC1-TSC2 complex upstream of mTORC1.

Molecular cell ·Vol. 47 ·No. 4 ·2012-08-24 ·Pages 535-46

Dibble CC, Elis W, Menon S, Qin W, Klekota J, Asara JM, Finan PM, Kwiatkowski DJ, Murphy LO, Manning BD

Abstract

The tuberous sclerosis complex (TSC) tumor suppressors form the TSC1-TSC2 complex, which limits cell growth in response to poor growth conditions. Through its GTPase-activating protein (GAP) activity toward Rheb, this complex inhibits the mechanistic target of rapamycin (mTOR) complex 1 (mTORC1), a key promoter of cell growth. Here, we identify and biochemically characterize TBC1D7 as a stably associated and ubiquitous third core subunit of the TSC1-TSC2 complex. We demonstrate that the TSC1-TSC2-TBC1D7 (TSC-TBC) complex is the functional complex that senses specific cellular growth conditions and possesses Rheb-GAP activity. Sequencing analyses of samples from TSC patients suggest that TBC1D7 is unlikely to represent TSC3. TBC1D7 knockdown decreases the association of TSC1 and TSC2 leading to decreased Rheb-GAP activity, without effects on the localization of TSC2 to the lysosome. Like the other TSC-TBC components, TBC1D7 knockdown results in increased mTORC1 signaling, delayed induction of autophagy, and enhanced cell growth under poor growth conditions.

MeSH Terms
Amino Acid Sequence Carrier Proteins/genetics,metabolism GTPase-Activating Proteins/genetics,metabolism HEK293 Cells HeLa Cells Humans Intracellular Signaling Peptides and Proteins Lysosomes/genetics,metabolism Mechanistic Target of Rapamycin Complex 1 Molecular Sequence Data Monomeric GTP-Binding Proteins/genetics,metabolism Multiprotein Complexes Neuropeptides/genetics,metabolism Protein Binding Proteins/genetics,metabolism Ras Homolog Enriched in Brain Protein Signal Transduction TOR Serine-Threonine Kinases Tuberous Sclerosis Complex 1 Protein Tuberous Sclerosis Complex 2 Protein Tumor Cells, Cultured Tumor Suppressor Proteins/genetics,metabolism
Chemicals
Carrier Proteins GTPase-Activating Proteins Intracellular Signaling Peptides and Proteins Multiprotein Complexes Neuropeptides Proteins RHEB protein, human Ras Homolog Enriched in Brain Protein TBC1D7 protein, human TSC1 protein, human TSC2 protein, human Tuberous Sclerosis Complex 1 Protein Tuberous Sclerosis Complex 2 Protein Tumor Suppressor Proteins Mechanistic Target of Rapamycin Complex 1 TOR Serine-Threonine Kinases Monomeric GTP-Binding Proteins
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Dibble Christian C
Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, MA 02115, USA.
Elis Winfried
Menon Suchithra
Qin Wei
Klekota Justin
Asara John M
Finan Peter M
Kwiatkowski David J
Murphy Leon O
Manning Brendan D
References (51)
51 references, click to expand
  1. The primate-specific protein TBC1D3 is required for optimal macropinocytosis in a novel ARF6-dependent pathway.
    Mol Biol Cell. 2008 Apr;19(4):1304-16 PMID: 18199687
  2. mTOR signaling in growth control and disease.
    Cell. 2012 Apr 13;149(2):274-93 PMID: 22500797
  3. Tuberous sclerosis complex gene products, Tuberin and Hamartin, control mTOR signaling by acting as a GTPase-activating protein complex toward Rheb.
    Curr Biol. 2003 Aug 5;13(15):1259-68 PMID: 12906785
  4. The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1.
    Science. 2008 Jun 13;320(5882):1496-501 PMID: 18497260
  5. Functional dissection of Rab GTPases involved in primary cilium formation.
    J Cell Biol. 2007 Jul 30;178(3):363-9 PMID: 17646400
  6. PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinase.
    Mol Cell. 2007 Mar 23;25(6):903-15 PMID: 17386266
  7. The TSC1-TSC2 complex: a molecular switchboard controlling cell growth.
    Biochem J. 2008 Jun 1;412(2):179-90 PMID: 18466115
  8. Rheb is a direct target of the tuberous sclerosis tumour suppressor proteins.
    Nat Cell Biol. 2003 Jun;5(6):578-81 PMID: 12771962
  9. Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathway.
    Mol Cell. 2002 Jul;10(1):151-62 PMID: 12150915
  10. Interaction between hamartin and tuberin, the TSC1 and TSC2 gene products.
    Hum Mol Genet. 1998 Jun;7(6):1053-7 PMID: 9580671
  11. Identification of TBC7 having TBC domain as a novel binding protein to TSC1-TSC2 complex.
    Biochem Biophys Res Commun. 2007 Sep 14;361(1):218-23 PMID: 17658474
  12. A complex interplay between Akt, TSC2 and the two mTOR complexes.
    Biochem Soc Trans. 2009 Feb;37(Pt 1):217-22 PMID: 19143635
  13. Regulation of TORC1 by Rag GTPases in nutrient response.
    Nat Cell Biol. 2008 Aug;10(8):935-45 PMID: 18604198
  14. Common corruption of the mTOR signaling network in human tumors.
    Oncogene. 2008 Dec;27 Suppl 2:S43-51 PMID: 19956179
  15. Chronic activation of mTOR complex 1 is sufficient to cause hepatocellular carcinoma in mice.
    Sci Signal. 2012 Mar 27;5(217):ra24 PMID: 22457330
  16. TSC1, TSC2, TSC3? Or mosaicism?
    Eur J Hum Genet. 2005 Jun;13(6):695-6 PMID: 15912141
  17. Illuminating the functional and structural repertoire of human TBC/RABGAPs.
    Nat Rev Mol Cell Biol. 2012 Jan 18;13(2):67-73 PMID: 22251903
  18. The Drosophila tuberous sclerosis complex gene homologs restrict cell growth and cell proliferation.
    Cell. 2001 May 4;105(3):345-55 PMID: 11348591
  19. AMPK phosphorylation of raptor mediates a metabolic checkpoint.
    Mol Cell. 2008 Apr 25;30(2):214-26 PMID: 18439900
  20. Ultra deep sequencing detects a low rate of mosaic mutations in tuberous sclerosis complex.
    Hum Genet. 2010 Mar;127(5):573-82 PMID: 20165957
  21. Hamartin, the product of the tuberous sclerosis 1 (TSC1) gene, interacts with tuberin and appears to be localized to cytoplasmic vesicles.
    Cancer Res. 1998 Nov 1;58(21):4766-70 PMID: 9809973
  22. Akt regulates growth by directly phosphorylating Tsc2.
    Nat Cell Biol. 2002 Sep;4(9):658-65 PMID: 12172554
  23. Loss of Tsc1/Tsc2 activates mTOR and disrupts PI3K-Akt signaling through downregulation of PDGFR.
    J Clin Invest. 2003 Oct;112(8):1223-33 PMID: 14561707
  24. Tandem affinity purification and identification of the human TSC1 protein complex.
    Acta Biochim Biophys Sin (Shanghai). 2010 Apr;42(4):266-73 PMID: 20383465
  25. mTORC1 senses lysosomal amino acids through an inside-out mechanism that requires the vacuolar H(+)-ATPase.
    Science. 2011 Nov 4;334(6056):678-83 PMID: 22053050
  26. TSC1 and TSC2 tumor suppressors antagonize insulin signaling in cell growth.
    Genes Dev. 2001 Jun 1;15(11):1383-92 PMID: 11390358
  27. The LKB1 tumor suppressor negatively regulates mTOR signaling.
    Cancer Cell. 2004 Jul;6(1):91-9 PMID: 15261145
  28. Drosophila Tsc1 functions with Tsc2 to antagonize insulin signaling in regulating cell growth, cell proliferation, and organ size.
    Cell. 2001 May 4;105(3):357-68 PMID: 11348592
  29. The TBC (Tre-2/Bub2/Cdc16) domain protein TRE17 regulates plasma membrane-endosomal trafficking through activation of Arf6.
    Mol Cell Biol. 2004 Nov;24(22):9752-62 PMID: 15509780
  30. Amino acid sufficiency and mTOR regulate p70 S6 kinase and eIF-4E BP1 through a common effector mechanism.
    J Biol Chem. 1998 Jun 5;273(23):14484-94 PMID: 9603962
  31. The TSC1-TSC2 complex is required for proper activation of mTOR complex 2.
    Mol Cell Biol. 2008 Jun;28(12):4104-15 PMID: 18411301
  32. Tumorigenesis in tuberous sclerosis complex is autophagy and p62/sequestosome 1 (SQSTM1)-dependent.
    Proc Natl Acad Sci U S A. 2011 Jul 26;108(30):12455-60 PMID: 21746920
  33. Metformin, independent of AMPK, inhibits mTORC1 in a rag GTPase-dependent manner.
    Cell Metab. 2010 May 5;11(5):390-401 PMID: 20444419
  34. Ragulator-Rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids.
    Cell. 2010 Apr 16;141(2):290-303 PMID: 20381137
  35. Rapamycin differentially inhibits S6Ks and 4E-BP1 to mediate cell-type-specific repression of mRNA translation.
    Proc Natl Acad Sci U S A. 2008 Nov 11;105(45):17414-9 PMID: 18955708
  36. 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. 2000 Dec 14;19(54):6306-16 PMID: 11175345
  37. A mouse model of TSC1 reveals sex-dependent lethality from liver hemangiomas, and up-regulation of p70S6 kinase activity in Tsc1 null cells.
    Hum Mol Genet. 2002 Mar 1;11(5):525-34 PMID: 11875047
  38. Rapamycin for treating Tuberous sclerosis and Autism spectrum disorders.
    Trends Mol Med. 2011 Feb;17(2):78-87 PMID: 21115397
  39. TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling.
    Nat Cell Biol. 2002 Sep;4(9):648-57 PMID: 12172553
  40. Activation of an oncogenic TBC1D7 (TBC1 domain family, member 7) protein in pulmonary carcinogenesis.
    Genes Chromosomes Cancer. 2010 Apr;49(4):353-67 PMID: 20095038
  41. Characterization of the cytosolic tuberin-hamartin complex. Tuberin is a cytosolic chaperone for hamartin.
    J Biol Chem. 1999 Dec 10;274(50):35647-52 PMID: 10585443
  42. Insulin activation of Rheb, a mediator of mTOR/S6K/4E-BP signaling, is inhibited by TSC1 and 2.
    Mol Cell. 2003 Jun;11(6):1457-66 PMID: 12820960
  43. TSC2 mediates cellular energy response to control cell growth and survival.
    Cell. 2003 Nov 26;115(5):577-90 PMID: 14651849
  44. Evolution of the TSC1/TSC2-TOR signaling pathway.
    Sci Signal. 2010 Jun 29;3(128):ra49 PMID: 20587805
  45. Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling.
    Genes Dev. 2003 Aug 1;17(15):1829-34 PMID: 12869586
  46. The tuberous sclerosis gene products hamartin and tuberin are multifunctional proteins with a wide spectrum of interacting partners.
    Mutat Res. 2008 Mar-Apr;658(3):234-46 PMID: 18291711
  47. The tuberous sclerosis protein TSC2 is not required for the regulation of the mammalian target of rapamycin by amino acids and certain cellular stresses.
    J Biol Chem. 2005 May 13;280(19):18717-27 PMID: 15772076
  48. Tuberous sclerosis complex tumor suppressor-mediated S6 kinase inhibition by phosphatidylinositide-3-OH kinase is mTOR independent.
    J Cell Biol. 2002 Oct 28;159(2):217-24 PMID: 12403809
  49. Distinct clinical characteristics of tuberous sclerosis complex patients with no mutation identified.
    Ann Hum Genet. 2009 Mar;73(2):141-6 PMID: 19133941
  50. The tuberous sclerosis complex.
    N Engl J Med. 2006 Sep 28;355(13):1345-56 PMID: 17005952
  51. Signaling events downstream of mammalian target of rapamycin complex 2 are attenuated in cells and tumors deficient for the tuberous sclerosis complex tumor suppressors.
    Cancer Res. 2009 Aug 1;69(15):6107-14 PMID: 19602587
Article Info
Journal
Molecular cell
Abbr.
Mol Cell
ISSN
1097-4164
DOI
10.1016/j.molcel.2012.06.009
Published
2012-08-24
Epub
2012-00-12
Pages
535-46
Language
English
Region
United States
NLM ID
9802571
PMCID
PMC3693578
Subset
IM
Grants
NCI NIH HHS · P30-CA006516 · United States
NCI NIH HHS · P01 CA120964 · United States
NCI NIH HHS · R01 CA122617 · United States
NCI NIH HHS · P01-CA120964 · United States
NCI NIH HHS · P30 CA006516 · United States
NCI NIH HHS · R01-CA122617 · United States
External Links
PubMed source DOI: 10.1016/j.molcel.2012.06.009 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2