Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Progress
  • Published:

Illuminating the functional and structural repertoire of human TBC/RABGAPs

An Addendum to this article was published on 22 May 2012

Abstract

The Tre2–Bub2–Cdc16 (TBC) domain-containing RAB-specific GTPase-activating proteins (TBC/RABGAPs) are characterized by the presence of highly conserved TBC domains and act as negative regulators of RABs. The importance of TBC/RABGAPs in the regulation of specific intracellular trafficking routes is now emerging, as is their role in different diseases. Importantly, TBC/RABGAPs act as key regulatory nodes, integrating signalling between RABs and other small GTPases and ensuring the appropriate retrieval, transport and delivery of different intracellular vesicles.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Mechanisms of RAB regulation.

Similar content being viewed by others

References

  1. Stenmark, H. Rab GTPases as coordinators of vesicle traffic. Nature Rev. Mol. Cell Biol. 10, 513–525 (2009).

    Article  CAS  Google Scholar 

  2. Mosesson, Y., Mills, G. B. & Yarden, Y. Derailed endocytosis: an emerging feature of cancer. Nature Rev. Cancer 8, 835–850 (2008).

    Article  CAS  Google Scholar 

  3. Schmidt, A. & Hall, A. Guanine nucleotide exchange factors for Rho GTPases: turning on the switch. Genes Dev. 16, 1587–1609 (2002).

    Article  CAS  Google Scholar 

  4. Tcherkezian, J. & Lamarche-Vane, N. Current knowledge of the large RhoGAP family of proteins. Biol. Cell. 99, 67–86 (2007).

    Article  CAS  Google Scholar 

  5. Bos, J. L., Rehmann, H. & Wittinghofer, A. GEFs and GAPs: critical elements in the control of small G proteins. Cell 129, 865–877 (2007).

    Article  CAS  Google Scholar 

  6. Bernards, A. GAPs galore! A survey of putative Ras superfamily GTPase activating proteins in man and Drosophila. Biochim. Biophys. Acta 1603, 47–82 (2003).

    CAS  Google Scholar 

  7. Fukuda, M. TBC proteins: GAPs for mammalian small GTPase Rab? Biosci. Rep. 31, 159–168 (2011).

    Article  CAS  Google Scholar 

  8. Yoshimura, S., Egerer, J., Fuchs, E., Haas, A. K. & Barr, F. A. Functional dissection of Rab GTPases involved in primary cilium formation. J. Cell Biol. 178, 363–369 (2007).

    Article  CAS  Google Scholar 

  9. Frittoli, E. et al. The primate-specific protein TBC1D3 is required for optimal macropinocytosis in a novel ARF6-dependent pathway. Mol. Biol. Cell 19, 1304–1316 (2008).

    Article  CAS  Google Scholar 

  10. Lanzetti, L., Palamidessi, A., Areces, L., Scita, G. & Di Fiore, P. P. Rab5 is a signalling GTPase involved in actin remodelling by receptor tyrosine kinases. Nature 429, 309–314 (2004).

    Article  CAS  Google Scholar 

  11. Patino-Lopez, G. et al. Rab35 and its GAP EPI64C in T cells regulate receptor recycling and immunological synapse formation. J. Biol. Chem. 283, 18323–18330 (2008).

    Article  CAS  Google Scholar 

  12. Faitar, S. L., Dabbeekeh, J. T., Ranalli, T. A. & Cowell, J. K. EVI5 is a novel centrosomal protein that binds to α- and γ-tubulin. Genomics 86, 594–605 (2005).

    Article  CAS  Google Scholar 

  13. Faitar, S. L., Sossey-Alaoui, K., Ranalli, T. A. & Cowell, J. K. EVI5 protein associates with the INCENP–Aurora B kinase–survivin chromosomal passenger complex and is involved in the completion of cytokinesis. Exp. Cell. Res. 312, 2325–2335 (2006).

    Article  CAS  Google Scholar 

  14. Behrends, C., Sowa, M. E., Gygi, S. P. & Harper, J. W. Network organization of the human autophagy system. Nature 466, 68–76 (2010).

    Article  CAS  Google Scholar 

  15. Itoh, T., Kanno, E., Uemura, T., Waguri, S. & Fukuda, M. OATL1, a novel autophagosome-resident Rab33B-GAP, regulates autophagosomal maturation. J. Cell Biol. 192, 839–853 (2011).

    Article  CAS  Google Scholar 

  16. Albert, S., Will, E. & Gallwitz, D. Identification of the catalytic domains and their functionally critical arginine residues of two yeast GTPase-activating proteins specific for Ypt/Rab transport GTPases. EMBO J. 18, 5216–5225 (1999).

    Article  CAS  Google Scholar 

  17. Fuchs, E. et al. Specific Rab GTPase-activating proteins define the Shiga toxin and epidermal growth factor uptake pathways. J. Cell Biol. 177, 1133–1143 (2007).

    Article  CAS  Google Scholar 

  18. Frasa, M. A. et al. Armus is a Rac1 effector that inactivates Rab7 and regulates E-cadherin degradation. Curr. Biol. 20, 198–208 (2010).

    Article  CAS  Google Scholar 

  19. Hanono, A., Garbett, D., Reczek, D., Chambers, D. N. & Bretscher, A. EPI64 regulates microvillar subdomains and structure. J. Cell Biol. 175, 803–813 (2006).

    Article  CAS  Google Scholar 

  20. Martinu, L. et al. The TBC (Tre-2/Bub2/Cdc16) domain protein TRE17 regulates plasma membrane-endosomal trafficking through activation of Arf6. Mol. Cell. Biol. 24, 9752–9762 (2004).

    Article  CAS  Google Scholar 

  21. Donaldson, J. G., Porat-Shliom, N. & Cohen, L. A. Clathrin-independent endocytosis: a unique platform for cell signaling and PM remodeling. Cell. Signal. 21, 1–6 (2009).

    Article  CAS  Google Scholar 

  22. Sano, H. et al. Insulin-stimulated phosphorylation of a Rab GTPase-activating protein regulates GLUT4 translocation. J. Biol. Chem. 278, 14599–14602 (2003).

    Article  CAS  Google Scholar 

  23. Chavez, J. A., Roach, W. G., Keller, S. R., Lane, W. S. & Lienhard, G. E. Inhibition of GLUT4 translocation by Tbc1d1, a Rab GTPase-activating protein abundant in skeletal muscle, is partially relieved by AMP-activated protein kinase activation. J. Biol. Chem. 283, 9187–9195 (2008).

    Article  CAS  Google Scholar 

  24. Peck, G. R. et al. Insulin-stimulated phosphorylation of the Rab GTPase activating protein TBC1D1 regulates GLUT4 translocation. J. Biol. Chem. 284, 30016–30023 (2009).

    Article  CAS  Google Scholar 

  25. Eberth, A. et al. A BAR domain-mediated autoinhibitory mechanism for RhoGAPs of the GRAF family. Biochem. J. 417, 371–377 (2009).

    Article  CAS  Google Scholar 

  26. Meyre, D. et al. R125W coding variant in TBC1D1 confers risk for familial obesity and contributes to linkage on chromosome 4p14 in the French population. Hum. Mol. Genet. 17, 1798–1802 (2008).

    Article  CAS  Google Scholar 

  27. Stone, S. et al. TBC1D1 is a candidate for a severe obesity gene and evidence for a gene/gene interaction in obesity predisposition. Hum. Mol. Genet. 15, 2709–2720 (2006).

    Article  CAS  Google Scholar 

  28. DiNitto, J. P. & Lambright, D. G. Membrane and juxtamembrane targeting by PH and PTB domains. Biochim. Biophys. Acta 1761, 850–867 (2006).

    Article  CAS  Google Scholar 

  29. Larance, M. et al. Characterization of the role of the Rab GTPase-activating protein AS160 in insulin-regulated GLUT4 trafficking. J. Biol. Chem. 280, 37803–37813 (2005).

    Article  CAS  Google Scholar 

  30. Kanno, E. et al. Comprehensive screening for novel Rab-binding proteins by GST pull-down assay using 60 different mammalian Rabs. Traffic 11, 491–507 (2010).

    Article  CAS  Google Scholar 

  31. Rivera-Molina, F. E. & Novick, P. J. A Rab GAP cascade defines the boundary between two Rab GTPases on the secretory pathway. Proc. Natl Acad. Sci. USA 106, 14408–14413 (2009).

    Article  CAS  Google Scholar 

  32. Rink, J., Ghigo, E., Kalaidzidis, Y. & Zerial, M. Rab conversion as a mechanism of progression from early to late endosomes. Cell 122, 735–749 (2005).

    Article  CAS  Google Scholar 

  33. Qualmann, B. & Mellor, H. Regulation of endocytic traffic by Rho GTPases. Biochem. J. 371, 233–241 (2003).

    Article  CAS  Google Scholar 

  34. Zhang, J., Fonovic, M., Suyama, K., Bogyo, M. & Scott, M. P. Rab35 controls actin bundling by recruiting fascin as an effector protein. Science 325, 1250–1254 (2009).

    Article  CAS  Google Scholar 

  35. Lanzetti, L. et al. The Eps8 protein coordinates EGF receptor signalling through Rac and trafficking through Rab5. Nature 408, 374–377 (2000).

    Article  CAS  Google Scholar 

  36. Pan, F. et al. Feedback inhibition of calcineurin and Ras by a dual inhibitory protein carabin. Nature 445, 433–436 (2007).

    Article  CAS  Google Scholar 

  37. Bizimungu, C. et al. Expression in a RabGAP yeast mutant of two human homologues, one of which is an oncogene. Biochem. Biophys. Res. Commun. 310, 498–504 (2003).

    Article  CAS  Google Scholar 

  38. Bizimungu, C. & Vandenbol, M. At least two regions of the oncoprotein Tre2 are involved in its lack of GAP activity. Biochem. Biophys. Res. Commun. 335, 883–890 (2005).

    Article  CAS  Google Scholar 

  39. Hsu, C. et al. Regulation of exosome secretion by Rab35 and its GTPase-activating proteins TBC1D10A-C. J. Cell Biol. 189, 223–232 (2010).

    Article  CAS  Google Scholar 

  40. Itoh, T. & Fukuda, M. Identification of EPI64 as a GTPase-activating protein specific for Rab27A. J. Biol. Chem. 281, 31823–31831 (2006).

    Article  CAS  Google Scholar 

  41. Nie, Z. & Randazzo, P. A. Arf GAPs and membrane traffic. J. Cell Sci. 119, 1203–1211 (2006).

    Article  CAS  Google Scholar 

  42. Corbett, M. A. et al. A focal epilepsy and intellectual disability syndrome is due to a mutation in TBC1D24. Am. J. Hum. Genet. 87, 371–375 (2010).

    Article  CAS  Google Scholar 

  43. Falace, A. et al. TBC1D24, an ARF6-interacting protein, is mutated in familial infantile myoclonic epilepsy. Am. J. Hum. Genet. 87, 365–370 (2010).

    Article  CAS  Google Scholar 

  44. Shin, N. et al. Identification of frequently mutated genes with relevance to nonsense mediated mRNA decay in the high microsatellite instability cancers. Int. J. Cancer 128, 2872–2880 (2010).

    Article  Google Scholar 

  45. Dechamps, C., Bach, S., Portetelle, D. & Vandenbol, M. The Tre2 oncoprotein, implicated in Ewing's sarcoma, interacts with two components of the cytoskeleton. Biotechnol. Lett. 28, 223–231 (2006).

    Article  CAS  Google Scholar 

  46. Hsu, Y. H. et al. An integration of genome-wide association study and gene expression profiling to prioritize the discovery of novel susceptibility loci for osteoporosis-related traits. PLoS Genet. 6, e1000977 (2010).

    Article  Google Scholar 

  47. Janz, M. et al. Interphase cytogenetic analysis of distinct X-chromosomal translocation breakpoints in synovial sarcoma. J. Pathol. 175, 391–396 (1995).

    Article  CAS  Google Scholar 

  48. Oliveira, A. M. et al. USP6 (Tre2) fusion oncogenes in aneurysmal bone cyst. Cancer Res. 64, 1920–1923 (2004).

    Article  CAS  Google Scholar 

  49. Shipley, J. M. et al. The t(X;18)(p11.2;q11.2) translocation found in human synovial sarcomas involves two distinct loci on the X chromosome. Oncogene 9, 1447–1453 (1994).

    CAS  PubMed  Google Scholar 

  50. Hodzic, D. et al. TBC1D3, a hominoid oncoprotein, is encoded by a cluster of paralogues located on chromosome 17q12. Genomics 88, 731–736 (2006).

    Article  CAS  Google Scholar 

  51. Pei, L. et al. PRC17, a novel oncogene encoding a Rab GTPase-activating protein, is amplified in prostate cancer. Cancer Res. 62, 5420–5424 (2002).

    CAS  PubMed  Google Scholar 

  52. Starczynowski, D. T. et al. High-resolution whole genome tiling path array CGH analysis of CD34+ cells from patients with low-risk myelodysplastic syndromes reveals cryptic copy number alterations and predicts overall and leukemia-free survival. Blood 112, 3412–3424 (2008).

    Article  CAS  Google Scholar 

  53. Cheng, B. H. et al. Microarray studies on effects of Pneumocystis carinii infection on global gene expression in alveolar macrophages. BMC Microbiol. 10, 103 (2010).

    Article  Google Scholar 

  54. Lu, C. et al. Grtp1, a novel gene regulated by growth hormone. Endocrinology 142, 4568–4571 (2001).

    Article  CAS  Google Scholar 

  55. Matsumoto, Y. et al. Upregulation of the transcript level of GTPase activating protein KIAA0603 in T cells from patients with atopic dermatitis. FEBS Lett. 572, 135–140 (2004).

    Article  CAS  Google Scholar 

  56. Sato, N. et al. Activation of an oncogenic TBC1D7 (TBC1 domain family, member 7) protein in pulmonary carcinogenesis. Genes Chromosomes Cancer 49, 353–367 (2010).

    CAS  PubMed  Google Scholar 

  57. Zhou, Y. et al. Serological cloning of PARIS-1: a new TBC domain-containing, immunogenic tumor antigen from a prostate cancer cell line. Biochem. Biophys. Res. Commun. 290, 830–838 (2002).

    Article  CAS  Google Scholar 

  58. Sklan, E. H. et al. TBC1D20 is a RAB1 GAP that mediates HCV replication. J. Biol. Chem. 282, 36354–36361 (2007).

    Article  CAS  Google Scholar 

  59. Sklan, E. H. et al. A Rab-GAP TBC domain protein binds hepatitis C virus NS5A and mediates viral replication. J. Virol. 81, 11096–11105 (2007).

    Article  CAS  Google Scholar 

  60. Nakamura, T. et al. A novel transcriptional unit of the Tre oncogene widely expressed in human cancer cells. Oncogene 7, 733–741 (1992).

    CAS  PubMed  Google Scholar 

  61. Akavia, U. D. et al. An integrated approach to uncover drivers of cancer. Cell 143, 1005–1017 (2010).

    Article  CAS  Google Scholar 

  62. Palamidessi, A. et al. Endocytic trafficking of Rac is required for the spatial restriction of signaling in cell migration. Cell 134, 135–147 (2008).

    Article  CAS  Google Scholar 

  63. Wainszelbaum, M. J. et al. The hominoid-specific oncogene TBC1D3 activates Ras and modulates epidermal growth factor receptor signaling and trafficking. J. Biol. Chem. 283, 13233–13242 (2008).

    Article  CAS  Google Scholar 

  64. Haas, A. K., Fuchs, E., Kopajtich, R. & Barr, F. A. A GTPase-activating protein controls Rab5 function in endocytic trafficking. Nature Cell Biol. 7, 887–893 (2005).

    Article  CAS  Google Scholar 

  65. Haas, A. K. et al. Analysis of GTPase-activating proteins: Rab1 and Rab43 are key Rabs required to maintain a functional Golgi complex in human cells. J. Cell Sci. 120, 2997–3010 (2007).

    Article  CAS  Google Scholar 

  66. Peralta, E. R., Martin, B. C. & Edinger, A. L. Differential effects of TBC1D15 and mammalian VPS39 on RAB7 activation state, lysosomal morphology, and growth factor dependence. J. Biol. Chem. 285, 16814–16821 (2010).

    Article  CAS  Google Scholar 

  67. Ishibashi, K., Kanno, E., Itoh, T. & Fukuda, M. Identification and characterization of a novel Tre-2/Bub2/Cdc16 (TBC) protein that possesses Rab3A-GAP activity. Genes Cells 14, 41–52 (2009).

    Article  CAS  Google Scholar 

  68. Ceresa, B. P. & Bahr, S. J. Rab7 activity affects epidermal growth factor: epidermal growth factor receptor degradation by regulating endocytic trafficking from the late endosome. J. Biol. Chem. 281, 1099–1106 (2006).

    Article  CAS  Google Scholar 

  69. Itoh, T., Satoh, M., Kanno, E. & Fukuda, M. Screening for target Rabs of TBC (Tre-2/Bub2/Cdc16) domain-containing proteins based on their Rab-binding activity. Genes Cells 11, 1023–1037 (2006).

    Article  CAS  Google Scholar 

  70. Dabbeekeh, J. T., Faitar, S. L., Dufresne, C. P. & Cowell, J. K. The EVI5 TBC domain provides the GTPase-activating protein motif for RAB11. Oncogene 26, 2804–2808 (2006).

    Article  Google Scholar 

  71. Westlake, C. J. et al. Identification of Rab11 as a small GTPase binding protein for the Evi5 oncogene. Proc. Natl Acad. Sci. USA 104, 1236–1241 (2007).

    Article  CAS  Google Scholar 

  72. Pan, X., Eathiraj, S., Munson, M. & Lambright, D. G. TBC-domain GAPs for Rab GTPases accelerate GTP hydrolysis by a dual-finger mechanism. Nature 442, 303–306 (2006).

    Article  CAS  Google Scholar 

  73. Hou, X. et al. A structural basis for Lowe syndrome caused by mutations in the Rab-binding domain of OCRL1. EMBO J. 30, 1659–1670 (2011).

    Article  CAS  Google Scholar 

  74. Miinea, C. P. et al. AS160, the Akt substrate regulating GLUT4 translocation, has a functional Rab GTPase-activating protein domain. Biochem. J. 391, 87–93 (2005).

    Article  CAS  Google Scholar 

  75. Sun, Y., Bilan, P. J., Liu, Z. & Klip, A. Rab8A and Rab13 are activated by insulin and regulate GLUT4 translocation in muscle cells. Proc. Natl Acad. Sci. USA 107, 19909–19914 (2010).

    Article  CAS  Google Scholar 

  76. Bouzakri, K. et al. Rab GTPase-activating protein AS160 is a major downstream effector of protein kinase B/Akt signaling in pancreatic β-cells. Diabetes 57, 1195–1204 (2008).

    Article  CAS  Google Scholar 

  77. Seaman, M. N., Harbour, M. E., Tattersall, D., Read, E. & Bright, N. Membrane recruitment of the cargo-selective retromer subcomplex is catalysed by the small GTPase Rab7 and inhibited by the Rab-GAP TBC1D5. J. Cell Sci. 122, 2371–2382 (2009).

    Article  CAS  Google Scholar 

  78. Cuif, M. H. et al. Characterization of GAPCenA, a GTPase activating protein for Rab6, part of which associates with the centrosome. EMBO J. 18, 1772–1782 (1999).

    Article  CAS  Google Scholar 

  79. Miserey-Lenkei, S. et al. A role for the Rab6A′ GTPase in the inactivation of the Mad2-spindle checkpoint. EMBO J. 25, 278–289 (2006).

    Article  CAS  Google Scholar 

  80. Sudmant, P. H. et al. Diversity of human copy number variation and multicopy genes. Science 330, 641–646 (2010).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

M.R.A. acknowledges J. Scheller and R. P. Piekorz for intellectual support and DFG (grant AH 92/5-1), BMBF/NGFNplus (01GS08100) and NsEuroNet E-Rare for financial support. V.M.M.B. acknowledges the support of the Medical Research Council, Cancer Research UK and the Association for International Cancer Research.

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to M. Reza Ahmadian or Vania M. M. Braga.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Related links

Related links

DATABASES

Protein Data Bank

2G77

FURTHER INFORMATION

Vania M. M. Braga's homepage

Rights and permissions

Reprints and permissions

About this article

Cite this article

Frasa, M., Koessmeier, K., Ahmadian, M. et al. Illuminating the functional and structural repertoire of human TBC/RABGAPs. Nat Rev Mol Cell Biol 13, 67–73 (2012). https://doi.org/10.1038/nrm3267

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrm3267

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing