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.
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References
Stenmark, H. Rab GTPases as coordinators of vesicle traffic. Nature Rev. Mol. Cell Biol. 10, 513–525 (2009).
Mosesson, Y., Mills, G. B. & Yarden, Y. Derailed endocytosis: an emerging feature of cancer. Nature Rev. Cancer 8, 835–850 (2008).
Schmidt, A. & Hall, A. Guanine nucleotide exchange factors for Rho GTPases: turning on the switch. Genes Dev. 16, 1587–1609 (2002).
Tcherkezian, J. & Lamarche-Vane, N. Current knowledge of the large RhoGAP family of proteins. Biol. Cell. 99, 67–86 (2007).
Bos, J. L., Rehmann, H. & Wittinghofer, A. GEFs and GAPs: critical elements in the control of small G proteins. Cell 129, 865–877 (2007).
Bernards, A. GAPs galore! A survey of putative Ras superfamily GTPase activating proteins in man and Drosophila. Biochim. Biophys. Acta 1603, 47–82 (2003).
Fukuda, M. TBC proteins: GAPs for mammalian small GTPase Rab? Biosci. Rep. 31, 159–168 (2011).
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).
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).
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).
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).
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).
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).
Behrends, C., Sowa, M. E., Gygi, S. P. & Harper, J. W. Network organization of the human autophagy system. Nature 466, 68–76 (2010).
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).
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).
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).
Frasa, M. A. et al. Armus is a Rac1 effector that inactivates Rab7 and regulates E-cadherin degradation. Curr. Biol. 20, 198–208 (2010).
Hanono, A., Garbett, D., Reczek, D., Chambers, D. N. & Bretscher, A. EPI64 regulates microvillar subdomains and structure. J. Cell Biol. 175, 803–813 (2006).
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).
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).
Sano, H. et al. Insulin-stimulated phosphorylation of a Rab GTPase-activating protein regulates GLUT4 translocation. J. Biol. Chem. 278, 14599–14602 (2003).
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).
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).
Eberth, A. et al. A BAR domain-mediated autoinhibitory mechanism for RhoGAPs of the GRAF family. Biochem. J. 417, 371–377 (2009).
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).
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).
DiNitto, J. P. & Lambright, D. G. Membrane and juxtamembrane targeting by PH and PTB domains. Biochim. Biophys. Acta 1761, 850–867 (2006).
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).
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).
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).
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).
Qualmann, B. & Mellor, H. Regulation of endocytic traffic by Rho GTPases. Biochem. J. 371, 233–241 (2003).
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).
Lanzetti, L. et al. The Eps8 protein coordinates EGF receptor signalling through Rac and trafficking through Rab5. Nature 408, 374–377 (2000).
Pan, F. et al. Feedback inhibition of calcineurin and Ras by a dual inhibitory protein carabin. Nature 445, 433–436 (2007).
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).
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).
Hsu, C. et al. Regulation of exosome secretion by Rab35 and its GTPase-activating proteins TBC1D10A-C. J. Cell Biol. 189, 223–232 (2010).
Itoh, T. & Fukuda, M. Identification of EPI64 as a GTPase-activating protein specific for Rab27A. J. Biol. Chem. 281, 31823–31831 (2006).
Nie, Z. & Randazzo, P. A. Arf GAPs and membrane traffic. J. Cell Sci. 119, 1203–1211 (2006).
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).
Falace, A. et al. TBC1D24, an ARF6-interacting protein, is mutated in familial infantile myoclonic epilepsy. Am. J. Hum. Genet. 87, 365–370 (2010).
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).
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).
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).
Janz, M. et al. Interphase cytogenetic analysis of distinct X-chromosomal translocation breakpoints in synovial sarcoma. J. Pathol. 175, 391–396 (1995).
Oliveira, A. M. et al. USP6 (Tre2) fusion oncogenes in aneurysmal bone cyst. Cancer Res. 64, 1920–1923 (2004).
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).
Hodzic, D. et al. TBC1D3, a hominoid oncoprotein, is encoded by a cluster of paralogues located on chromosome 17q12. Genomics 88, 731–736 (2006).
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).
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).
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).
Lu, C. et al. Grtp1, a novel gene regulated by growth hormone. Endocrinology 142, 4568–4571 (2001).
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).
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).
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).
Sklan, E. H. et al. TBC1D20 is a RAB1 GAP that mediates HCV replication. J. Biol. Chem. 282, 36354–36361 (2007).
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).
Nakamura, T. et al. A novel transcriptional unit of the Tre oncogene widely expressed in human cancer cells. Oncogene 7, 733–741 (1992).
Akavia, U. D. et al. An integrated approach to uncover drivers of cancer. Cell 143, 1005–1017 (2010).
Palamidessi, A. et al. Endocytic trafficking of Rac is required for the spatial restriction of signaling in cell migration. Cell 134, 135–147 (2008).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
Sudmant, P. H. et al. Diversity of human copy number variation and multicopy genes. Science 330, 641–646 (2010).
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.
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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
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DOI: https://doi.org/10.1038/nrm3267
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