TBC proteins: GAPs for mammalian small GTPase Rab?

The TBC (Tre-2/Bub2/Cdc16) domain was originally identified as a conserved domain among the tre-2 oncogene product and the yeast cell cycle regulators Bub2 and Cdc16, and it is now widely recognized as a conserved protein motif that consists of approx. 200 amino acids in all eukaryotes. Since the TBC domain of yeast Gyps [GAP (GTPase-activating protein) for Ypt proteins] has been shown to function as a GAP domain for small GTPase Ypt/Rab, TBC domain-containing proteins (TBC proteins) in other species are also expected to function as a certain Rab-GAP. More than 40 different TBC proteins are present in humans and mice, and recent accumulating evidence has indicated that certain mammalian TBC proteins actually function as a specific Rab-GAP. Some mammalian TBC proteins {e.g. TBC1D1 [TBC (Tre-2/Bub2/Cdc16) domain family, member 1] and TBC1D4/AS160 (Akt substrate of 160 kDa)} play an important role in homoeostasis in mammals, and defects in them are directly associated with mouse and human diseases (e.g. leanness in mice and insulin resistance in humans). The present study reviews the structure and function of mammalian TBC proteins, especially in relation to Rab small GTPases.

[1]  M. Fukuda,et al.  Identification and characterization of a novel Tre‐2/Bub2/Cdc16 (TBC) protein that possesses Rab3A‐GAP activity , 2009, Genes to Cells.

[2]  Pier Paolo Di Fiore,et al.  The Eps8 protein coordinates EGF receptor signalling through Rac and trafficking through Rab5 , 2000, Nature.

[3]  T. Sasaki,et al.  Isolation and Characterization of a GTPase Activating Protein Specific for the Rab3 Subfamily of Small G Proteins* , 1997, The Journal of Biological Chemistry.

[4]  L. Zon,et al.  Molecular cloning of a cDNA with a novel domain present in the tre-2 oncogene and the yeast cell cycle regulators BUB2 and cdc16. , 1995, Oncogene.

[5]  Christopher G. Burd,et al.  The GAP activity of Msb3p and Msb4p for the Rab GTPase Sec4p is required for efficient exocytosis and actin organization , 2003, The Journal of cell biology.

[6]  F. Barr,et al.  A GTPase-activating protein controls Rab5 function in endocytic trafficking , 2005, Nature Cell Biology.

[7]  C. Mitchell,et al.  TBC domain family, member 15 is a novel mammalian Rab GTPase-activating protein with substrate preference for Rab7. , 2005, Biochemical and biophysical research communications.

[8]  H. Stenmark.  Rab GTPases as coordinators of vesicle traffic , 2009, Nature Reviews Molecular Cell Biology.

[9]  N. Nomura,et al.  RN-tre identifies a family of tre-related proteins displaying a novel potential protein binding domain. , 1996, Oncogene.

[10]  Y. Takai,et al.  Isolation and Characterization of a GDP/GTP Exchange Protein Specific for the Rab3 Subfamily Small G Proteins* , 1997, The Journal of Biological Chemistry.

[11]  P. Novick,et al.  A Rab GAP cascade defines the boundary between two Rab GTPases on the secretory pathway , 2009, Proceedings of the National Academy of Sciences.

[12]  G. Lienhard,et al.  Rab10 in insulin-stimulated GLUT4 translocation. , 2008, The Biochemical journal.

[13]  M. Bornens,et al.  Characterization of GAPCenA, a GTPase activating protein for Rab6, part of which associates with the centrosome , 1999, The EMBO journal.

[14]  J. Hartwig,et al.  GLUT4 Vesicle Recruitment and Fusion Are Differentially Regulated by Rac, AS160, and Rab8A in Muscle Cells* , 2008, Journal of Biological Chemistry.

[15]  C. Preisinger,et al.  Analysis of GTPase-activating proteins: Rab1 and Rab43 are key Rabs required to maintain a functional Golgi complex in human cells , 2007, Journal of Cell Science.

[16]  M. Rubin,et al.  PRC17, a novel oncogene encoding a Rab GTPase-activating protein, is amplified in prostate cancer. , 2002, Cancer research.

[17]  F. Barr,et al.  Functional dissection of Rab GTPases involved in primary cilium formation , 2007, The Journal of cell biology.

[18]  J. Pereira-Leal,et al.  Evolution of the Rab family of small GTP-binding proteins. , 2001, Journal of molecular biology.

[19]  F. Barr,et al.  Specific Rab GTPase-activating proteins define the Shiga toxin and epidermal growth factor uptake pathways , 2007, The Journal of cell biology.

[20]  Yubin Du,et al.  Proviral integrations at the Evi5 locus disrupt a novel 90 kDa protein with homology to the Tre2 oncogene and cell-cycle regulatory proteins , 1997, Oncogene.

[21]  S. Kane,et al.  AS160, the Akt substrate regulating GLUT4 translocation, has a functional Rab GTPase-activating protein domain. , 2005, The Biochemical journal.

[22]  Z. Lan,et al.  Novel rab GAP-like protein, CIP85, interacts with connexin43 and induces its degradation. , 2005, Biochemistry.

[23]  Jeffrey S. Glenn,et al.  A Rab-GAP TBC Domain Protein Binds Hepatitis C Virus NS5A and Mediates Viral Replication , 2007, Journal of Virology.

[24]  D. Lambright,et al.  Rab GEFs and GAPs. , 2010, Current opinion in cell biology.

[25]  John M Asara,et al.  Insulin-stimulated Phosphorylation of a Rab GTPase-activating Protein Regulates GLUT4 Translocation* , 2003, The Journal of Biological Chemistry.

[26]  Eigen R. Peralta,et al.  Differential Effects of TBC1D15 and Mammalian Vps39 on Rab7 Activation State, Lysosomal Morphology, and Growth Factor Dependence* , 2010, The Journal of Biological Chemistry.

[27]  H. Yamamoto,et al.  Antisense Display: A New Method for Functional Gene Screen and Its Application to Angiogenesis‐Related Gene Isolation , 2001, Annals of the New York Academy of Sciences.

[28]  H. Willard,et al.  Ornithine aminotransferase-related sequences map to two nonadjacent intervals on the human X chromosome short arm. , 1991, Genomics.

[29]  Rob C Hoeben,et al.  Tbc1d1 mutation in lean mouse strain confers leanness and protects from diet-induced obesity , 2008, Nature Genetics.

[30]  G. Lienhard,et al.  Rab10, a target of the AS160 Rab GAP, is required for insulin-stimulated translocation of GLUT4 to the adipocyte plasma membrane. , 2007, Cell metabolism.

[31]  M. Ahmadian,et al.  Armus Is a Rac1 Effector that Inactivates Rab7 and Regulates E-Cadherin Degradation , 2010, Current Biology.

[32]  M. Fukuda,et al.  Identification of EPI64 as a GTPase-activating Protein Specific for Rab27A* , 2006, Journal of Biological Chemistry.

[33]  D. Lambright,et al.  TBC-2 Regulates RAB-5/RAB-7-mediated Endosomal Trafficking in Caenorhabditis elegans , 2010, Molecular biology of the cell.

[34]  M. Fukuda,et al.  Membrane traffic in the secretory pathway , 2008, Cellular and Molecular Life Sciences.

[35]  A. Bretscher,et al.  EPI64 regulates microvillar subdomains and structure , 2006, The Journal of cell biology.

[36]  J. Gécz,et al.  A focal epilepsy and intellectual disability syndrome is due to a mutation in TBC1D24. , 2010, American journal of human genetics.

[37]  A. Bretscher,et al.  Identification of Epi64, a Tbc/Rabgap Domain–Containing Microvillar Protein That Binds to the First PDZ Domain of Ebp50 and E3karp , 2001, The Journal of cell biology.

[38]  Jun O. Liu,et al.  Feedback inhibition of calcineurin and Ras by a dual inhibitory protein Carabin , 2007, Nature.

[39]  N. Segev.  Ypt and Rab GTPases: insight into functions through novel interactions. , 2001, Current opinion in cell biology.

[40]  M. Chou,et al.  The TBC (Tre-2/Bub2/Cdc16) Domain Protein TRE17 Regulates Plasma Membrane-Endosomal Trafficking through Activation of Arf6 , 2004, Molecular and Cellular Biology.

[41]  H. Federoff,et al.  Identification of a Novel Nurr1-Interacting Protein , 2008, The Journal of Neuroscience.

[42]  C. Mecucci,et al.  RABGAP1L gene rearrangement resulting from a der(Y)t(Y;1)(q12;q25) in acute myeloid leukemia arising in a child with Klinefelter syndrome , 2009, Virchows Archiv.

[43]  A. Wandinger-Ness,et al.  Rab GTPases at a glance , 2007, Journal of Cell Science.

[44]  G. Scita,et al.  The primate-specific protein TBC1D3 is required for optimal macropinocytosis in a novel ARF6-dependent pathway. , 2008, Molecular biology of the cell.

[45]  M. Fukuda,et al.  Comprehensive Screening for Novel Rab‐Binding Proteins by GST Pull‐Down Assay Using 60 Different Mammalian Rabs ‡ , 2010, Traffic.

[46]  C. Croce,et al.  A novel transcriptional unit of the tre oncogene widely expressed in human cancer cells. , 1992, Oncogene.

[47]  A. Klip,et al.  Glucose transporter 4: cycling, compartments and controversies , 2005, EMBO reports.

[48]  S. J. Monahan,et al.  Serological cloning of PARIS-1: a new TBC domain-containing, immunogenic tumor antigen from a prostate cancer cell line. , 2002, Biochemical and biophysical research communications.

[49]  R. Watson,et al.  Bridging the GAP between insulin signaling and GLUT4 translocation. , 2006, Trends in biochemical sciences.

[50]  A. Bernards.  GAPs galore! A survey of putative Ras superfamily GTPase activating proteins in man and Drosophila. , 2003, Biochimica et biophysica acta.

[51]  Alistair N. Hume,et al.  Rab GTPases, intracellular traffic and disease. , 2002, Trends in molecular medicine.

[52]  W. Möbius,et al.  Regulation of exosome secretion by Rab35 and its GTPase-activating proteins TBC1D10A–C , 2010, The Journal of cell biology.

[53]  S. Minoshima,et al.  Identification of three novel proteins (SGSM1, 2, 3) which modulate small G protein (RAP and RAB)-mediated signaling pathway. , 2007, Genomics.

[54]  Peter Novick,et al.  Rabs and their effectors: Achieving specificity in membrane traffic , 2006, Proceedings of the National Academy of Sciences.

[55]  B. Budnik,et al.  Insulin-stimulated Phosphorylation of the Rab GTPase-activating Protein TBC1D1 Regulates GLUT4 Translocation* , 2009, The Journal of Biological Chemistry.

[56]  Yusuke Nakamura,et al.  Activation of an oncogenic TBC1D7 (TBC1 domain family, member 7) protein in pulmonary carcinogenesis , 2010, Genes, chromosomes & cancer.

[57]  D. Lambright,et al.  TBC-domain GAPs for Rab GTPases accelerate GTP hydrolysis by a dual-finger mechanism , 2006, Nature.

[58]  M. Fukuda,et al.  Screening for target Rabs of TBC (Tre‐2/Bub2/Cdc16) domain‐containing proteins based on their Rab‐binding activity , 2006, Genes to cells : devoted to molecular & cellular mechanisms.

[59]  F. Benfenati,et al.  TBC1D24, an ARF6-interacting protein, is mutated in familial infantile myoclonic epilepsy. , 2010, American journal of human genetics.

[60]  S. Kane,et al.  A Method to Identify Serine Kinase Substrates , 2002, The Journal of Biological Chemistry.

[61]  B. Goud,et al.  RUN domains: a new family of domains involved in Ras-like GTPase signaling. , 2001, Trends in biochemical sciences.

[62]  J. Glenn,et al.  TBC1D20 Is a Rab1 GTPase-activating Protein That Mediates Hepatitis C Virus Replication* , 2007, Journal of Biological Chemistry.

[63]  M. Fukuda,et al.  Large Scale Screening for Novel Rab Effectors Reveals Unexpected Broad Rab Binding Specificity*S , 2008, Molecular & Cellular Proteomics.

[64]  S. O’Rahilly,et al.  A truncation mutation in TBC1D4 in a family with acanthosis nigricans and postprandial hyperinsulinemia , 2009, Proceedings of the National Academy of Sciences.

[65]  M. Fukuda.  How can mammalian Rab small GTPases be comprehensively analyzed?: Development of new tools to comprehensively analyze mammalian Rabs in membrane traffic. , 2010, Histology and histopathology.

[66]  M. Fukuda,et al.  Broad-minded links cell cycle-related kinase to cilia assembly and hedgehog signal transduction. , 2010, Developmental cell.

[67]  G. Lienhard,et al.  Substrate specificity and effect on GLUT4 translocation of the Rab GTPase-activating protein Tbc1d1. , 2007, The Biochemical journal.

[68]  Zuoyan Zhu,et al.  C. elegans Rab GTPase activating protein TBC-2 promotes cell corpse degradation by regulating the small GTPase RAB-5 , 2009, Development.