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.

INTRODUCTION

Rab small GTPases are evolutionarily conserved membrane trafficking proteins in all eukaryotic cells [1], and they are thought to be involved in a variety of steps in membrane trafficking, including vesicle formation, vesicle transport along the cytoskeleton, tethering/docking of transport vesicles to the target membrane and fusion of transport vesicles with the target membrane [25]. In general, Rab cycles between two nucleotide-bound states, a GTP (guanosine triphosphate)-bound active state and a GDP (guanosine diphosphate)-bound inactive state, and the GTP-bound active form of Rab promotes transport of vesicles/organelles through interaction with a specific binding partner, a so-called ‘Rab effector’ (Figure 1). Two key regulatory enzymes, ‘GEF (guanine-nucleotide-exchange factor)’, which activates Rab by accelerating the exchange of GDP for GTP, and ‘GAP (GTPase-activating protein)’, which inactivates Rabs by promoting their GTPase activity, are involved in the Rab cycling (Figure 1). Thus identification and characterization of the specific Rab effectors, GEFs and GAPs, are crucial to understand the spatio-temporal regulation of Rab-mediated membrane trafficking events at the molecular level. A great deal of information on candidate mammalian Rab effectors has accumulated during the past two decades ([5] and references therein), and because of the recent development of new tools (e.g. ‘Rab panels’) to systematically analyse all the mammalian Rab isoforms [6], the specificity and diversity of a variety of Rab effector candidates have been elucidated [7,8].

A Rab cycle in membrane trafficking

Figure 1
A Rab cycle in membrane trafficking

Rab cycles between two nucleotide-bound states, a GDP-bound inactive state and a GTP-bound active state. Cycling between the two states is regulated by an activating enzyme, GEF, and an inactivating enzyme, GAP (e.g. TBC proteins). The GTP-bound, activated form of Rab is recruited to a specific type of organelle/vesicle and promotes the transport of the organelle/vesicle by interacting with its specific effector molecule.

Figure 1
A Rab cycle in membrane trafficking

Rab cycles between two nucleotide-bound states, a GDP-bound inactive state and a GTP-bound active state. Cycling between the two states is regulated by an activating enzyme, GEF, and an inactivating enzyme, GAP (e.g. TBC proteins). The GTP-bound, activated form of Rab is recruited to a specific type of organelle/vesicle and promotes the transport of the organelle/vesicle by interacting with its specific effector molecule.

In contrast with Rab effectors, however, the GEFs and GAPs for most mammalian Rabs have largely remained unknown. Except for Rab3-GAP and Rab3-GEF [9,10], the mammalian GEFs and GAPs identified thus far have essentially been on the basis of the sequence information for budding yeast GEFs and GAPs for Ypt/Rab (reviewed in [11] and references therein). As examples, mammalian homologues of VPS9p, SEC2p and HOPS (homotypic fusion and protein sorting) complex have been shown to function as GEFs for certain mammalian Rabs (e.g. Rab3, Rab5, Rab7 and Rab8) [11]. However, only a small number of mammalian homologues of yeast GEFs have been found in human genomes, and additional mammal-specific GEFs that cannot be identified by sequence homology to yeast GEFs must be present in mammals. In contrast, with the exception of Rab3-GAP [9], the mammalian Rab-GAPs identified so far have contained a TBC (Tre-2/Bub2/Cdc16) domain that consists of approx. 200 amino acids. The TBC domain was originally identified as a domain that was conserved among the tre-2 oncogene product and the yeast cell cycle regulators Bub2 and Cdc16 [12], and subsequently as a shared domain among the yeast Rab-GAPs, most of which were named Gyps (GAP for Ypt proteins) [13,14]. Interestingly, more than 40 different TBC domain-containing proteins (simply referred to as TBC proteins hereafter) have been found in humans and mice, and this number is almost the same as the number of the Rab subfamily (i.e. human Rab1–43). Recent biochemical and cellular analyses have clearly demonstrated that some TBC proteins possess GAP activity towards certain Rabs, suggesting that members of the TBC protein family function as a specific Rab-GAP. In the present review, the Rab-GAP activity and function of TBC proteins in membrane trafficking are summarized and the problems in TBC research with regard to Rab-GAP specificity is discussed.

MOST MAMMALIAN TBC PROTEINS HAVE BEEN IDENTIFIED INDEPENDENTLY OF RAB SMALL GTPases

As summarized in Table 1 and Figure 2, at least 42 different TBC proteins are present in humans and mice. Interestingly, most mammalian TBC proteins have been identified as a protein associated with cancer [1520], cell signalling [21] or other cellular events [22] independent of Rab GTPases, especially before 2005: for example, USP (ubiquitin-specific peptidase) 6/TRE17 (tre-2 oncogene product 17) was identified as a protein with an ability to transform NIH 3T3 cells [15]; USP6NL (USP6 N-terminal like)/RN-tre and EVI5 (ecotropic viral integration site 5) as proteins with homology to the tre-2 oncogene product [16,17]; TBC1D2A/PARIS-1/Armus as an immunogenic prostate tumour antigen [18]; TBC1D3/PRC17 as a protein with an oncogenic activity [19]; TBC1D4/AS160 (Akt substrate of 160 kDa) as an Akt substrate in insulin signalling in adipocytes [21]; TBC1D8/VRP as a protein involved in angiogenesis [22]; TBC1D10A/EPI64 as an EBP50 (ERM-binding phosphoprotein of 50 kDa)-binding protein that regulates the microvillar structure [23]; and RUTBC3 {RUN [RPIP8 (Rap2-interacting protein 8), UNC-14 (unco-ordinated family member 14) and NESCA (new molecule containing SH3 at the C-terminal)] and TBC1 domain-containing 3} RabGAP-5/CIP85 (connexin 43-interacting protein of 85 kDa) as a connexin43-binding protein [24]. In addition, a gene for TBC1D25/OATL1 (ornithine aminotransferase-like 1) on human chromosome Xp11.23 has been identified as a genetic marker for the diagnosis and mapping of X-linked human disorders [25]. In contrast, only a few TBC proteins were originally identified as proteins directly related to Rabs before 2005. The centrosome-associated protein TBC1D11/GAPCenA, for example, was originally identified as a Rab6-binding protein and Rab6-GAP [26]. Despite the increasing number of TBC proteins reported, no attempts to identify the target Rab of most of them were made until recently. Candidate targets of some TBC proteins (e.g. TBC1D3, TBC1D11, TBC1D15 and USP6NL) have been identified by investigating GAP activity towards a limited number of Rab isoforms, but their Rab-GAP specificity was not extensively investigated at the time [19,2628].

Table 1
TBC proteins in humans

Since names of mammalian TBC proteins have variously been reported in the literature, we used gene symbols in the NCBI (National Center for Biotechnology Information) rather than commonly used names throughout this review for clarity.

Gene symbolOther namesGene IDChromosome locationCatalytic arginineRab-binding activityRab-GAP activity
TBC1D1 KIAA1108 23216 4p14 Yes   
TBC1D2A FLJ22452/PARIS-1/Armus 55357 9q22.33 Yes  Rab7 
TBC1D2B KIAA1055 23102 15q24.3–q25.1 Yes Rab22A/B*  
TBC1D3 PRC17 729873 17q12 Yes  Rab5 
TBC1D4 AS160 9882 13q22.2 Yes  Rab2A/8A/10/14 
TBC1D5 KIAA0210 9779 3p24.3 Yes  Rab7 
TBC1D6 FLJ22474 79774 13q34 Yes   
TBC1D7 FLJ32666 51256 6p24.1 No  Rab17 
TBC1D8A VRP 11138 2q11.2 Yes   
TBC1D8B FLJ33929 54885 Xq22.3 Yes   
TBC1D9A KIAA0882 23158 4q31.21 Yes   
TBC1D9B KIAA0676 23061 5q35.3 Yes   
TBC1D10A EPI64/Rab27A-GAPα 83874 22q12.1–qter Yes  Rab27A/35 
TBC1D10B FLJ13130 26000 16p11.2 Yes  Rab3A/22/27A/35 
TBC1D10C EPI64C/Carabin/FLJ00332 374403 11q13.2 Yes  Rab35 
TBC1D11 GAPCenA/RABGAP1 23637 9q33.2–q33.3 Yes Rab4/11/36* Rab2/4/6/11/36 
TBC1D12 KIAA0608 23232 10q23.33 Yes   
TBC1D13 FLJ10743 54662 9q34.11 Yes   
TBC1D14 KIAA1322 57533 4p16.1 Yes   
TBC1D15 FLJ12085 64786 12q21.1 Yes Rab5A–C Rab7/11A 
TBC1D16 FLJ12168-like 125058 17q25.3 Yes   
TBC1D17 FLJ12168 79735 19q13.33 Yes Rab5A–C Rab21/35 
TBC1D18 RABGAP1L/FLJ38519 9910 1q24 Yes Rab13/34/36 Rab22A 
TBC1D19 FLJ11082 55296 4p15.2 No   
TBC1D20 DJ852M4.2 128637 4p15.2 Yes  Rab1/2 
TBC1D21 MGC34741 161514 15q24.1 No   
TBC1D22A C22orf4 25771 22q13.3 No   
TBC1D22B FLJ20337 55633 6p21.2 No   
TBC1D23 FLJ11046 55773 3q12.1–q12.2 No   
TBC1D24 KIAA1171 57465 16p13.3 No   
TBC1D25 OATL1 4943 Xp11.3–p11.23 Yes Rab2A Rab2A 
TBC1D26 AAH47400 353149 17p11.2 No   
TBC1D30 KIAA0984 23329 12q14.3 No Rab8A  
RUTBC1 SGSM2/KIAA0397/NuIP 9905 17p13.3 Yes   
RUTBC2 SGSM1/KIAA1941 129049 22q11.23 Yes   
RUTBC3 SGSM3/RabGAP-5/CIP85/DJ1042K10.2 27352 22q13.1–q13.2 Yes Rab5A–C/39B Rab5A–C/39B 
EVI5 Evi5 7813 1p22.1 Yes Rab10* Rab11/35 
EVI5L Evi5-like 115704 19p13.2 Yes Rab10* Rab23 
TBCK HSPC302 93627 4q24 Yes   
USP6NL RN-tre 9712 10p13 Yes Rab30/41 Rab5/41 
USP6 TRE17 9098 17p13 No Rab33B  
BROMI C6orf170 221322 6q22.31 No   
Gene symbolOther namesGene IDChromosome locationCatalytic arginineRab-binding activityRab-GAP activity
TBC1D1 KIAA1108 23216 4p14 Yes   
TBC1D2A FLJ22452/PARIS-1/Armus 55357 9q22.33 Yes  Rab7 
TBC1D2B KIAA1055 23102 15q24.3–q25.1 Yes Rab22A/B*  
TBC1D3 PRC17 729873 17q12 Yes  Rab5 
TBC1D4 AS160 9882 13q22.2 Yes  Rab2A/8A/10/14 
TBC1D5 KIAA0210 9779 3p24.3 Yes  Rab7 
TBC1D6 FLJ22474 79774 13q34 Yes   
TBC1D7 FLJ32666 51256 6p24.1 No  Rab17 
TBC1D8A VRP 11138 2q11.2 Yes   
TBC1D8B FLJ33929 54885 Xq22.3 Yes   
TBC1D9A KIAA0882 23158 4q31.21 Yes   
TBC1D9B KIAA0676 23061 5q35.3 Yes   
TBC1D10A EPI64/Rab27A-GAPα 83874 22q12.1–qter Yes  Rab27A/35 
TBC1D10B FLJ13130 26000 16p11.2 Yes  Rab3A/22/27A/35 
TBC1D10C EPI64C/Carabin/FLJ00332 374403 11q13.2 Yes  Rab35 
TBC1D11 GAPCenA/RABGAP1 23637 9q33.2–q33.3 Yes Rab4/11/36* Rab2/4/6/11/36 
TBC1D12 KIAA0608 23232 10q23.33 Yes   
TBC1D13 FLJ10743 54662 9q34.11 Yes   
TBC1D14 KIAA1322 57533 4p16.1 Yes   
TBC1D15 FLJ12085 64786 12q21.1 Yes Rab5A–C Rab7/11A 
TBC1D16 FLJ12168-like 125058 17q25.3 Yes   
TBC1D17 FLJ12168 79735 19q13.33 Yes Rab5A–C Rab21/35 
TBC1D18 RABGAP1L/FLJ38519 9910 1q24 Yes Rab13/34/36 Rab22A 
TBC1D19 FLJ11082 55296 4p15.2 No   
TBC1D20 DJ852M4.2 128637 4p15.2 Yes  Rab1/2 
TBC1D21 MGC34741 161514 15q24.1 No   
TBC1D22A C22orf4 25771 22q13.3 No   
TBC1D22B FLJ20337 55633 6p21.2 No   
TBC1D23 FLJ11046 55773 3q12.1–q12.2 No   
TBC1D24 KIAA1171 57465 16p13.3 No   
TBC1D25 OATL1 4943 Xp11.3–p11.23 Yes Rab2A Rab2A 
TBC1D26 AAH47400 353149 17p11.2 No   
TBC1D30 KIAA0984 23329 12q14.3 No Rab8A  
RUTBC1 SGSM2/KIAA0397/NuIP 9905 17p13.3 Yes   
RUTBC2 SGSM1/KIAA1941 129049 22q11.23 Yes   
RUTBC3 SGSM3/RabGAP-5/CIP85/DJ1042K10.2 27352 22q13.1–q13.2 Yes Rab5A–C/39B Rab5A–C/39B 
EVI5 Evi5 7813 1p22.1 Yes Rab10* Rab11/35 
EVI5L Evi5-like 115704 19p13.2 Yes Rab10* Rab23 
TBCK HSPC302 93627 4q24 Yes   
USP6NL RN-tre 9712 10p13 Yes Rab30/41 Rab5/41 
USP6 TRE17 9098 17p13 No Rab33B  
BROMI C6orf170 221322 6q22.31 No   
*

Interaction between TBC1D2B and Rab22A/B, TBC1D11 and Rab362, and EVI5/EVI5L and Rab10 occurs independent of the TBC domain [7,8].

Rab-GAP specificity of these TBC proteins is a matter of controversy in the literature (see text for details).

Rab-GAP activity of human TBC1D5 is estimated by analogy with the function of its Caenorhabditis elegans orthologue.

Structure of human TBC proteins

Figure 2
Structure of human TBC proteins

Protein motifs of human TBC domain (light blue boxes)-containing proteins were analysed by using the SMART (Simple Modular Architecture Research Tool) program (available at http://smart.embl-heidelberg.de/) or the Blastp program (available at http://blast.ncbi.nlm.nih.gov/). Amino acid numbers are shown on both sides. Abbreviations: RHOD, rhodanese homology domain; SH3, Src homology domain 3; STYKc, protein kinase domain of undetermined specificity; TLDc, TBC and LysM domain-containing; TM, transmembrane.

Figure 2
Structure of human TBC proteins

Protein motifs of human TBC domain (light blue boxes)-containing proteins were analysed by using the SMART (Simple Modular Architecture Research Tool) program (available at http://smart.embl-heidelberg.de/) or the Blastp program (available at http://blast.ncbi.nlm.nih.gov/). Amino acid numbers are shown on both sides. Abbreviations: RHOD, rhodanese homology domain; SH3, Src homology domain 3; STYKc, protein kinase domain of undetermined specificity; TLDc, TBC and LysM domain-containing; TM, transmembrane.

Rab-GAP ACTIVITY AND THE SPECIFICITY OF MAMMALIAN TBC PROTEINS

Systematic analysis to identify the target Rabs of TBC proteins was first based on the physical interaction between the TBC domain and its substrate Rab (i.e. a GTP-fixed mutant) and conducted by performing yeast two-hybrid assays [29]. Barr and co-workers found that RUTBC3/RabGAP-5 physically and specifically interacts with Rab5A–C and that it specifically activates the GTPase activity of Rab5 isoforms [29]. Similarly, USP6NL/RN-tre, originally described as a Rab5-GAP [27], was found to interact with Rab41 (also called Rab43 in the literature) and show specific Rab41-GAP activity [29], and TBC1D11/GAPCenA, originally described as a Rab6-GAP [26], to strongly interact with Rab4 and Rab11 and function as a GAP towards their binding Rabs [30] (note that there is controversy in the literature regarding the in vitro Rab-GAP specificity of RUTBC3 [29,31], USP6NL [27,29,32] and TBC1D11 [8,26,30]; see the next paragraph). A subsequent nearly genome-wide analysis of the interaction between mammalian TBC proteins and Rabs, however, indicated that the GAP activity of TBC proteins does not always require a close physical interaction, although few TBC proteins have shown clear GAP activity towards their binding Rabs [31]. Moreover, some TBC proteins (e.g. TBC1D11, EVI5 and TBC1D2B/KIAA1055) have been shown to bind specific Rab isoforms via a domain other than a TBC domain [7,8]. Thus TBC–Rab interaction alone is insufficient to determine the target Rab of TBC proteins.

The second approach to identifying the target Rabs of TBC proteins has been to investigate their in vitro GAP activity towards many Rab isoforms (at least more than 10 different Rab isoforms) [2931,3339]. The reported in vitro GAP activity of mammalian TBC proteins is summarized in Table 1. Although this approach appears to be a reliable means of investigating the GAP specificity of TBC proteins, the in vitro GAP specificity of some TBC proteins has been variously reported in the literature (see footnote † in Table 1). As an example, Lanzetti et al. [27] reported that USP6NL exhibited Rab5-GAP activity, whereas Haas et al. [29] found that it had Rab41-GAP activity and no Rab5-GAP activity. Cuif et al. [26] reported that TBC1D11 displayed Rab6-GAP activity, whereas Fuchs et al. [30] found that it had Rab4/11-GAP activity, but no Rab6-GAP activity. Similar discrepancies between the findings of different investigations can be found in the literature with regard to RUTBC3 [29,31], TBC1D3 [19,40], TBC1D10A/EPI64 [39,41] and TBC1D10B/FLJ13130 [32,35,39]. The discrepancies may be attributable to differences between methods of in vitro GAP assays or differences in sources of recombinant TBC proteins, i.e. whether prepared from bacteria or mammalian cultured cells, and post-translational modification of TBC1D4 (i.e. phosphorylation by Akt) has been reported to affect its GAP activity [42]. Future study of the endogenous function of TBC proteins (i.e. elucidation of their GAP activity in vivo) will be necessary to resolve these discrepancies.

TBC PROTEINS ARE USED AS TOOLS TO INACTIVATE SPECIFIC MEMBRANE TRAFFICKING EVENTS

Since TBC proteins are thought to inactivate specific Rab isoforms by accelerating their GTPase activity, overexpression of a TBC protein in mammalian cells should inhibit the specific membrane trafficking event in which the target Rab of the TBC protein is specifically involved. Using wild-type TBC protein and its catalytic arginine mutant (often designated an RK mutant), which lacks GAP activity as a result of replacement of a catalytic arginine residue by a lysine residue [43,44], as a negative control, has recently made it possible to demonstrate involvement of TBC proteins and their substrate Rabs in specific membrane trafficking events. As an example, expression of TBC1D10A/EPI64, but not its catalytically inactive EPI64(R160K) mutant, in melanocytes has been shown to inhibit actin-based melanosome transport as a result of inactivation of Rab27A [41]. Similarly, expression of any one of the three TBC proteins, TBC1D7 (in vitro target: Rab17), TBC1D30 (in vitro target: Rab8A) and EVI5L (in vitro target: Rab23), inhibited primary cilium formation of telomerase-immortalized retinal pigment epithelial (hTERT-RPE1) cells [35]; expression of TBC1D11 inhibited Shiga toxin uptake [30]; expression of TBC1D20 or USP6NL caused the loss of the Golgi complex [33]; and expression of TBC1D10A–C inhibited exosome secretion [39]. Despite the problems with regard to the in vitro GAP specificity of these TBC proteins found in the literature (see the previous section), a collection of TBC proteins and their catalytic arginine mutants is considered a powerful tool to screen for Rabs that regulate specific membrane trafficking events [6,29,31].

TBC PROTEIN BINDING TO NON-SUBSTRATE Rabs AND OTHER SMALL GTPases

As shown in Figure 2, TBC proteins often contain additional protein motifs, including a PTB domain (phosphotyrosine-binding domain), PH (pleckstrin homology) domain, GRAM (glucosyltransferases, Rab-like GTPase activators, and myotubularins) domain, RUN domain and/or CC (coiled-coil) domain. It should be noted that some of these domains (e.g. GRAM domain [45] and RUN domain [46]) are known to be associated with other small G protein signalling molecules (e.g. Rap). Actually, some TBC proteins have been shown to be involved in the regulation of Arf6 (ADP-ribosylation factor 6) without accelerating the GTPase activity of Arf6. As an example, USP6 directly interacts with GDP-Arf6 through the TBC domain and promotes the activation of Arf6 on the plasma membrane [47]. Similarly, TBC1D3 is involved in macropinocytosis in an Arf6-dependent pathway [40], and TBC1D10A directly binds GTP-Arf6 through its TBC domain and regulates the microvillar structure [48]. In addition, TBC1D2A/PARIS-1/Armus has been shown to function as a Rac1 effector (i.e. TBC1D2A binds GTP-Rac1) that inactivates Rab7 and regulates E-cadherin degradation [38], and TBC1D10C/carabin has been shown to exhibit Ras-GAP activity [49]. Since approx. a quarter of human TBC proteins lack a conserved catalytic arginine residue [43,44] (see Table 1), such TBC proteins are very unlikely to function as a Rab-GAP. It is therefore tempting to speculate that these GAP-activity-deficient TBC proteins regulate other small G proteins, possibly as an effector, without accelerating their GTPase activity. Future study will clarify whether these GAP-activity-deficient TBC proteins are actually involved in G protein signalling other than Rab-mediated membrane trafficking.

In addition to the Arf6/Rac1-binding described above, some TBC proteins have been shown to bind non-substrate Rabs via a domain other than the TBC domain (see footnote * in Table 1). TBC1D11 directly binds Rab36 via its N-terminal PTB domain, and EVI5/EVI5L and TBC1D2B bind Rab10 and Rab22A/B respectively via their CC domain-containing region [7,8,31]. The physiological significance of the binding of non-substrate Rabs by TBC proteins largely remains unknown, but one possibility is that Rab-binding may be required for the targeting of TBC proteins to specific organelles by functioning as a landmark and/or for the efficient inactivation of a substrate Rab that functions upstream of a non-substrate binding Rab (i.e. a Rab-GAP cascade) [5,8,50].

TBC PROTEINS THAT FUNCTION IN THE INSULIN SIGNALLING

Although, as described above, many more TBC proteins and their target Rab have been reported recently, the physiological function of most mammalian TBC proteins remains unknown. The best-characterized TBC proteins associated with cellular (or physiological) function in mammals are TBC1D4/AS160 and TBC1D1 (reviewed in [51,52]). TBC1D4/AS160 was originally identified as a novel Akt substrate of 160 kDa in insulin signalling in adipocytes that is involved in the insulin-stimulated transport of GLUT4 (glucose transporter 4) to the plasma membrane [21], which is a crucial process for glucose uptake into fat cells (i.e. adipocytes) that reduces the blood glucose level. Both the Akt phosphorylation and GAP activity of TBC1D4 have subsequently been shown to be required for GLUT4 translocation by the results of mutational analyses [42]. In vitro, the TBC domain of TBC1D4 showed GAP activity towards Rab2A, Rab8A/B, Rab10 and Rab14 [36], and Rab10 is the most likely in vivo target of TBC1D4 in 3T3-L1 adipocytes [53,54]. Involvement of Rab8A and Rab14, in vitro targets of TBC1D4, in GLUT4 translocation in L6 muscle cells has also been reported [55], suggesting that the target of TBC1D4 may be cell-type specific. A possible mechanism of the TBC1D4–Rab10 pathway in GLUT4 translocation to the plasma membrane in adipocytes is illustrated in Figure 3. Under resting conditions, TBC1D4 suppresses GLUT4 translocation to the plasma membrane by constitutively inactivating Rab10, a substrate of TBC1D4. Upon insulin stimulation, Akt is activated downstream of the insulin receptor and phosphorylates TBC1D4. Phosphorylated TBC1D4 presumably loses its Rab10-GAP activity and Rab10 is activated as a result. Activated Rab10 mediates GLUT4 translocation to the plasma membrane by largely unknown mechanisms, because, e.g. the Rab10 effector that functions in GLUT4 translocation has never been identified.

A possible mechanism of TBC1D4/AS160 in GLUT4 translocation to the plasma membrane in adipocytes

Figure 3
A possible mechanism of TBC1D4/AS160 in GLUT4 translocation to the plasma membrane in adipocytes

(A) Under resting conditions, Rab10 is constitutively inactivated by TBC1D4/AS160 through its GAP activity, and inactive Rab10 is unable to target the GLUT4-containing vesicle (GLUT4 vesicle). (B) Upon insulin stimulation, the insulin receptor phosphorylates IRS-1 (insulin receptor substrate-1) and the phosphorylated IRS-1 activates PI3K (phosphoinositide 3kinase). PIP3 (phosphatidylinositol 3,4,5-trisphosphate) produced by PI3K at the plasma membrane then activates Akt/PKB, and the activated Atk phosphorylates a variety of target molecules, including TBC1D4. Since phosphorylated TBC1D4 loses its GAP activity, Rab10 is activated and promotes the translocation of GLUT4 into the plasma membrane.

Figure 3
A possible mechanism of TBC1D4/AS160 in GLUT4 translocation to the plasma membrane in adipocytes

(A) Under resting conditions, Rab10 is constitutively inactivated by TBC1D4/AS160 through its GAP activity, and inactive Rab10 is unable to target the GLUT4-containing vesicle (GLUT4 vesicle). (B) Upon insulin stimulation, the insulin receptor phosphorylates IRS-1 (insulin receptor substrate-1) and the phosphorylated IRS-1 activates PI3K (phosphoinositide 3kinase). PIP3 (phosphatidylinositol 3,4,5-trisphosphate) produced by PI3K at the plasma membrane then activates Akt/PKB, and the activated Atk phosphorylates a variety of target molecules, including TBC1D4. Since phosphorylated TBC1D4 loses its GAP activity, Rab10 is activated and promotes the translocation of GLUT4 into the plasma membrane.

TBC1D1, a close homologue of TBC1D4 (see Figures 2 and 4), is abundantly expressed in muscle cells and shows the same substrate specificity as TBC1D4 [37]. TBC1D1 has also been shown to be involved in the GLUT4 translocation in muscle cells [56]. Both TBC1D1 and TBC1D4 are crucial for regulation of the blood glucose level, and defects in them have been shown to be associated with mouse and human diseases (see below).

Molecular dendrogram of human (Homo sapiens) and nematode (Ce, Caenorhabditis elegans) TBC proteins

Figure 4
Molecular dendrogram of human (Homo sapiens) and nematode (Ce, Caenorhabditis elegans) TBC proteins

The phylogenetic tree was drawn by using the ClustalW program set at the default parameters (available at http://clustalw.ddbj.nig.ac.jp/top-e.html). TBC proteins that are conserved between humans and C. elegans are shown in blue. Human TBC proteins associated with diseases (i.e. TBC1D1 and TBC1D4) are highlighted by a red background, and solid red circles and broken red circles indicate nematode TBC proteins, whose deficiency causes lethality and certain abnormalities respectively (see the Wormbase for details).

Figure 4
Molecular dendrogram of human (Homo sapiens) and nematode (Ce, Caenorhabditis elegans) TBC proteins

The phylogenetic tree was drawn by using the ClustalW program set at the default parameters (available at http://clustalw.ddbj.nig.ac.jp/top-e.html). TBC proteins that are conserved between humans and C. elegans are shown in blue. Human TBC proteins associated with diseases (i.e. TBC1D1 and TBC1D4) are highlighted by a red background, and solid red circles and broken red circles indicate nematode TBC proteins, whose deficiency causes lethality and certain abnormalities respectively (see the Wormbase for details).

TBC PROTEINS ASSOCIATED WITH HUMAN DISEASES

Dysfunctions of proper membrane trafficking mediated by a Rab protein, e.g. Rab3A, Rab7, Rab23, Rab27A, Rab38 and Rab39B, or its regulators, e.g. GDI (GDP dissociation inhibitor), REP (Rab escort protein) and GGTA (geranylgeranyl transferase α-subunit), have been reported to cause human and mouse diseases (reviewed in [57]), and dysfunctions of Rab-GAP are expected to be associated with human diseases. Actually, a mutation in the TBC1D1 gene was found in a lean mouse strain [58], and a truncation mutation was found in the TBC1D4 gene of an insulin-resistant patient [59]. Since, as described above, both TBC1D1 and TBC1D4 regulate insulin-stimulated GLUT4 translocation to the plasma membrane in mammals, their dysfunction affects insulin actions and glucose uptake, thereby causing overweight or leanness. In addition, a TBC1D18/RABGAP1L gene rearrangement was found in acute myeloid leukaemia that developed in a child with Klinefelter syndrome [60], although it has not yet been determined whether the gene rearrangement is directly related to the cause of the disease. A Rab1-GAP TBC1D20 [34] interacts with HCV (hepatitis C virus) NS5A protein [61] and mediates the replication of HCV, which is a major cause of liver disease. Furthermore, many TBC proteins have been shown to be associated with cancer [1520], but the exact mechanism by which they associated with cancer remains largely unknown.

Preparing knockout animals is one effective strategy for determining the physiological function of mammalian TBC proteins. However, no TBC protein knockout mice have ever been reported. In contrast, knockout [or knockdown by RNAi (RNA interference)] phenotypes of nematode TBC proteins have already been deposited in the Wormbase (available at http://www.wormbase.org/) (see red circles in Figure 4), and the target of TBC-2 has been analysed in vivo [62,63]. As examples, knockout worms of TBC-1, TBC-2 and TBC-7 exhibit a lethal phenotype (i.e. embryonic development ending in birth and egg hatching), and certain abnormalities in embryonic development, reproductive ability, lipid storage and/or accumulation of protein aggregates are observed in some TBC-knockdown worms. Because almost half of the nematode TBC proteins have human orthologues and some of the knockout/knockdown worms showed certain defects (red circles in Figure 4), dysfunctions of human or mouse orthologues are expected to cause certain diseases. Actually, mutations of TBC1D24, the mammalian orthologue of nematode TBC-7, were found in patients with familial infantile myoclonic epilepsy [64,65] just after the initial draft of this review article was written. Future investigation of the relationship between mammalian orthologues and diseases by analysis of knockout animals should reveal the physiological significance of TBC proteins.

PERSPECTIVES

The TBC domain is now widely recognized as a putative Rab-GAP domain, and the number of papers reporting mammalian TBC proteins has even increased during the preparation of this review article [66,67]. Nevertheless, most mammalian TBC proteins continue to be reported independently of Rab small GTPases [66,68], and whether all mammalian TBC proteins actually function as a specific Rab-GAP is still an open question. Several attempts to identify target Rab of mammalian TBC proteins have been made recently, but the specificity of the in vitro Rab-GAP activity has variously been reported in the literature [6]. The discrepancies may have been attributable to differences between the in vitro GAP assay methods and/or the sources of the recombinant proteins used. Therefore one of the most important directions of future research will be the elucidation of the true targets of TBC proteins in vivo. Future investigation of the in vivo GAP activity of mammalian TBC proteins, e.g. the effect of knockdown of endogenous TBC proteins on the amount of the GTP-bound form of their substrate Rab in mammalian cells, will be necessary to determine their true targets. Another important direction of research will be towards the determination of the mechanisms that govern when and where the Rab-GAP activity of the TBC proteins is activated and inactivated. This information is critical to understand the spatio-temporal regulation of Rab proteins in membrane trafficking. A long, winding road still lies ahead before full understanding of the roles of the mammalian TBC proteins in Rab-mediated membrane trafficking at the molecular level is achieved.

Abbreviations

     
  • Arf6

    ADP-ribosylation factor 6

  •  
  • AS160

    Akt substrate of 160 kDa

  •  
  • CC

    coiled-coil

  •  
  • EVI5

    ecotropic viral integration site 5

  •  
  • GAP

    GTPase-activating protein

  •  
  • GDP

    guanosine diphosphate

  •  
  • GEF

    guanine-nucleotide-exchange factor

  •  
  • GLUT4

    glucose transporter 4

  •  
  • GRAM

    glucosyltransferases, Rab-like GTPase activators, and myotubularins

  •  
  • GTP

    guanosine triphosphate

  •  
  • HCV

    hepatitis C virus

  •  
  • PTB

    domain, phosphotyrosine-binding domain

  •  
  • RUN

    RPIP8, UNC-14 and NESCA

  •  
  • RUTBC3

    RUN and TBC1 domain-containing 3

  •  
  • TBC

    Tre-2/Bub2/Cdc16

  •  
  • USP

    ubiquitin-specific peptidase

  •  
  • USP6NL

    USP6 N-terminal like

I thank Koutaro Ishibashi and Hotaka Kobayashi for preparing the manuscript and members of my laboratory for valuable discussions.

FUNDING

This work was supported in part by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, and Technology (MEXT) of Japan and the Global COE Program (Basic and Translational Research Center for Global Brain Science) of the MEXT of Japan.

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