| 8.A.87 The TBC1 Domain (TBC1) Family
The 160 kDa protein (designated AS160, for Akt substrate of 160 kDa) with a predicted Rab GAP (GTPase-activating protein) domain is phosphorylated on multiple sites by the protein kinase, Akt.
Phosphorylation of AS160 in adipocytes is required for
insulin-stimulated translocation of the glucose transporter GLUT4 from an intracellular site to the
plasma membrane (Mîinea et al. 2005). Several Isoforms promote insulin-induced glucose
transporter SLC2A4/GLUT4 translocation to the plasma membrane, thus
increasing glucose uptake (Baus et al. 2008; Chen et al. 2012).
AS160 is a crucial mediator of insulin-stimulated glucose transport, and skeletal muscle is the major tissue for insulin-mediated
glucose disposal. Insulin
increases muscle membrane localization of AKT2, but not AKT1; insulin
increased AKT2 phosphorylation in the cytosol and membrane fractions. Insulin also increased AS160 localization to the cytosol and membranes but it increased AS160 phosphorylation only in the cytosol, not in the membranes (Zheng and Cartee 2016).
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| References: |
Baus, D., K. Heermeier, M. De Hoop, C. Metz-Weidmann, J. Gassenhuber, W. Dittrich, S. Welte, and N. Tennagels. (2008). Identification of a novel AS160 splice variant that regulates GLUT4 translocation and glucose-uptake in rat muscle cells. Cell Signal 20: 2237-2246.
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Cartee, G.D. (2015). Roles of TBC1D1 and TBC1D4 in insulin- and exercise-stimulated glucose transport of skeletal muscle. Diabetologia 58: 19-30.
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Chen, Y., Y. Wang, J. Zhang, Y. Deng, L. Jiang, E. Song, X.S. Wu, J.A. Hammer, T. Xu, and J. Lippincott-Schwartz. (2012). Rab10 and myosin-Va mediate insulin-stimulated GLUT4 storage vesicle translocation in adipocytes. J. Cell Biol. 198: 545-560.
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Giepmans, B.N. (2006). Role of connexin43-interacting proteins at gap junctions. Adv Cardiol 42: 41-56.
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Harbour, M.E., S.Y. Breusegem, R. Antrobus, C. Freeman, E. Reid, and M.N. Seaman. (2010). The cargo-selective retromer complex is a recruiting hub for protein complexes that regulate endosomal tubule dynamics. J Cell Sci 123: 3703-3717.
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Janssens, D.H., H. Komori, D. Grbac, K. Chen, C.T. Koe, H. Wang, and C.Y. Lee. (2014). Earmuff restricts progenitor cell potential by attenuating the competence to respond to self-renewal factors. Development 141: 1036-1046.
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Kvainickas, A., H. Nägele, W. Qi, L. Dokládal, A. Jimenez-Orgaz, L. Stehl, D. Gangurde, Q. Zhao, Z. Hu, J. Dengjel, C. De Virgilio, R. Baumeister, and F. Steinberg. (2019). Retromer and TBC1D5 maintain late endosomal RAB7 domains to enable amino acid-induced mTORC1 signaling. J. Cell Biol. [Epub: Ahead of Print]
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Li, X., R. Chen, and S. Zhu. (2017). bHLH-O proteins balance the self-renewal and differentiation of Drosophila neural stem cells by regulating Earmuff expression. Dev Biol 431: 239-251.
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Medina-Yáñez, I., G.H. Olivares, F. Vega-Macaya, M. Mlodzik, and P. Olguín. (2020). Phosphatidic acid increases Notch signalling by affecting Sanpodo trafficking during Drosophila sensory organ development. Sci Rep 10: 21731.
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Mîinea, C.P., H. Sano, S. Kane, E. Sano, M. Fukuda, J. Peränen, W.S. Lane, and G.E. Lienhard. (2005). AS160, the Akt substrate regulating GLUT4 translocation, has a functional Rab GTPase-activating protein domain. Biochem. J. 391: 87-93.
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Mikłosz, A., B. Łukaszuk, M. Żendzian-Piotrowska, K. Kurek, and A. Chabowski. (2016). The Effects of AS160 Modulation on Fatty Acid Transporters Expression and Lipid Profile in L6 Myotubes. Cell Physiol Biochem 38: 267-282.
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Nakanishi, T., T. Nishida, T. Shimo, K. Kobayashi, T. Kubo, T. Tamatani, K. Tezuka, and M. Takigawa. (2000). Effects of CTGF/Hcs24, a product of a hypertrophic chondrocyte-specific gene, on the proliferation and differentiation of chondrocytes in culture. Endocrinology 141: 264-273.
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Popovic, D. and I. Dikic. (2014). TBC1D5 and the AP2 complex regulate ATG9 trafficking and initiation of autophagy. EMBO Rep 15: 392-401.
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Popovic, D., M. Akutsu, I. Novak, J.W. Harper, C. Behrends, and I. Dikic. (2012). Rab GTPase-activating proteins in autophagy: regulation of endocytic and autophagy pathways by direct binding to human ATG8 modifiers. Mol. Cell Biol. 32: 1733-1744.
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Seaman, M.N., M.E. Harbour, D. Tattersall, E. Read, and N. Bright. (2009). 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.
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Uemura, T., S. Shepherd, L. Ackerman, L.Y. Jan, and Y.N. Jan. (1989). numb, a gene required in determination of cell fate during sensory organ formation in Drosophila embryos. Cell 58: 349-360.
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Xiao, P., Y. Zhu, H. Xu, J. Li, A. Tao, H. Wang, D. Cheng, X. Dou, and L. Guo. (2024). CTGF regulates mineralization in human mature chondrocyte by controlling Pit-1 and modulating ANK via the BMP/Smad signalling. Cytokine 174: 156460.
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Zheng, X. and G.D. Cartee. (2016). Insulin-induced Effects on the Subcellular Localization of AKT1, AKT2 and AS160 in Rat Skeletal Muscle. Sci Rep 6: 39230.
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| Examples: |
| TC# | Name | Organismal Type | Example |
| 8.A.87.1.1 | AS160, TBC1 domain family member 4 of 1298 aas and 3 or 4 TMSs, one N-terminal and 3 C-terminal. It regulates energy utilization and promotes translocation of various transporters from an intracellular site to the plasma membrane. These include the glucose transporter, GLUT4, and several proteins involved in fatty acid transport (Mikłosz et al. 2016). | | AS160 of Homo sapiens |
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| 8.A.87.1.2 | Tbc domain protein of 745 aas and 2 or 3 TMSs | | Tcb domain protein of Sporothrix insectorum |
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| 8.A.87.1.3 | TBC1 homologue of 1159 aas and 3 or 4 TMSs. | | TBC1 homologue of Takifugu rubripes (Japanese pufferfish) (Fugu rubripes) |
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| 8.A.87.1.4 | TBC1D1 of 1168 aas and 3 or 4 TMSs as for TBC1D4 which is 50 % identical to TBC1D1 (Cartee 2015). | | TBC1D1 of Homo sapiens |
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| 8.A.87.1.47 | CTGF (CON2, HCS24, IGFBP80) protein of 349 aas and 2 - 4 TMSs, N-terminal between residues 1 and 140. It regulates mineralization in human mature chondrocyte by controlling Pit-1 (Xiao et al. 2024). It mediates heparin- and divalent cation-dependent cell adhesion in many
cell types including fibroblasts, myofibroblasts, endothelial and
epithelial cells (Nakanishi et al. 2000). | | CTGF of Homo sapiens |
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| 8.A.87.1.5 | Small G-protein signaling modulator, Sgsm3, (Cip85, Rutbc3) of 749 aas. Interacts with connexin 43 and probably regulates gap junctional permeability (Giepmans 2006). | | Cip85 of Homo sapiens |
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| 8.A.87.1.6 | NOV (CCN3, NOVH, IGFBP9) of 357 aas and 3 putative TMSs. Binds and may regulate Connexin 43, influencing gap junctional permeability (Giepmans 2006). | | NOV of Homo sapiens |
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| Examples: |
| TC# | Name | Organismal Type | Example |
| 8.A.87.2.1 | TBC1 domain family member 5 of 795 aas and 2 or 3 putative TMSs. It may act as a GTPase-activating protein (GAP) for Rab family proteins and can displace RAB7A and the retromer CSC subcomplex from the endosomal membrane to the cytosol (Seaman et al. 2009; Harbour et al. 2010). Required for retrograde transport of cargo proteins from endosomes to the trans-Golgi network and for regulation of autophagy (Popovic et al. 2012). It may act as a molecular switch between endosomal
and autophagosomal transport and is involved in reprogramming vesicle
trafficking upon autophagy induction (Popovic and Dikic 2014). Retromer and TBC1D5 maintain late endosomal RAB7 domains to enable amino acid-induced mTORC1 signaling (Kvainickas et al. 2019).
| | TBC1D5 of Homo sapiens |
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| Examples: |
| TC# | Name | Organismal Type | Example |
| 8.A.87.3.1 | Numb protein of 556 aas and 3 TMSs in a 1 + 2 TMS arrangement. It is required for determination of cell fate during sensory organ formation in embryos (Uemura et al. 1989). It restricts developmental potential and promotes maturation of
intermediary neuronal progenitor cells, probably acting as an
antagonist of Notch signaling (Janssens et al. 2014, Li et al. 2017). Increased phosphatidic acid derived from Phospholipase D action leads to defects in binary cell-fate decisions that are compatible with ectopic Notch activation in precursor cells. Null mutants of numb or the alpha-subunit of Adaptor Protein complex-2 enhances dominantly this phenotype (Medina-Yáñez et al. 2020). | | Numb of Drosophila melanogaster (Fruit fly) |
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