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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).

References associated with 8.A.87 family:

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. 18771725
Cartee, G.D. (2015). Roles of TBC1D1 and TBC1D4 in insulin- and exercise-stimulated glucose transport of skeletal muscle. Diabetologia 58: 19-30. 25280670
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. 22908308
Giepmans, B.N. (2006). Role of connexin43-interacting proteins at gap junctions. Adv Cardiol 42: 41-56. 16646583
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. 20923837
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. 24550111
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] 31431476
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. 28899667
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. 33303974
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. 15971998
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. 26784579
Popovic, D. and I. Dikic. (2014). TBC1D5 and the AP2 complex regulate ATG9 trafficking and initiation of autophagy. EMBO Rep 15: 392-401. 24603492
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. 22354992
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. 19531583
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. 2752427
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. 27966646