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).

This family belongs to the .



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.

Cartee, G.D. (2015). Roles of TBC1D1 and TBC1D4 in insulin- and exercise-stimulated glucose transport of skeletal muscle. Diabetologia 58: 19-30.

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.

Giepmans, B.N. (2006). Role of connexin43-interacting proteins at gap junctions. Adv Cardiol 42: 41-56.

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.

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.

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.


TC#NameOrganismal TypeExample

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


Tbc domain protein of 745 aas and 2 or 3 TMSs

Tcb domain protein of Sporothrix insectorum


TBC1 homologue of 1159 aas and 3 or 4 TMSs. 

TBC1 homologue of Takifugu rubripes (Japanese pufferfish) (Fugu rubripes)


TBC1D1 of 1168 aas and 3 or 4 TMSs as for TBC1D4 which is 50 % identical to TBC1D1 (Cartee 2015).

TBC1D1 of Homo sapiens


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


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


TC#NameOrganismal TypeExample