Roles of TBC1D1 and TBC1D4 in insulin- and exercise-stimulated glucose transport of skeletal muscle

Abstract

This review focuses on two paralogue Rab GTPase activating proteins known as TBC1D1 Tre-2/BUB2/cdc 1 domain family (TBC1D) 1 and TBC1D4 (also called Akt Substrate of 160 kDa, AS160) and their roles in controlling skeletal muscle glucose transport in response to the independent and combined effects of insulin and exercise. Convincing evidence implicates Akt2-dependent TBC1D4 phosphorylation on T642 as a key part of the mechanism for insulin-stimulated glucose uptake by skeletal muscle. TBC1D1 phosphorylation on several insulin-responsive sites (including T596, a site corresponding to T642 in TBC1D4) does not appear to be essential for in vivo insulin-stimulated glucose uptake by skeletal muscle. In vivo exercise or ex vivo contraction of muscle result in greater TBC1D1 phosphorylation on S237 that is likely to be secondary to increased AMP-activated protein kinase activity and potentially important for contraction-stimulated glucose uptake. Several studies that evaluated both normal and insulin-resistant skeletal muscle stimulated with a physiological insulin concentration after a single exercise session found that greater post-exercise insulin-stimulated glucose uptake was accompanied by greater TBC1D4 phosphorylation on several sites. In contrast, enhanced post-exercise insulin sensitivity was not accompanied by greater insulin-stimulated TBC1D1 phosphorylation. The mechanism for greater TBC1D4 phosphorylation in insulin-stimulated muscles after acute exercise is uncertain, and a causal link between enhanced TBC1D4 phosphorylation and increased post-exercise insulin sensitivity has yet to be established. In summary, TBC1D1 and TBC1D4 have important, but distinct roles in regulating muscle glucose transport in response to insulin and exercise.

Fig. 1

Schematic diagrams illustrating some of the prominent structural features of TBC1D1 and TBC1D4 (Akt substrate of 160 kDa, AS160). Each protein includes a Rab GTPase-activating (GAP) domain, two phosphotyrosine-binding (PTB) domains and a calmodulin-binding domain (CBD). The potential phosphomotifs that are depicted for each protein are designated by the amino acid numbers for the respective human proteins, and each of these sites can be phosphorylated in response to insulin and/or exercise in skeletal muscle

Fig. 2

Effect of acute exercise on subsequent site-specific TBC1D1 and TBC1D4 phosphorylation in normal muscle in response to a physiological insulin dose. This figure depicts the results of published experiments for acute endurance exercise that resulted in a subsequent elevation of insulin-stimulated glucose uptake with a physiological insulin dose in non-insulin resistant, non-diabetic rats or humans [, , –50, 86]. The phosphomotifs shown in red font did not have an exercise-induced increase in insulin-stimulated phosphorylation compared with unexercised control muscle. The phosphomotifs that shown in green font were found in most of the published studies to have an exercise-induced increase in insulin-stimulated phosphorylation vs unexercised controls. The numbers in parentheses below each phosphomotif represent the ratio of the number of publications with a significant exercise-induced increase in insulin-stimulated phosphorylation and the total number of publications making the relevant exercise comparison

Fig. 3

Potential mechanisms for increased TBC1D4 phosphorylation in the absence of greater Akt activity in insulin-stimulated muscle after acute exercise. This figure depicts potential mechanisms that might account for acute exercise effects on TBC1D4 phosphorylation in insulin-stimulated muscle. One exercise session can increase the subsequent (~3–27 h post exercise) TBC1D4 phosphorylation in insulin-stimulated muscle without an increase in Akt activity determined by a conventional Akt enzyme activity assay (using immunoprecipitated Akt with an Akt peptide substrate) [49, 50]. Muscle TBC1D4 phosphorylation depends on the relevant kinase activity, the relevant S/T phosphatase activity and the properties of TBC1D4 that influence its susceptibility to the kinase and phosphatase. A conventional cell-free Akt assay cannot account for the in-cell co-localisation of TBC1D4 with Akt and S/T phosphatases. Enzyme activity of Akt and S/T phosphatases can be influenced by their binding to other proteins. TBC1D4 also binds to regulatory proteins that can influence its phosphorylation. Post-translational modifications (other than S/T phosphorylation) can regulate the activity of Akt and some S/T phosphatases, but it is currently unknown whether TBC1D4 has any post-translational modifications other than S/T phosphorylation