Figure 6.

Schematic depiction of cooperative governance for stimulus-dependent GLUT4 liberation process via Tbc1d1 and AS160. Under coexistence of Tbc1d1 and AS160 conditions, Tbc1d1 functionally dominates AS160, given that stimuli-dependent GLUT4 liberation predominantly relies on Tbc1d1-evoking proximal stimuli, such as AMPK activation (AICAR) and an increase in intracellular Ca²⁺. However, AS160 modulates sensitivity to external stimuli in the Tbc1d1-dominated GLUT4 release process via promoting the regulatory mode shift of Tbc1d1, resulting in efficient acquisition of insulin responsiveness, which requires an intact PTB1 domain and Ser²³⁷ phosphorylation of Tbc1d1. This potentiating action of AS160 also relies on the CBD of both Tbc1d1 and Thr⁶⁴² (Akt site) of AS160. This cooperative governance, which relies on combined regulatory modes involving both Tbc1d1 (e.g. PTB1, CBD, Ser²³⁷ phosphorylation) and AS160 (e.g. Thr⁶⁴² phosphorylation), plays a key role in deciphering biochemical signals (e.g. phosphorylation and [Ca²⁺]_i) into physical GLUT4 release processes in response to insulin and exercise-related stimuli.