In both unstimulated and insulin-stimulated cells, Glut4 is transported among the PM, endosomes, a peri-nuclear storage compartment and transport vesicles (referred to as "GLUT4 specialized vesicles" or GSVs). Basal intracellular retention involves 2 Glut4 transport cycles: 1) between endosomes and the peri-nuclear storage compartment, and 2) between GSVs and endosomes. The peri-nuclear compartment has a major role in the intracellular sequestration of Glut4 in unstimulated cells, and the GSVs are the specialized vesicles that ferry Glut4 to the PM.
Insulin achieves translocation by specifically altering the Glut4 trafficking kinetics of a number of steps. Insulin signaling, via distinct effectors, intersects Glut4 trafficking at multiple steps. Since the effect of insulin on the expression of Glut4 in the PM is the sum of these steps, it is important to have a comprehensive understanding of each of the regulated steps. Work in the lab currently focuses on different aspects of Glut4 behavior and insulin signal transduction.
In past studies. we elucidated the role of the AKT - AS160 - Rab10 signaling module in the regulation of Glut4 trafficking. We have recently identified Sec16A as a Rab10 effector, and we have shown that Rab10-Sec16A function to mobilize Glut4 from the perinuclear storage compartment (PNSC). We hypothesize Rab10 - Sec16A play a key role in generating GSVs at the increased rate required to support the enhanced PM expression of Glut4 in insulin-stimulated cells. Rab10 is responsible for about 50% of insulin’s effect on Glut4.
We have demonstrated that the TBC1D4-Rab10 complex is responsible for Glut4 mobilization from the trans-Golgi network compartment. Furthermore, we have shown that Insulin effect on Glut4 translocation happens in a specific region of the TGN where specialized cargo is transported to the PM.