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Submitted on July 12, 2005
Accepted on August 4, 2005
Programme in Cell Biology, The Hospital for Sick Children, Toronto, Ontario, Canada, M5G 1X8
* To whom correspondence should be addressed. E-mail: amira{at}sickkids.ca.
GLUT4 is the major glucose transporter of muscle and adipose cells, exquisitely regulated by insulin through post-translational events. Twenty years after the seminal observations that GLUT4 levels rapidly rise at the plasma membrane (PM) and drop in endomembranes in response to an acute insulin challenge, we are still mapping the intracellular traffic of the transporter and the regulatory events that insulin unleashes. Newly synthesized GLUT4 enters an insulin-responsive compartment aided by GGA2 (an Arf-binding protein). In cultured adipocytes and myocytes, GLUT4 concentrates in a perinuclear pole through participation of microtubules and the protein EHD1. In the absence of stimuli, GLUT4 distributes between recycling endosomes (RE) and the insulin-responsive compartment. A handful of proteins that bind to GLUT4 appear to regulate its half-life (e.g. Ubc9) and tethering within endomembranes (e.g. TUG). Insulin-derived signals promote not only GLUT4 mobilization toward the PM but also its traffic between endosomal compartments and internalization from the PM. Class IA phosphatidylinositol (PI) 3-kinase plays a pivotal role at several steps of GLUT4 mobilization. The PI 3-kinase 
atypical PKC and Akt/PKB AS160 signaling cascades are major regulators of GLUT4 exocytosis aided by small GTPases. At the cell periphery, GLUT4-containing vesicles tether, dock and fuse with the PM assisted by the exocyst complex followed by engagement of a SNARE complex (with VAMP2 as the v-SNARE, and SNAP23 and syntaxin4 as t-SNAREs) regulated by the accessory proteins Munc18c, Synip and Tomosyn. Vesicle tethering and fusion are regulated by insulin through input from class IA PI 3-kinase.
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