Journal
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY
Volume 306, Issue 10, Pages C879-C886Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpcell.00069.2014
Keywords
GLUT4; insulin; Rab; Rac1; vesicle traffic
Categories
Funding
- Canada Research Chair in The Cell Biology of Insulin Action
- Canadian Diabetes Association
- Banting and Best Diabetes Centre of the University of Toronto
- Banting studentship of the Canadian Institutes of Health Research
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Skeletal muscle is the major tissue disposing of dietary glucose, a function regulated by insulin-elicited signals that impart mobilization of GLUT4 glucose transporters to the plasma membrane. This phenomenon, also central to adipocyte biology, has been the subject of intense and productive research for decades. We focus on muscle cell studies scrutinizing insulin signals and vesicle traffic in a spatiotemporal manner. Using the analogy of an integrated circuit to approach the intersection between signal transduction and vesicle mobilization, we identify signaling relays (software) that engage structural/mechanical elements (hardware) to enact the rapid mobilization and incorporation of GLUT4 into the cell surface. We emphasize how insulin signal transduction switches from tyrosine through lipid and serine phosphorylation down to activation of small G proteins of the Rab and Rho families, describe key negative regulation step of Rab GTPases through the GTPase-activating protein activity of the Akt substrate of 160 kDa (AS160), and focus on the mechanical effectors engaged by Rabs 8A and 10 (the molecular motor myosin Va), and the Rho GTPase Rac1 (actin filament branching and severing through Arp2/3 and cofilin). Finally, we illustrate how actin filaments interact with myosin 1c and alpha-Actinin4 to promote vesicle tethering as preamble to fusion with the membrane.
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