Abstract
BackgroundInsulin stimulates glucose uptake by adipocytes through increasing translocation of the glucose transporter GLUT4 from an intracellular compartment to the plasma membrane. Fusion of GLUT4-containing vesicles at the cell surface is thought to involve phospholipase D activity, generating the signalling lipid phosphatidic acid, although the mechanism of action is not yet clear.ResultsHere we report the identification of a putative phosphatidic acid-binding motif in a GLUT4 intracellular loop. Mutation of this motif causes a decrease in the insulin-induced exposure of GLUT4 at the cell surface of 3T3-L1 adipocytes via an effect on vesicle fusion.ConclusionThe potential phosphatidic acid-binding motif identified in this study is unique to GLUT4 among the sugar transporters, therefore this motif may provide a unique mechanism for regulating insulin-induced translocation by phospholipase D signalling.
Highlights
Insulin stimulates glucose uptake by adipocytes through increasing translocation of the glucose transporter GLUT4 from an intracellular compartment to the plasma membrane
Identification of PtdOH-target proteins is often achieved by dissection of the pathways involving phospholipase D (PLD), screening methods using a PtdOH-coated resin have indicated a number of interesting potential target proteins such as N-ethylmaleimide-sensitive factor (NSF), coatomer and ARF proteins [10]
The phage display technique used in this study identified a motif present in GLUT4, but absent in other GLUT family members that are not thought to be regulated by PLD
Summary
Insulin stimulates glucose uptake by adipocytes through increasing translocation of the glucose transporter GLUT4 from an intracellular compartment to the plasma membrane. The lipid second messenger, phosphatidic acid (PtdOH) is produced by phospholipase D (PLD) in a variety of intracellular signalling pathways, including cell adhesion and migration, vesicular trafficking and phagocytosis [13]. Phage display is a wellestablished method for identifying novel proteins capable of interactions with a range of ligands, including proteins [11,12], lipids [13] and carbohydrates [14], so was used in the present study to identify potential PtdOH-target proteins. This highlighted a potential PtdOH-binding motif in the transmembrane solute transporter GLUT4
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