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Submitted on January 12, 2005
Accepted on March 9, 2005
Boston University School of Medicine, Boston, MA 02118
* To whom correspondence should be addressed. E-mail: kandror{at}biochem.bumc.bu.edu.
Small Glut4-containing vesicles represent the major insulin-responsive compartment in fat and skeletal muscle cells. The molecular mechanism of their biogenesis is not yet elucidated. Here, we studied the role of the newly discovered family of monomeric adaptor proteins, GGA (Golgi-localized, 
-ear-containing, Arf-binding proteins), in the formation of small Glut4-vesicles and acquisition of insulin responsiveness in 3T3-L1 adipocytes. In these cells, all three GGA isoforms are expressed throughout the differentiation process. In particular, GGA2 is primarily present in trans-Golgi network and endosomes where it demonstrates a significant co-localization with the recycling pool of Glut4. Using the techniques of immunoadsorption as well as GST pull down assay we found that Glut4-vesicles (but not Glut4 per se) interact with GGA via the VHS domain. Moreover, a dominant negative GGA mutant inhibits formation of Glut4-vesicles in vitro. To study a possible role of GGA in Glut4 traffic in the living cell, we stably expressed a dominant negative GGA mutant in 3T3-L1 adipocytes. Formation of small insulin-responsive Glut4-containing vesicles and insulin-stimulated glucose uptake in these cells were markedly impaired. Thus, GGA adaptors participate in the formation of the insulin-responsive vesicular compartment from the intracellular donor membranes both in vivo and in vitro.
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