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AS160 phosphotyrosine-binding domain constructs inhibit insulin-stimulated GLUT4 vesicle fusion with the plasma membrane.

Authors: Koumanov, F  Richardson, JD  Murrow, BA  Holman, GD 
Citation: Koumanov F, etal., J Biol Chem. 2011 May 13;286(19):16574-82. doi: 10.1074/jbc.M111.226092. Epub 2011 Mar 17.
Pubmed: (View Article at PubMed) PMID:21454690
DOI: Full-text: DOI:10.1074/jbc.M111.226092

AS160 (TBC1D4) is a known Akt substrate that is phosphorylated downstream of insulin action and that leads to regulated traffic of GLUT4. As GLUT4 vesicle fusion with the plasma membrane is a highly regulated step in GLUT4 traffic, we investigated whether AS160 and 14-3-3 interactions are involved in this process. Fusion was inhibited by a human truncated AS160 variant that encompasses the first N-terminal phosphotyrosine-binding (PTB) domain, by either of the two N-terminal PTB domains, and by a tandem construct of both PTB domains of rat AS160. We also found that in vitro GLUT4 vesicle fusion was strongly inhibited by the 14-3-3-quenching inhibitors R18 and fusicoccin. To investigate the mode of interaction of AS160 and 14-3-3, we examined insulin-dependent increases in the levels of these proteins on GLUT4 vesicles. 14-3-3gamma was enriched on insulin-stimulated vesicles, and its binding to AS160 on GLUT4 vesicles was inhibited by the AS160 tandem PTB domain construct. These data suggest a model for PTB domain action on GLUT4 vesicle fusion in which these constructs inhibit insulin-stimulated 14-3-3gamma interaction with AS160 rather than AS160 phosphorylation.

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CRRD Object Information
CRRD ID: 7247577
Created: 2013-07-17
Species: All species
Last Modified: 2013-07-17
Status: ACTIVE



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