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Department of Medicine (G.R.P.), Royal Melbourne Hospital, Howard Florey Institute (G.R.P., S.Y., V.P., R.N.F., S.Y.C., A.L.A.), Department of Biochemistry and Molecular Biology (S.Y.), Department of Genetics (R.N.F.), and Department of Anatomy and Cell Biology (S.Y.C.), University of Melbourne, Parkville, Victoria 3010, Australia; and Commonwealth Scientific and Industrial Research Organization Molecular and Health Technologies (S.L.M.), Parkville, Victoria 3052, Australia
Address all correspondence and requests for reprints to: Anthony L. Albiston, Howard Florey Institute, University of Melbourne, Parkville, Victoria 3052, Australia. E-mail: a.albiston{at}hfi.unimelb.edu.au.
Insulin-regulated aminopeptidase (IRAP), a marker of glucose transporter 4 (GLUT4) storage vesicles (GSVs), is the only protein known to traffic with GLUT4. In the basal state, GSVs are sequestered from the constitutively recycling endosomal system to an insulin-responsive, intracellular pool. Insulin induces a rapid translocation of GSVs to the cell surface from this pool, resulting in the incorporation of IRAP and GLUT4 into the plasma membrane. We sought to identify proteins that interact with IRAP to further understand this GSV trafficking process. This study describes our identification of a novel interaction between the amino terminus of IRAP and the Akt substrate, AS160 (Akt substrate of 160 kDa). The validity of this interaction was confirmed by coimmunoprecipitation of both overexpressed and endogenous proteins. Moreover, confocal microscopy demonstrated colocalization of these proteins. In addition, we demonstrate that the IRAP-binding domain of AS160 falls within its second phosphotyrosine-binding domain and the interaction is not regulated by AS160 phosphorylation. We hypothesize that AS160 is localized to GLUT4-containing vesicles via its interaction with IRAP where it inhibits the activity of Rab substrates in its vicinity, effectively tethering the vesicles intracellularly.
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