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J. Biol. Chem., Vol. 282, Issue 12, 9008-9016, March 23, 2007

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The Luminal Vps10p Domain of Sortilin Plays the Predominant Role in Targeting to Insulin-responsive Glut4-containing Vesicles^*

From the Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts 02118

In fat and skeletal muscle cells, insulin-responsive vesicles, or IRVs, deliver glucose transporter Glut4 and several associated proteins to the plasma membrane in response to hormonal stimulation. Although the protein composition of the IRVs is well studied, the mechanism of their formation is unknown. It is believed, however, that the cytoplasmic tails of the IRV component proteins carry targeting information to this compartment. To test this hypothesis, we have studied targeting of sortilin, one of the major IRV constituents. We have found that the reporter protein consisting of the cytoplasmic tail of sortilin and EGFP is co-localized with ectopically expressed Glut4 in the perinuclear compartment of undifferentiated 3T3-L1 cells that do not form insulin-responsive vesicles. Upon cell differentiation, this reporter protein does not enter the IRVs; moreover, it loses its perinuclear localization and becomes randomly distributed throughout the whole intracellular space. In contrast, the tagged luminal Vps10p domain of sortilin demonstrates partial co-localization with Glut4 in both undifferentiated and differentiated cells and is targeted to the IRVs upon cell differentiation. Using chemical cross-linking and the yeast two-hybrid system, we show that sortilin interacts with Glut4 and IRAP in the vesicular lumen. Our results suggest that luminal interactions between component proteins play an important role in the process of IRV biogenesis.

Received for publication, September 20, 2006 , and in revised form, January 9, 2007.

^* This work was supported by Grants DK52057 and DK56736 from the National Institutes of Health (to K. V. K.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Boston University School of Medicine, Dept. of Biochemistry, K124D, 715 Albany St., Boston, MA 02118. Tel.: 617-638-5049; Fax: 617-638-5339; E-mail: kandror{at}biochem.bumc.bu.edu.

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