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J. Biol. Chem., Vol. 281, Issue 44, 33457-33466, November 3, 2006

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A Specific Dileucine Motif Is Required for the GGA-dependent Entry of Newly Synthesized Insulin-responsive Aminopeptidase into the Insulin-responsive Compartment^*

From the Department of Pharmacological Sciences, Stony Brook University, Stony Brook, New York 11794-8651

In muscle and adipose cells, the insulin-responsive aminopeptidase (IRAP) is localized to intracellular storage sites and undergoes insulin-dependent redistribution to the cell surface. Following expression, the newly synthesized IRAP protein traffics to the perinuclear insulin-sensitive compartment and acquires insulin sensitivity 6-9 h following biosynthesis. Knockdown of GGA1 by RNA interference prevented IRAP from entering, but not exiting, the insulin-responsive compartment. Mutation of the dileucine motif at positions 76 and 77 (EGFP-IRAP/AA^76,77), but not the dileucine motif at positions 53 and 54, resulted in the rapid default of the reporter to the cell surface beginning at 3 h following biosynthesis. Alanine substitution of 9 residues amino- or carboxyl-terminal to LL^76,77 did not perturb basal intracellular sequestration or abrogate insulin-stimulated IRAP translocation. Moreover, a dominant interfering GGA mutant (VHS-GAT) potently inhibited insulin-stimulated translocation of EGFP-IRAP/WT but did not block the constitutive exocytotic trafficking of EGFP-IRAP/AA^76,77. In addition, the EGFP-IRAP/WT and EGFP-IRAP/AA^76,77 constructs occupied morphologically distinct tubulovesicular compartments in the perinuclear region. Taken together, these data indicate that LL^76,77 functions during the GGA-dependent sorting of newly made IRAP into the insulin-responsive storage compartment.

Received for publication, February 17, 2006 , and in revised form, August 1, 2006.

^* This work was supported by National Institutes of Health Grants DK33823 and DK55811 (to J. E. P.) and the American Cancer Society Grant PF-03-133-01-TBE (to R. T. W.). 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. Tel.: 631-444-3059; Fax: 631-444-9749; E-mail: Watson{at}pharm.stonybrook.edu.

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