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Vol. 14, Issue 11, 4448-4457, November 2003

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Recycling of Raft-associated Prohormone Sorting Receptor Carboxypeptidase E Requires Interaction with ARF6

Irina Arnaoutova ^*, Catherine L. Jackson , Omayma S. Al-Awar , Julie G. Donaldson , and Y. Peng Loh ^* 

^* Section of Cellular Neurobiology, Laboratory of Developmental Neurobiology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892; Cell Biology and Metabolism Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892; and Laboratory of Cell Biology, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892

Submitted November 22, 2002; Revised July 22, 2003; Accepted July 23, 2003
Monitoring Editor: Peter Walter

Little is known about the molecular mechanism of recycling of intracellular receptors and lipid raft-associated proteins. Here, we have investigated the recycling pathway and internalization mechanism of a transmembrane, lipid raft-associated intracellular prohormone sorting receptor, carboxypeptidase E (CPE). CPE is found in the trans-Golgi network (TGN) and secretory granules of (neuro)endocrine cells. An extracellular domain of the IL2 receptor -subunit (Tac) fused to the transmembrane domain and cytoplasmic tail of CPE (Tac-CPE₂₅) was used as a marker to track recycling of CPE. We show in (neuro)endocrine cells, that upon stimulated secretory granule exocytosis, raft-associated Tac-CPE₂₅ was rapidly internalized from the plasma membrane in a clathrin-independent manner into early endosomes and then transported through the endocytic recycling compartment to the TGN. A yeast two-hybrid screen and in vitro binding assay identified the CPE cytoplasmic tail sequence S₄₇₂ETLNF₄₇₇ as an interactor with active small GTPase ADP-ribosylation factor (ARF) 6, but not ARF1. Expression of a dominant negative, inactive ARF6 mutant blocked this recycling. Mutation of residues S₄₇₂ or E₄₇₃ to A in the cytoplasmic tail of CPE obliterated its binding to ARF6, and internalization from the plasma membrane of Tac-CPE₂₅ mutated at S₄₇₂ or E₄₇₃ was significantly reduced. Thus, CPE recycles back to the TGN by a novel mechanism requiring ARF6 interaction and activity.

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