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J. Biol. Chem., Vol. 281, Issue 17, 12112-12122, April 28, 2006

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Recycling of MUC1 Is Dependent on Its Palmitoylation^*

From the Laboratory of Epithelial Cell Biology, Department of Medicine, Renal-Electrolyte Division, University of Pittsburgh, Pittsburgh, Pennsylvania 15261

MUC1 is a mucin-like transmembrane protein expressed on the apical surface of epithelia, where it protects the cell surface. The cytoplasmic domain has numerous sites for phosphorylation and docking of proteins involved in signal transduction. In a previous study, we showed that the cytoplasmic YXX motif Y²⁰HPM and the tyrosine-phosphorylated Y⁶⁰TNP motif are required for MUC1 clathrin-mediated endocytosis through binding AP-2 and Grb2, respectively (Kinlough, C. L., Poland, P. A., Bruns, J. B., Harkleroad, K. L., and Hughey, R. P. (2004) J. Biol. Chem. 279, 53071-53077). Palmitoylation of transmembrane proteins can affect their membrane trafficking, and the MUC1 sequence CQC³RRK at the boundary of the transmembrane and cytoplasmic domains mimics reported site(s) of S-palmitoylation. [³H]Palmitate labeling of Chinese hamster ovary cells expressing MUC1 with mutations in CQC³RRK revealed that MUC1 is dually palmitoylated at the CQC motif independent of RRK. Lack of palmitoylation did not affect the cold detergent solubility profile of a chimera (Tac ectodomain and MUC1 transmembrane and cytoplasmic domains), the rate of chimera delivery to the cell surface, or its half-life. Calculation of rate constants for membrane trafficking of wild-type and mutant Tac-MUC1 indicated that the lack of palmitoylation blocked recycling, but not endocytosis, and caused the chimera to accumulate in a EGFP-Rab11-positive endosomal compartment. Mutations CQC/AQA and Y20N inhibited Tac-MUC1 co-immunoprecipitation with AP-1, although mutant Y20N had reduced rates of both endocytosis and recycling, but a normal subcellular distribution. The double mutant chimera AQA+Y20N had reduced endocytosis and recycling rates and accumulated in EGFP-Rab11-positive endosomes, indicating that palmitoylation is the dominant feature modulating MUC1 recycling from endosomes back to the plasma membrane.

Received for publication, December 6, 2005 , and in revised form, February 24, 2006.

^* This work was supported in part by National Institutes of Health Grants DK054787, P50-CA9044, and P50-DK056490 (to R. P. H.) and Grant DK054407 (to O. A. W.), the Pennsylvania American Lung Association (to R. P. H.) and by Dialysis Clinic, Inc. (to R. P. H.). 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 Supported in part by National Institutes of Health Grant T32-DK061296.

² To whom correspondence should be addressed: Dept. of Medicine, Renal-Electrolyte Div., University of Pittsburgh School of Medicine, 933 Scaife Hall, 3550 Terrace St., Pittsburgh, PA 15261. Tel.: 412-383-8949; Fax: 412-383-8956; E-mail: hughey{at}dom.pitt.edu.

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