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J. Biol. Chem., Vol. 279, Issue 51, 53071-53077, December 17, 2004

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MUC1 Membrane Trafficking Is Modulated by Multiple Interactions^*

Carol L. Kinlough, Paul A. Poland, James B. Bruns, Keri L. Harkleroad, and Rebecca P. Hughey

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 found on the apical surface of many epithelia. Because aberrant intracellular localization of MUC1 in tumor cells correlates with an aggressive tumor and a poor prognosis for the patient, experiments were designed to characterize the features that modulate MUC1 membrane trafficking. By following [³⁵S]Met/Cys-labeled MUC1 in glycosylation-defective Chinese hamster ovary cells, we found previously that truncation of O-glycans on MUC1 inhibited its surface expression and stimulated its internalization by clathrin-mediated endocytosis. To identify signals for MUC1 internalization that are independent of its glycosylation state, the ectodomain of MUC1 was replaced with that of Tac, and chimera endocytosis was measured by the same protocol. Endocytosis of the chimera was significantly faster than for MUC1, indicating that features of the highly extended ectodomain inhibit MUC1 internalization. Analysis of truncation mutants and tyrosine mutants showed that Tyr²⁰ and Tyr⁶⁰ were both required for efficient endocytosis. Mutation of Tyr²⁰ significantly blocked coimmunoprecipitation of the chimera with AP-2, indicating that Y²⁰HPM is recognized as a YXX motif by the µ2 subunit. The tyrosine-phosphorylated Y⁶⁰TNP was previously identified as an SH2 site for Grb2 binding, and we found that mutation of Tyr⁶⁰ blocked coimmunoprecipitation of the chimera with Grb2. This is the first indication that Grb2 plays a significant role in the endocytosis of MUC1.

Received for publication, August 16, 2004 , and in revised form, September 30, 2004.

^* This work was supported by National Institutes of Health Grants DK54787, P50-CA9044, and P50-DK56490 and by the Pennsylvania American Lung Association. 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.

To whom correspondence should be addressed. Tel.: 412-383-8949; Fax: 412-383-8956; E-mail: hughey{at}msx.dept-med.pitt.edu.

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