The Epithelial Mucin MUC1 Contains at Least Two Discrete Signals Specifying Membrane Localization in Cells (∗)

The MUC1 gene product (PEM, polymorphic epithelial mucin) is a cell-associated glycoprotein expressed on the apical surface of most simple secretory epithelia. The transmembrane and cytoplasmic domains of MUC1 have been shown to be highly conserved between mammalian species, and it has been shown that this molecule interacts with the actin cytoskeleton. Apical targeting signals in polarized cells have yet to be defined. The mechanism by which MUC1 is targeted and maintained on the apical surface is not known; correct localization, however, would be predicted to be crucial for function. In order to determine which domains of MUC1 were important for this localization, mutational analysis of the protein was undertaken. Using cytoplasmic tail deletion mutants, fusion proteins of MUC1 and CD2, and site-directed mutagenesis, it could be shown that MUC1 appeared to contain at least two motifs involved in apical localization. The first was located in the extracellular domain and was sufficient to confer apical localization on the fusion protein. The second was the Cys-Gln-Cys (CQC) motif at the junction of the cytoplasmic and transmembrane domains. This sequence was necessary for surface expression. These results suggest that MUC1 contains two discrete motifs important in its apical localization.