THE EPITHELIAL MUCIN MUC1 CONTAINS AT LEAST 2 DISCRETE SIGNALS SPECIFYING MEMBRANE LOCALIZATION IN CELLS

The MUC1 gene product (PEM, polymorphic epithelial mucin) is a cell-as sociated glycoprotein expressed on the apical surface of most simple s ecretory 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 cytoskel eton, Apical targeting signals in polarized cells have yet to be defin ed. The mechanism by which MUC1 is targeted and maintained on the apic al surface is not known; correct localization, however, would be predi cted to be crucial for function, In order to determine which domains o f MUC1 were important for this localization, mutational analysis of th e protein was undertaken, Using cytoplasmic tail deletion mutants, fus ion 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 domai n and was sufficient to confer apical localization on the fusion prote in. 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 disc rete motifs important in its apical localization.