The epidermal growth factor receptor regulates interaction of the human DF3/MUC1 carcinoma antigen with c-Src and beta-catenin

The DF3/MUC1 mucin-like, transmembrane glycoprotein is aberrantly overexpre ssed in most human carcinomas. The MUC1 cytoplasmic domain interacts with t he c-Src tyrosine kinase and thereby increases binding of MUC1 and beta -ca tenin. In the present work, coimmunoprecipitation studies demonstrate that MUC1 associates constitutively with the epidermal growth factor receptor (E GF-R) in human ZR-75-1 breast carcinoma cells. Immunofluorescence studies s how that EGF-R and MUC1 associate at the cell membrane. We also show that t he activated EGF-R phosphorylates the MUC1 cytoplasmic tail on tyrosine at a YEKV motif that functions as a binding site for the c-Src SH2 domain. The results demonstrate that EGF-R-mediated phosphorylation of MUC1 induces bi nding of MUC1 to c-Src in cells. Moreover, in vitro and in vivo studies dem onstrate that EGF-R increases binding of MUC1 and beta -catenin. These find ings support a novel role for EGF-R in regulating interactions of MUC1 with c-Src and beta -catenin.