The c-Src Tyrosine Kinase Regulates Signaling of the Human DF3/MUC1 Carcinoma-associated Antigen with GSK3β and β-Catenin

The DF3/MUC1 mucin-like glycoprotein is aberrantly overexpressed in most human carcinomas. The cytoplasmic domain of MUC1 interacts with glycogen synthase kinase 3β (GSK3β) and thereby decreases binding of MUC1 and β-catenin. The present studies demonstrate that MUC1 associates with the c-Src tyrosine kinase. c-Src phosphorylates the MUC1 cytoplasmic domain at a YEKV motif located between sites involved in interactions with GSK3β and β-catenin. The results demonstrate that the c-Src SH2 domain binds directly to pYEKV and inhibits the interaction between MUC1 and GSK3β. Moreover and in contrast to GSK3β, in vitro and in vivo studies demonstrate that c-Src-mediated phosphorylation of MUC1 increases binding of MUC1 and β-catenin. The findings support a novel role for c-Src in regulating interactions of MUC1 with GSK3β and β-catenin.