The c-Src tyrosine kinase regulates signaling of the human DF3/MUC1 carcinoma-associated antigen with GSK3 beta and beta-catenin

The DF3/MUC1 mucin-like glycoprotein is aberrantly overexpressed in most hu man carcinomas. The cytoplasmic domain of MUC1 interacts with glycogen synt hase kinase 3 beta (GSK3 beta) and thereby decreases binding of MUC1 and be ta -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 GSK3 beta and beta -catenin. The results demonstrate that the c-Src SH2 domain binds directly to pYEKV and inhibits the interaction between MUC1 and GSK3 beta. Moreover and in contrast to GSK3 beta, in vitro and in vivo studies demonst rate that c-Src-mediated phosphorylation of MUC1 increases binding of MUC1 and beta -catenin. The findings support a novel role for c-Src in regulatin g interactions of MUC1 with GSK3 beta and beta -catenin.