The human DF3/MUC1 transmembrane protein is aberrantly expressed at high levels over the entire surface of breast carcinoma cells. The functional significance of MUC1 overexpression in breast cancer is unknown. Certain insights have been derived from the recent finding that the cytoplasmic domain of MUC1 associates with beta-catenin, a signaling molecule that interacts at the cell membrane with E-cadherin, in the cytosol with the adenomatous polyposis coli (APC) protein and in the nucleus with Tcf/LEF-1 as a transcriptional coactivator. Dysregulation of beta-catenin signaling has been associated with the development of diverse human tumors. Importantly, MUC1 overexpression suppresses binding of beta-catenin to E-cadherin and thereby disrupts the adherens junction, an event associated with tumor progression. The finding that the MUC1 cytoplasmic domain is phosphorylated on tyrosine has led to the demonstration that MUC1 interacts with the c-Src tyrosine kinase. The preliminary results indicate that c-Src regulates binding of MUC1 and beta-catenin. Our hypothesis is that, as a consequence of MUC1 overexpression in breast cancer cells, c-Src subverts binding of beta-catenin to E-cadherin by inducing the interaction between MUC1 and beta-catenin. The regulation of MUC1 by c-Src extends to the p120ctn adherens junction protein which has been implicated in v-Src transformation and also associates with E-cadherin. Preliminary findings support a model in which MUC1 interacts with p120ctn under the control of a c-Src-dependent mechanism.
The Specific Aims are: 1) to elucidate the role of c-Src in regulating the interaction of the MUC1 and beta-catenin signaling pathways; and 2) to define the role of c-Src in controlling the interaction of MUC1 and p120ctn. The proposed pilot studies are designed to develop a new area in breast cancer research.
| Ren, Jian; Li, Yongqing; Kufe, Donald (2002) Protein kinase C delta regulates function of the DF3/MUC1 carcinoma antigen in beta-catenin signaling. J Biol Chem 277:17616-22 |
| Li, Y; Kufe, D (2001) The Human DF3/MUC1 carcinoma-associated antigen signals nuclear localization of the catenin p120(ctn). Biochem Biophys Res Commun 281:440-3 |
| Li, Y; Kuwahara, H; Ren, J et al. (2001) The c-Src tyrosine kinase regulates signaling of the human DF3/MUC1 carcinoma-associated antigen with GSK3 beta and beta-catenin. J Biol Chem 276:6061-4 |
| Li, Y; Ren, J; Yu, W et al. (2001) The epidermal growth factor receptor regulates interaction of the human DF3/MUC1 carcinoma antigen with c-Src and beta-catenin. J Biol Chem 276:35239-42 |
