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 overexpressed in most human carcinomas. The MUC1 cytoplasmic domain interacts with the c-Src tyrosine kinase and thereby increases binding of MUC1 and beta-catenin. In the present work, coimmunoprecipitation studies demonstrate that MUC1 associates constitutively with the epidermal growth factor receptor (EGF-R) in human ZR-75-1 breast carcinoma cells. Immunofluorescence studies show that EGF-R and MUC1 associate at the cell membrane. We also show that the 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 binding of MUC1 to c-Src in cells. Moreover, in vitro and in vivo studies demonstrate that EGF-R increases binding of MUC1 and beta-catenin. These findings support a novel role for EGF-R in regulating interactions of MUC1 with c-Src and beta-catenin.
Li
Y
Y
Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
Ren
J
J
Yu
W
W
Li
Q
Q
Kuwahara
H
H
Yin
L
L
Carraway
K L
KL
Kufe
D
D
D000951:Antigens, Neoplasm / Q000378:metabolism*; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism*; D006801:Humans; D008856:Microscopy, Fluorescence; D018396:Mucin-1 / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism*; D015534:Trans-Activators; D014407:Tumor Cells, Cultured; D051176:beta Catenin
D000951:Antigens, Neoplasm; C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D018396:Mucin-1; D015534:Trans-Activators; D051176:beta Catenin; D066246:ErbB Receptors; D016392:Proto-Oncogene Proteins pp60(c-src)