Protein kinase C delta regulates function of the DF3/MUC1 carcinoma antigen in beta-catenin signaling.
The DF3/MUC1 mucin-like glycoprotein is aberrantly overexpressed in most human carcinomas. The MUC1 cytoplasmic domain interacts directly with beta-catenin, a component of the adherens junction of mammalian epithelial cells. The present results demonstrate that MUC1 associates with protein kinase Cdelta (PKCdelta). A TDR sequence adjacent to the beta-catenin binding motif in the MUC1 cytoplasmic domain functions as a site for PKCdelta phosphorylation. We show that phosphorylation of MUC1 by PKCdelta increases binding of MUC1 and beta-catenin in vitro and in vivo. The functional significance of the MUC1-PKCdelta interaction is further supported by the demonstration that mutation of the PKCdelta phosphorylation site abrogates MUC1-mediated decreases in binding of beta-catenin to E-cadherin. We also show that the stimulatory effects of MUC1 on anchorage-independent growth are abrogated by mutation of the PKCdelta phosphorylation site. These findings support a novel role for PKCdelta in regulating the interaction between MUC1 and the beta-catenin signaling pathway.
Ren
Jian
J
Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
Li
Yongqing
Y
Kufe
Donald
D
D000595:Amino Acid Sequence; D000818:Animals; D000951:Antigens, Neoplasm / Q000502:physiology*; D001483:Base Sequence; D015820:Cadherins / Q000378:metabolism; D002448:Cell Adhesion; D003598:Cytoskeletal Proteins / Q000502:physiology*; D004591:Electrophoresis, Polyacrylamide Gel; D005260:Female; D006801:Humans; D007527:Isoenzymes / Q000502:physiology*; D051379:Mice; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011485:Protein Binding; D011493:Protein Kinase C / Q000502:physiology*; D051745:Protein Kinase C-delta; D015534:Trans-Activators; D014407:Tumor Cells, Cultured; D051176:beta Catenin
D000951:Antigens, Neoplasm; C495270:CTNNB1 protein, human; C495267:CTNNB1 protein, mouse; D015820:Cadherins; D003598:Cytoskeletal Proteins; D007527:Isoenzymes; D015534:Trans-Activators; D051176:beta Catenin; C497259:Prkcd protein, mouse; C497258:PRKCD protein, human; D011493:Protein Kinase C; D051745:Protein Kinase C-delta