Abstract
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.
Highlights
Cells to genotoxic and oxidative stress (9 –12)
The results show that protein kinase C (PKC)␦ regulates binding of MUC1 to -catenin and that the T41A mutant abrogates the effects of MUC1 on anchorage-independent cell growth
The present studies demonstrate that PKC␦ interacts with the transmembrane MUC1 protein
Summary
Cells to genotoxic and oxidative stress (9 –12). Targeting of PKC␦ to mitochondria induces apoptosis through loss of the mitochondrial transmembrane potential, release of cytochrome c, and activation of caspase-3 [12,13,14,15]. -Catenin, a component of the adherens junction of mammalian epithelial cells, binds directly to the MUC1/CD at a serine-rich motif that is similar to -catenin-binding sites on E-cadherin and the adenomatous polyposis coli (APC) tumor suppressor [19]. The interaction between MUC1 and -catenin is down-regulated by phosphorylation of the MUC1/CD by glycogen synthase kinase 3 (GSK3) [20]. Phosphorylation of MUC1 by c-Src stimulates binding of MUC1 to -catenin [21]. The recent findings that EGFRmediated phosphorylation of MUC1 regulates the interaction of MUC1 with c-Src and -catenin has suggested that aberrant overexpression of MUC1 in human carcinoma cells could contribute to the transformed phenotype by dysregulation of EGFR signaling [22, 23]. The results show that PKC␦ regulates binding of MUC1 to -catenin and that the T41A mutant abrogates the effects of MUC1 on anchorage-independent cell growth
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