MUC1 is a novel regulator of ErbB1 receptor trafficking

Abstract

ErbB receptors are key regulators of cell survival and growth in normal and transformed tissues. The oncogenic glycoprotein MUC1 is a binding partner and substrate for erbB1 and MUC1 expression can potentiate erbBdependent signal transduction. After receptor activation, erbB1 is typically downregulated via an endocytic pathway that results in receptor degradation or recycling. We report here that MUC1 expression inhibits the degradation of ligand-activated erbB1. Through the use of both RNAi-mediated knock down and overexpression constructs of MUC1, we show that MUC1 expression inhibits erbB1 degradation after ligand treatment in breast epithelial cells. This MUC1-mediated protection against erbB1 degradation can increase total cellular pools of erbB1 over time. Biotinylation of surface proteins demonstrates that cell-surface associated erbB1 receptor is protected by MUC1 against ligand-induced degradation, although this is accompanied by an increase in erbB1 internalization. The MUC1-mediated protection against degradation occurs with a decrease in EGF-stimulated ubiquitination of erbB1, and an increase in erbB1 recycling. These data indicate that MUC1 expression is a potent regulator of erbB1 receptor stability upon activation and may promote transformation through the inhibition of erbB1 degradation.

Galectin-3 regulates MUC1 and EGFR cellular distribution and EGFR downstream pathways in pancreatic cancer cells

“…Interestingly, EGFR is also aberrantly expressed in pancreatic cancer from intraepithelial neoplasia lesions to PDAC and exhibits membrane and cytoplasmic staining (Ozaki et al, 2009). Previous reports demonstrated that MUC1 physically interacts with EGFR at the cell membrane, promotes its endocytosis and recycling, and inhibits its degradation (Li et al, 2001;Schroeder et al, 2001;Pochampalli et al, 2007;Ramasamy et al, 2007). These data raise evidence for a connection between MUC1 and EGFR trafficking, and downstream signalling pathways.…”

“…In contrast, in epithelial cancers MUC1 is often overexpressed and delocalized to the whole cell membrane and/or the cytoplasm thus allowing an interaction with EGFR. These interactions modulated the EGFR pathways at different levels, that is, inhibition of EGFR degradation, stimulation of EGFR recycling to the cell membrane and promotion of EGFR localization in the nucleus (Pochampalli et al, 2007;Bitler et al, 2010). Reciprocally, EGF-activated EGFR phosphorylates MUC1 CT on tyrosine, and facilitates its interaction with b-catenin (Singh and Hollingsworth, 2006).…”

NEU1 Sialidase Expressed in Human Airway Epithelia Regulates Epidermal Growth Factor Receptor (EGFR) and MUC1 Protein Signaling

“…MUC1 interacts with EGFR, and activated EGFR tyrosine phosphorylates the MUC1 cytoplasmic domain at a -YEKV-motif that upon phosphorylation serves as a docking site for the c-Src SH2 domain (67). MUC1 also protects against EGFR ubiquitination, thereby promoting its postinternalization plasma membrane recycling and signaling (68). The net effect of NEU1-mediated desialylation on the EGFR-MUC1 receptor signaling complex is likely complicated and incompletely understood.…”

Molecular mechanisms of membrane interaction at implantation

“…3) (Horne et al, 2005;Singh et al, 2010, Bastu et al, 2015. Moreover, paracrine signals from embryos appear to regulate MUC1 to alter local epithelial phenotypes, possibly via growth factors, including insulin-like growth factor (IGF) (Fluhr et al, 2008) and heparin-binding epidermal growth factor (HB-EGF) (Paria et al, 2001;Pochampalli et al, 2007;Lim and Dey, 2009). MUC1 therefore appears to be a key player in regulating endometrial receptivity for implantation and should be the focus of continued research.…”