MUC1 regulates nuclear localization and function of the epidermal growth factor receptor

Abstract

Alteration of protein trafficking and localization is associated with several diseases, including cystic fibrosis, breast cancer, colorectal cancer, leukemia and diabetes. Specifically, aberrant nuclear localization of the epidermal growth factor receptor (EGFR), a receptor tyrosine kinase, is a poor prognostic indicator in several epithelial carcinomas. It is now appreciated that in addition to signaling from the plasma membrane, EGFR also trafficks to the nucleus, and can directly bind the promoter regions of genes encoding cyclin D1 (CCND1) and B-Myb (MYBL2). We have previously established that loss of MUC1 in an EGFR-dependent transgenic mouse model of breast cancer correlates with the loss of cyclin D1 expression. Here, we provide evidence for a novel regulatory function of MUC1 in the trafficking and nuclear activity of EGFR. We found that MUC1 and EGFR interact in the nucleus of breast cancer cells, which promotes the accumulation of chromatin-bound EGFR. Additionally, the presence of MUC1 results in significant colocalization of EGFR and phosphorylated RNA polymerase II, indicating that MUC1 influences the association of EGFR with transcriptionally active promoter regions. Importantly, we found that the loss of MUC1 expression resulted in a decrease in the interaction between EGFR and the CCND1 promoter, which translated to a significant decrease in cyclin D1 protein expression. This data offers insights into a novel regulatory mechanism of EGFR nuclear function and could have important implications for evaluating nuclear localization in cancer.

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

“…Our data suggest that galectin-3 directly binds to EGFR to sequestrate it in the cytoplasm and prevents its nuclear shuttling but other (s) mechanism(s) are not excluded. Finally, we showed, in agreement with previous data (Song et al, 2009), that cyclin D1 is upregulated in galectin-3-expressing cells and that its levels are correlated with total MUC1 CT levels as recently described (Bitler et al, 2010). Cyclin-D1 upregulation in Sc control cells may contribute to their higher proliferative rate in vitro.…”

“…MUC1 CT levels were also increased in Sc cells by comparison with Sh1 cells, in accordance with the results obtained for full-length MUC1 levels ( Figure 2c). In conclusion, we confirm that variations of cyclin-D1 levels follow those of MUC1 CT as previously shown (Bitler et al, 2010) and demonstrate that in pancreatic cancer cells cyclin-D1 expression positively depends on galectin-3. Moreover, silencing of galectin-3 leads to a significant decrease of cell proliferation.…”

“…The EGFRnuclear localization signal is recognized by importin a, that forms a complex with importin b1 to favour the nuclear EGFR import (Lo et al, 2006;Wang et al, 2010). Moreover, MUC1 promotes the nuclear accumulation of EGFR in breast cancer cells and its interaction with DNA (Bitler et al, 2010). Here, we showed that EGF treatment promotes EGFR internalization and subsequent translocation to the perinuclear membrane and nucleus in pancreatic cancer cells.…”

“…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).…”

MUC1 and MUC4: Switching the Emphasis from Large to Small

“…20 MUC1b promotes the nuclear localization of EGFR, and interactions between MUC1b and EGFR in the nucleus contribute to accumulation of chromatinbound EGFR and higher expression of cyclin D1. 21 The cell survival advantage conferred by overexpression of MUC1b is further enhanced by the ability of MUC1b to block cell death mediated by both intrinsic and extrinsic apoptotic pathways. Binding of MUC1b dimers to heat shock proteins 70 or 90 is required for MUC1b import into the outer membrane of mitochondria, where MUC1b abolishes apoptotic responses to genotoxic, oxidative, hypoxic and metabolic stresses by blocking the loss of the mitochondrial transmembrane potential.…”