Juxtacrine Activation of Epidermal Growth Factor (EGF) Receptor by Membrane-anchored Heparin-binding EGF-like Growth Factor Protects Epithelial Cells from Anoikis While Maintaining an Epithelial Phenotype

Abstract

Loss of cell-matrix adhesion is often associated with acute epithelial injury, suggesting that "anoikis" may be an important contributor to cell death. Resistance against anoikis is a key characteristic of transformed cells. When nontransformed epithelia are injured, activation of the epidermal growth factor (EGF) receptor (EGFR) by paracrine/autocrine release of soluble ligands can induce a prosurvival program, but there is generally evidence for concomitant dedifferentiation. The EGFR ligand, heparin-binding EGF-like growth factor (HB-EGF), is synthesized as a membrane-anchored precursor that can activate the EGFR via juxtacrine signaling or can be released and act as a soluble growth factor. In Madin-Darby canine kidney cells, expression of membrane-anchored HB-EGF increases cell-cell and cell-matrix adhesion. Therefore, these studies were designed to test the effects of juxtacrine HB-EGF signaling upon cell survival and epithelial integrity when cells are denied proper cell-matrix interactions. Cells expressing a noncleavable mutated form of membrane-anchored HB-EGF demonstrated increased survival from anoikis, formed larger cell aggregates, and maintained epithelial characteristics even following prolonged detachment from the substratum. Physical association between membrane-anchored HB-EGF and EGFR was observed. Signaling studies indicated synergistic effects of EGFR activation and phosphatidylinositol 3-kinase signaling to regulate apoptotic and survival pathways. In contrast, although administration of exogenous EGF partially suppressed anoikis in wild type cells, it also led to an increased expression of mesenchymal markers, suggesting dedifferentiation. Taken together, we propose a novel role for membrane-anchored HB-EGF in the cytoprotection of epithelial cells.

Distinct Activation of Epidermal Growth Factor Receptor by UTP Contributes to Epithelial Cell Wound Repair

“…3 This may occur in communication between purinergic and EGFR signaling, especially in corneal epithelium, where apoptosis is rare. Other researchers have shown that stimulation of kidney epithelial cells with pro-HB-EGF protects cells from anoikis 41 ; in epithelial cells, HB-EGF may play a role in nucleotide-induced ERK1/2 signaling and migration. 18 In addition, when cells that express high levels of EGFR are stimulated with EGF, the enhanced levels of activated EGFR may be accompanied by an accumulation of the receptors within the cell because of a decrease in the rate of receptor degradation.…”

Epidermal Growth Factor Receptor Signaling in the Kidney

“…64 Moreover, EGFR activation by HB-EGF protected kidney cells from apoptosis in a cell-cell or cell-matrix deprived environment, indicating that HB-EGF has cytoprotective effects. 65 In rat unilateral ureteral obstruction, EGF expression was decreased when compared with normal kidneys. Administration of EGF during acute tubular injury and after relief of unilateral ureteral obstruction attenuated tubular damage and accelerated tubular regeneration.…”

Acquisition of anoikis resistance through CD147 upregulation: A new mechanism underlying metastasis of hepatocellular carcinoma cells

“…A number of studies have validated that anoikis can be inhibited despite loss of cellmatrix adhesion when cell-cell adhesion is preserved among various epithelial carcinoma cell lines (16,28,29). Our research model also revealed a multi-cellular spheroid formation in a time-dependent manner.…”