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.

Singh AB, Sugimoto K, Dhawan P, Harris RC. Juxtacrine activation of EGFR regulates claudin expression and increases transepithelial resistance.

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We developed solvent-soluble polyimides with good heat resistance and low dielectric constant (Dk)/dissipation factor (Df) characteristics by optimizing the composition ratio of the aliphatic, cycloaliphatic, and aromatic groups present in the polyimide back bone. We found that the adhesives prepared using our polyimides showed good adhesion to polyimide films and low profile copper foils and low Dk/Df. Furthermore, we developed a three-layer flexible copper clad laminate (3LFCCL) with our polyimde (PI) adhesives, low-pofile copper foils, and normal PI films. This 3LFCCL showed a transmission loss similar to that of liquid crystal polymer (LCP) FCCLs at frequencies less than 20 GHz. This result indicates that by using our PI adhesives, lower cost FCCLs can be prepared, which can then be used as high-frequency substrates.

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