Epidermal Growth Factor (EGF) Receptor Kinase Activity is Required for Tumor Necrosis Factor (TNF)-α Mediated Intestinal Epithelial Survival

Epidermal growth factor receptor (EGFR) plays a key role in the regulation of normal cellular process and in the hyper-proliferative diseases such as cancer. Recently it has been demonstrated that TNF-induced apoptosis is augmented by inhibition of EGFR. In the present study we demonstrated that EGFR expression and its tyrosine kinase activity is required for TNF-induced cell survival using EGFR tyrosine kinas inhibitor, AG1478 in stable transfected colon intestinal epithelial EGFR(-/-) cells model transfected with either wild-type (wt), or kianse inactive (ki) EGFR. Furthermore, for the first time, we demonstrated that EGFR transactivation leads to other ErbB receptors through TNF induced transactivation of ErbB fancily receptors (EGFR, ErbB2 and ErbB4). Mutational analysis demonstrated that EGFR autophosphorylation sites of Y1068 and Y1086, a Subsequent PI3-kinase/Akt activation sites, is required for TNF mediated transactivation of EGFR, ErbB2 and 4 through Src kinase activity and cell survival. Like as Src kinase inhibitor, PI 3-kinase inhibitor enhanced TNF-induced apoptosis, but not MAP kinase inhibitor. From the present study we postulate that EGFR and EGFR tyrosine kinase involving Y1068 and Y1086 is critical in inducing TNF-initiated colon epithelial cell apoptosis through activation of the PI3-kinase/AKT pathway. This novel observation has significant implications for understanding the role of EGFR regulation in maintaining intestinal epithelial cell homeostasis in an environment of chronic inflammation, injury and repair, such as inflammatory bowel disease and tumorigenesis.