Transient Suppression of Ligand-mediated Activation of Epidermal Growth Factor Receptor by Tumor Necrosis Factor-α through the TAK1-p38 Signaling Pathway

Epidermal growth factor receptor (EGFR) has been shown to be activated by specific ligands as well as other cellular stimuli including tumor necrosis factor-α (TNF-α). In the present study, we found that cellular stress suppressed ligand-mediated EGFR activity. Both TNF-α and osmotic stress rapidly induced phosphorylation of EGFR. This phosphorylation of EGFR and the activation of mitogen-activated protein kinases and NF-κB occurred independently of the shedding of extracellular membrane-bound EGFR ligands and intracellular EGFR tyrosine kinase activity. Transforming growth factor-β-activated kinase 1 (TAK1) was involved in the TNF-α-induced signaling pathway to EGFR. In addition, experiments using chemical inhibitors and small interfering RNA demonstrated that p38α is a common mediator for the cellular stress-induced phosphorylation of EGFR. Surprisingly, the modified EGFR was not able to respond to its extracellular ligand due to transient internalization through the clathrin-mediated mechanism. Furthermore, turnover of p38 activation led to dephosphorylation and recycling back to the cell surface of EGFR. These results demonstrated that TNF-α has opposite bifunctional activities in modulating the function of the EGFR.