Transient suppression of ligand-mediated activation of epidermal growth factor receptor by tumor necrosis factor-alpha 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-alpha (TNF-alpha). In the present study, we found that cellular stress suppressed ligand-mediated EGFR activity. Both TNF-alpha and osmotic stress rapidly induced phosphorylation of EGFR. This phosphorylation of EGFR and the activation of mitogen-activated protein kinases and NF-kappaB occurred independently of the shedding of extracellular membrane-bound EGFR ligands and intracellular EGFR tyrosine kinase activity. Transforming growth factor-beta-activated kinase 1 (TAK1) was involved in the TNF-alpha-induced signaling pathway to EGFR. In addition, experiments using chemical inhibitors and small interfering RNA demonstrated that p38 alpha 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-alpha has opposite bifunctional activities in modulating the function of the EGFR.
Singhirunnusorn
Pattama
P
Division of Pathogenic Biochemistry, Institute of Natural Medicine, University of Toyama, Toyama 930-0194, Japan.
Ueno
Yoko
Y
Matsuo
Mitsuhiro
M
Suzuki
Shunsuke
S
Saiki
Ikuo
I
Sakurai
Hiroaki
H
D004789:Enzyme Activation / Q000187:drug effects; D066246:ErbB Receptors / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D008024:Ligands; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D009997:Osmotic Pressure; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D000099151:MAP Kinase Kinase Kinase 7
D066246:ErbB Receptors; D008024:Ligands; D020930:MAP Kinase Kinase Kinases; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases; D000099151:MAP Kinase Kinase Kinase 7