Document Detail


Transient suppression of ligand-mediated activation of epidermal growth factor receptor by tumor necrosis factor-alpha through the TAK1-p38 signaling pathway.
MedLine Citation:
PMID:  17327237     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Pattama Singhirunnusorn; Yoko Ueno; Mitsuhiro Matsuo; Shunsuke Suzuki; Ikuo Saiki; Hiroaki Sakurai
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2007-02-27
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  282     ISSN:  0021-9258     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2007 Apr 
Date Detail:
Created Date:  2007-04-23     Completed Date:  2007-06-14     Revised Date:  2011-11-02    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  12698-706     Citation Subset:  IM    
Affiliation:
Division of Pathogenic Biochemistry, Institute of Natural Medicine, University of Toyama, Toyama 930-0194, Japan.
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MeSH Terms
Descriptor/Qualifier:
Enzyme Activation / drug effects
Hela Cells
Humans
Ligands
MAP Kinase Kinase Kinases / metabolism*
MAP Kinase Signaling System / drug effects*
Osmotic Pressure
Phosphorylation / drug effects
Protein Processing, Post-Translational / drug effects*
Receptor, Epidermal Growth Factor / metabolism*
Tumor Necrosis Factor-alpha / pharmacology*
p38 Mitogen-Activated Protein Kinases / metabolism
Chemical
Reg. No./Substance:
0/Ligands; 0/Tumor Necrosis Factor-alpha; EC 2.7.10.1/Receptor, Epidermal Growth Factor; EC 2.7.11.24/p38 Mitogen-Activated Protein Kinases; EC 2.7.11.25/MAP Kinase Kinase Kinases; EC 2.7.11.25/MAP kinase kinase kinase 7

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