HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 282, Issue 17, 12698-12706, April 27, 2007

This Article Full Text Full Text (PDF) All Versions of this Article: 282/17/12698    most recent M608723200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Singhirunnusorn, P. Articles by Sakurai, H. Search for Related Content PubMed PubMed Citation Articles by Singhirunnusorn, P. Articles by Sakurai, H. Social Bookmarking                      What's this?

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

Pattama Singhirunnusorn, Yoko Ueno, Mitsuhiro Matsuo, Shunsuke Suzuki, Ikuo Saiki^¶, and Hiroaki Sakurai^¶1

From the Division of Pathogenic Biochemistry, Institute of Natural Medicine, Department of Anatomy, Graduate School of Medicine and Pharmaceutical Sciences, ^¶21st Century Center of Excellence Program, University of Toyama, Toyama 930-0194, Japan

Epidermal growth factor receptor (EGFR) has been shown to be activated by specific ligands as well as other cellular stimuli including tumor necrosis factor- (TNF-). In the present study, we found that cellular stress suppressed ligand-mediated EGFR activity. Both TNF- and osmotic stress rapidly induced phosphorylation of EGFR. This phosphorylation of EGFR and the activation of mitogen-activated protein kinases and NF-B occurred independently of the shedding of extracellular membrane-bound EGFR ligands and intracellular EGFR tyrosine kinase activity. Transforming growth factor--activated kinase 1 (TAK1) was involved in the TNF--induced signaling pathway to EGFR. In addition, experiments using chemical inhibitors and small interfering RNA demonstrated that p38 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- has opposite bifunctional activities in modulating the function of the EGFR.

Received for publication, September 11, 2006 , and in revised form, February 16, 2007.

^* This work was supported in part by a grant-in-aid for Scientific Research (C) (No. 17590055) and the 21st Century COE Program from the Ministry of Education, Culture, Sports, Science, and Technology, Japan. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement"in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Div. of Pathogenic Biochemistry, Inst. of Natural Medicine, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan. Tel.: 81-76-434-7636; Fax: 81-76-434-5058; E-mail: hsakurai{at}inm.u-toyama.ac.jp.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				T. Yamaoka, F. Yan, H. Cao, S. S. Hobbs, R. S. Dise, W. Tong, and D. B. Polk Transactivation of EGF receptor and ErbB2 protects intestinal epithelial cells from TNF-induced apoptosis PNAS, August 19, 2008; 105(33): 11772 - 11777. [Abstract] [Full Text] [PDF]