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

J. Biol. Chem., Vol. 282, Issue 45, 32890-32901, November 9, 2007

This Article Full Text Full Text (PDF) All Versions of this Article: 282/45/32890    most recent M702677200v1 Alert me when this article is cited 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 Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Singh, A. B. Articles by Harris, R. C. Search for Related Content PubMed PubMed Citation Articles by Singh, A. B. Articles by Harris, R. C. Social Bookmarking                      What's this?

Juxtacrine Activation of Epidermal Growth Factor (EGF) Receptor by Membrane-anchored Heparin-binding EGF-like Growth Factor Protects Epithelial Cells from Anoikis While Maintaining an Epithelial Phenotype^*

From the Department of Medicine, Vanderbilt University, Nashville, Tennessee 37232

Loss of cell-matrix adhesion is often associated with acute epithelial injury, suggesting that "anoikis" may be an important contributor to cell death. Resistance against anoikis is a key characteristic of transformed cells. When nontransformed epithelia are injured, activation of the epidermal growth factor (EGF) receptor (EGFR) by paracrine/autocrine release of soluble ligands can induce a prosurvival program, but there is generally evidence for concomitant dedifferentiation. The EGFR ligand, heparin-binding EGF-like growth factor (HB-EGF), is synthesized as a membrane-anchored precursor that can activate the EGFR via juxtacrine signaling or can be released and act as a soluble growth factor. In Madin-Darby canine kidney cells, expression of membrane-anchored HB-EGF increases cell-cell and cell-matrix adhesion. Therefore, these studies were designed to test the effects of juxtacrine HB-EGF signaling upon cell survival and epithelial integrity when cells are denied proper cell-matrix interactions. Cells expressing a noncleavable mutated form of membrane-anchored HB-EGF demonstrated increased survival from anoikis, formed larger cell aggregates, and maintained epithelial characteristics even following prolonged detachment from the substratum. Physical association between membrane-anchored HB-EGF and EGFR was observed. Signaling studies indicated synergistic effects of EGFR activation and phosphatidylinositol 3-kinase signaling to regulate apoptotic and survival pathways. In contrast, although administration of exogenous EGF partially suppressed anoikis in wild type cells, it also led to an increased expression of mesenchymal markers, suggesting dedifferentiation. Taken together, we propose a novel role for membrane-anchored HB-EGF in the cytoprotection of epithelial cells.

Received for publication, March 28, 2007 , and in revised form, September 10, 2007.

^* This work was supported by funds from the Department of Veterans Affairs and National Institutes of Health Grant DK51265 (to R. C. H.) and AHA-Scientist Development Grant 0435471N (to A. B. S.). 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: C-3121 Medical Center North, Dept. of Medicine, Vanderbilt University, Nashville, TN 37232-4794. Tel.: 615-343-0030; Fax: 615-343-7156; E-mail: ray.harris{at}vanderbilt.edu.

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