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

J. Biol. Chem., Vol. 283, Issue 49, 34352-34364, December 5, 2008

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 283/49/34352    most recent M803364200v1 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 Google Scholar Google Scholar Articles by Smadja-Lamère, N. Articles by Lavoie, J. N. Search for Related Content PubMed PubMed Citation Articles by Smadja-Lamère, N. Articles by Lavoie, J. N. Social Bookmarking                      What's this?

JNK-mediated Phosphorylation of Paxillin in Adhesion Assembly and Tension-induced Cell Death by the Adenovirus Death Factor E4orf4^*

Nicolas Smadja-Lamère, Marie-Chloé Boulanger¹, Claudia Champagne¹, Philip E. Branton, and Josée N. Lavoie²

From the Centre de Recherche en Cancérologie de l'Université Laval, L'Hôtel-Dieu de Québec, CRCHUQ, Québec, G1R 2J6, Canada and Departments of Biochemistry and the McGill Cancer Centre, McGill University, McIntyre Medical Bldg., 3655 Promenade Sir William Osler, Montreal, Québec H3G 1Y6, Canada

The adenovirus type 2 Early Region 4 ORF4 (E4orf4) protein induces a caspase-independent death program in tumor cells involving changes in actin dynamics that are functionally linked to cell killing. Because an increase in myosin II-based contractility is needed for the death of E4orf4-expressing cells, we have proposed that alteration of cytoskeletal tension is part of the signals engaging the death pathway. Yet the mechanisms involved are poorly defined. Herein, we show that the Jun N-terminal kinase JNK is activated in part through a pathway involving Src, Rho, and ROCK (Rho kinase) and contributes to dysregulate adhesion dynamics and to kill cells in response to E4orf4. JNK supports the formation of atypically robust focal adhesions, which are bound to the assembly of the peculiar actomyosin network typifying E4orf4-induced cell death and which are required for driving nuclear condensation. Remarkably, the dramatic enlargement of focal adhesions, actin remodeling, and cell death all rely on paxillin phosphorylation at Ser-178, which is induced by E4orf4 in a JNK-dependent way. Furthermore, we found that Ser-178-paxillin phosphorylation is necessary to decrease adhesion turnover and to enhance the time residency of paxillin at focal adhesions, promoting its recruitment from an internal pool. Our results indicate that perturbation of tensional homeostasis by E4orf4 involves JNK-regulated changes in paxillin adhesion dynamics that are required to engage the death pathway. Moreover, our findings support a role for JNK-mediated paxillin phosphorylation in adhesion growth and stabilization during tension signaling.

Received for publication, May 2, 2008 , and in revised form, September 24, 2008.

^* This work was supported by the Canadian Institutes of Health Research Operating Grant MOP-49450 (to J. N. L.), a maintenance Grant for the Cell imaging core facility (to J. N. L.), and by the National Cancer Institute of Canada (to P. E. B.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1 and 2.

¹ Both authors contributed equally to this work.

² A Senior Scholar from the Fond de la Recherche en Santé du Québec. To whom correspondence should be addressed: CRC, L'Hôtel-Dieu de Québec, CRCHUQ, 9 Rue McMahon, Québec, Qc. Canada, G1R 2J6. Tel.: 418-525-4444 (ext. 15120), Fax: 418-691-5439; E-mail: josee.lavoie{at}crhdq.ulaval.ca.

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