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

J. Biol. Chem., Vol. 283, Issue 9, 5554-5566, February 29, 2008

This Article Full Text Full Text (PDF) All Versions of this Article: 283/9/5554    most recent M708566200v1 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 Ruiz, S. Articles by Bustelo, X. R. Search for Related Content PubMed PubMed Citation Articles by Ruiz, S. Articles by Bustelo, X. R. Social Bookmarking                      What's this?

CD147 Inhibits the Nuclear Factor of Activated T-cells by Impairing Vav1 and Rac1 Downstream Signaling^*

From the Centro de Investigación del Cáncer and Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Científicas-University of Salamanca, Campus Unamuno, E-37007 Salamanca, Spain

CD147 is a transmembrane protein that plays crucial roles in the development and function of the reproductive, visual, and nervous systems. CD147 also exerts positive and negative actions in T-cells by still obscure mechanisms. In this study, we have analyzed the expression, localization, and function of CD147 during T-cell receptor signaling responses. We show here that CD147 is an integral component of the T-cell immune synapse and that its overexpression leads to the inhibition of NF-AT (nuclear factor of activated T-cells) activity induced by Vav1, a Rac1 exchange factor. This inhibitory activity is mediated by the CD147 intracellular tail and is totally independent of its extracellular or transmembrane regions. The molecular dissection of the influence of CD147 on the Vav1 pathway indicates that its inhibitory action takes place downstream of Vav1 and Rac1 but upstream of the serine/threonine kinases JNK and Pak1. The interference of CD147 with these pathways is highly specific because the overexpression of CD147 does not affect the activity of other GDP/GTP exchange factors or the stimulation of the ERK cascade. Finally, we show that the CD147 knockdown in Jurkat cells promotes higher levels of NF-AT stimulation and Pak1 phosphorylation upon T-cell receptor cross-linking. Instead, the lack of CD147 does not affect other signaling cascades that participate in the same cellular response. Taken together, these results indicate that CD147, via the selective inhibition of specific downstream elements of the Vav1/Rac1 route, contributes to the negative regulation of T-cell responses.

Received for publication, October 16, 2007 , and in revised form, December 5, 2007.

^* This work was co-sponsored by the European Union FEDER program. 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 Supported in part by the NCI, National Institutes of Health, and the Spanish Ministry of Education and Science Juan de la Cierva program.

² Supported by Spanish Ministry of Education and Science FPU Graduate Student Fellowship AP-2004-0369.

³ To whom correspondence should be addressed: Centro de Investigación del Cáncer, CSIC, University of Salamanca, Campus Unamuno, E-37007 Salamanca, Spain. Tel.: 34-923-294802; Fax: 34-923-294743; E-mail: xbustelo{at}usal.es.

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