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

J. Biol. Chem., Vol. 283, Issue 28, 19255-19264, July 11, 2008

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 283/28/19255    most recent M800209200v1 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 Zhong, M.-C. Articles by Veillette, A. Search for Related Content PubMed PubMed Citation Articles by Zhong, M.-C. Articles by Veillette, A. Social Bookmarking                      What's this?

Control of T Lymphocyte Signaling by Ly108, a Signaling Lymphocytic Activation Molecule Family Receptor Implicated in Autoimmunity^*

Ming-Chao Zhong¹ and André Veillette^¶2

From the Laboratory of Molecular Oncology, Clinical Research Institute of Montréal, Montréal, Québec H2W 1R7, Department of Medicine, University of Montréal, Montréal, Québec H3T 1J4, and ^¶Department of Medicine, McGill University, Montréal, Québec H3G 1Y6, Canada

The signaling lymphocytic activation molecule family of receptors has been implicated in the pathophysiology of autoimmunity in humans and mice. One member of the family, Ly108, was strongly linked to lupus susceptibility in mice. High expression of a Ly108 isoform, Ly108-1, was observed in lymphocytes of lupus-prone mice. Herein, we examined the molecular basis for the influence of Ly108 on lupus susceptibility by studying Ly108 signal transduction in T cells. We observed that Ly108 was able to mediate a tyrosine phosphorylation signal implicating Ly108, Vav-1, and c-Cbl in a manner strictly dependent on engagement of the extracellular domain of Ly108 and co-expression of the Src homology 2 (SH2) domain-containing adaptor signaling lymphocytic activation molecule (SLAM)-associated protein (SAP). Evaluation of T cells from mice carrying mutations in the SAP-FynT pathway indicated that Ly108-triggered protein tyrosine phosphorylation was due to the capacity of SAP to recruit FynT. Importantly, Ly108-1 was more apt at triggering tyrosine phosphorylation signals in T cells when compared with the predominant Ly108 isoform found in non-lupus-prone mice, Ly108-2. This difference was due in part to the presence in Ly108-1 of a unique intra-cytoplasmic tyrosine-based motif that promoted Ly108 signal transduction. Together these data provided a molecular explanation for the involvement of Ly108 in lupus susceptibility in mice.

Received for publication, January 9, 2008 , and in revised form, May 6, 2008.

^* This work was supported by grants from the National Cancer Institute of Canada, the Canadian Institutes of Health Research, and the Howard Hughes Medical Institute (to A. V.). 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. 1–4.

¹ Supported by a fellowship from the Canadian Institutes of Health Research-funded Clinical Research Institute of Montréal Training Program in Cancer Research.

² Holds the Canada Research Chair in Signaling in the Immune System and is a Howard Hughes Medical Institute International Scholar. To whom correspondence should be addressed: IRCM, 110 Pine Ave. West, Montréal, Québec, Canada H2W 1R7. Tel.: 514-987-5561; Fax: 514-987-5562; E-mail: veillea{at}ircm.qc.ca.

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