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, 5402-5413, February 29, 2008

This Article Full Text Full Text (PDF) All Versions of this Article: 283/9/5402    most recent M706462200v1 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 Jia, S. H. Articles by Marshall, J. C. Search for Related Content PubMed PubMed Citation Articles by Jia, S. H. Articles by Marshall, J. C. Social Bookmarking                      What's this?

Dynamic Regulation of Neutrophil Survival through Tyrosine Phosphorylation or Dephosphorylation of Caspase-8^*

Song Hui Jia, Jean Parodo, Andras Kapus, Ori D. Rotstein, and John C. Marshall^¶1

From the Department of Surgery and the ^¶Interdepartmental Division of Critical Care Medicine, University of Toronto, Toronto, Ontario and the Sepsis Research Laboratory, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario M5B 1W8, Canada

Efficient expression of innate immunity is critically dependent upon the capacity of the neutrophil to be activated rapidly in the face of an acute threat and to involute once that threat has been eliminated. Here we report a novel mechanism regulating neutrophil survival dynamically through the tyrosine phosphorylation or dephosphorylation of caspase-8. Caspase-8 is tyrosine-phosphorylated in freshly isolated neutrophils but spontaneously dephosphorylates in culture, in association with the progression of constitutive apoptosis. Phosphorylation of caspase-8 on Tyr-310 facilitates its interaction with the Src-homology domain 2 containing tyrosine phosphatase-1 (SHP-1) and enables SHP-1 to dephosphorylate caspase-8, permitting apoptosis to proceed. The non-receptor tyrosine kinase, Lyn, can phosphorylate caspase-8 on Tyr-397 and Tyr-465, rendering it resistant to activational cleavage and inhibiting apoptosis. Exposure to lipopolysaccharide reduces SHP-1 activity and binding to caspase-8, caspase-8 activity, and rates of spontaneous apoptosis. SHP-1 activity is reduced and Lyn increased in neutrophils from patients with sepsis, in association with profoundly delayed apoptosis; inhibition of Lyn can partially reverse this delay. Thus the phosphorylation and dephosphorylation of caspase-8, mediated by Lyn and SHP-1, respectively, represents a novel, dynamic post-translational mechanism for the regulation of neutrophil apoptosis whose dysregulation contributes to persistent neutrophil survival in sepsis.

Received for publication, August 6, 2007 , and in revised form, November 14, 2007.

^* This work was supported by the Canadian Institutes for Health Research (Grant MOP62908). 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: St. Michael's Hospital, 4th Floor Bond Wing, Rm. 4-007, 30 Bond St., Toronto M5B 1W8, Ontario. Tel.: 416-864-5225; Fax: 416-864-5141; E-mail: marshallj{at}smh.toronto.on.ca.

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