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

J. Biol. Chem., Vol. 282, Issue 21, 15606-15618, May 25, 2007

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 282/21/15606    most recent M611004200v1 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 HighWire Citing Articles via Google Scholar Google Scholar Articles by Mitchell, D. Articles by Godson, C. Search for Related Content PubMed PubMed Citation Articles by Mitchell, D. Articles by Godson, C. Social Bookmarking                      What's this?

The Lipoxin A₄ Receptor Is Coupled to SHP-2 Activation

IMPLICATIONS FOR REGULATION OF RECEPTOR TYROSINE KINASES^*

Derick Mitchell¹, Sarah J. O'Meara, Andrew Gaffney, John K. G. Crean, B. Therese Kinsella, and Catherine Godson²

From the School of Medicine and Medical Science and the School of Biomolecular and Biomedical Science, Diabetes Research Centre, UCD Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland

Mesangial cell proliferation is pivotal to the pathology of glomerular injury in inflammation. We have previously reported that lipoxins, endogenously produced eicosanoids with anti-inflammatory and pro-resolution bioactions, can inhibit mesangial cell proliferation in response to several agents. This process is associated with elaborate receptor cross-talk involving modification receptor tyrosine kinase phosphorylation (McMahon, B., Mitchell, D., Shattock, R., Martin, F., Brady, H. R., and Godson, C. (2002) FASEB J. 16, 1817–1819). Here we demonstrate that the lipoxin A₄ (LXA₄) receptor is coupled to activation and recruitment of the SHP-2 (SH2 domain-containing tyrosine phosphatase-2) within a lipid raft microdomain. Using site-directed mutagenesis of the cytosolic domain of the platelet-derived growth factor receptor (PDGFR), we report that mutation of the sites for phosphatidylinositol 3-kinase (Tyr⁷⁴⁰ and Tyr⁷⁵¹) and SHP-2 (Tyr⁷⁶³ and Tyr¹⁰⁰⁹) recruitment specifically inhibit the effect of LXA₄ on the PDGFR signaling; furthermore inhibition of SHP-2 expression with short interfering RNA constructs blocked the effect of LXA₄ on PDGFR phosphorylation. We demonstrate that association of the PDGFR with lipid raft microdomains renders it susceptible to LXA₄-mediated dephosphorylation by possible reactivation of oxidatively inactivated SHP-2. These data further elaborate on the potential mechanisms underlying the anti-inflammatory, proresolution, and anti-fibrotic bioactions of lipoxins.

Received for publication, November 29, 2006 , and in revised form, March 29, 2007.

^* This work was supported by the Health Research Board, Ireland, Enterprise Ireland, The Wellcome Trust, European Commission FP6 Grant LSHM-CT-2004-0050333, Science Foundation Ireland, and The Government of Ireland Programme for Research in Third Level Institutions. 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. S1–S3 and supplemental text.

¹ Present address: Dept. of Pharmacology, New York University School of Medicine, New York, NY 10016.

² To whom correspondence should be addressed. Tel.: 353-1-716-6731; E-mail: catherine.godson{at}ucd.ie.

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

This article has been cited by other articles:

				Y. Decker, G. McBean, and C. Godson Lipoxin A4 inhibits IL-1{beta}-induced IL-8 and ICAM-1 expression in 1321N1 human astrocytoma cells Am J Physiol Cell Physiol, June 1, 2009; 296(6): C1420 - C1427. [Abstract] [Full Text] [PDF]

				N. Baker, S. J. O'Meara, M. Scannell, P. Maderna, and C. Godson Lipoxin A4: Anti-Inflammatory and Anti-Angiogenic Impact on Endothelial Cells J. Immunol., March 15, 2009; 182(6): 3819 - 3826. [Abstract] [Full Text] [PDF]

				V. Starosta, K. Pazdrak, I. Boldogh, T. Svider, and A. Kurosky Lipoxin A4 Counterregulates GM-CSF Signaling in Eosinophilic Granulocytes J. Immunol., December 15, 2008; 181(12): 8688 - 8699. [Abstract] [Full Text] [PDF]