Journal of Leukocyte Biology Myeloid cells, immune suppression, tumor immunology
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A more recent version of this article appeared on September 1, 2008

Published online before print June 11, 2008
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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0308197

Received for publication March 24, 2008.
Revised May 7, 2008.
Accepted for publication May 8, 2008.

Article

Regulation of cytosolic phospholipase A2{alpha} by hsp90 and a p54 kinase in okadaic acid-stimulated macrophages

Dawn E. Tucker *, Miguel A. Gijón *, Diane M. Spencer *, Zhi-Hua Qiu *, Michael H. Gelb {dagger}, and Christina C. Leslie *{ddagger}@

*Program in Cell Biology, National Jewish Medical and Research Center, Denver, Colorado, USA; {dagger}Departments of Chemistry and Biochemistry, University of Washington, Seattle, Washington, USA; and {ddagger}Departments of Pathology and Pharmacology, University of Colorado at Denver and Health Science Center, School of Medicine, Aurora, Colorado, USA

@ To whom correspondence should be addressed. E-mail: lesliec{at}njc.org.


  Abstract

In resident mouse peritoneal macrophages, group IVA cytosolic phospholipase A2 (cPLA2{alpha}) mediates arachidonic acid (AA) release and eicosanoid production in response to diverse agonists such as A23187, phorbol myristate acetate, zymosan, and the enterotoxin, okadaic acid (OA). cPLA2{alpha} is regulated by phosphorylation and by calcium that binds to the C2 domain and induces translocation from the cytosol to membranes. In contrast, OA activates cPLA2{alpha}-induced AA release and translocation to the Golgi in macrophages without an apparent increase in calcium. Inhibitors of heat shock protein 90 (hsp90), geldanamycin, and herbimycin blocked AA release in response to OA but not to A23187, PMA, or zymosan. OA, but not the other agonists, induced activation of a cytosolic serine/threonine 54-kDa kinase (p54), which phosphorylated cPLA2{alpha} in in-gel kinase assays and was associated with cPLA2{alpha} in immunoprecipitates. Activation of the p54 kinase was inhibited by geldanamycin. The kinase coimmunoprecipitated with hsp90 in unstimulated macrophages, and OA induced its loss from hsp90, concomitant with its association with cPLA2{alpha}. The results demonstrate a role for hsp90 in regulating cPLA2{alpha}-mediated AA release that involves association of a p54 kinase with cPLA2{alpha} upon OA stimulation.

Key Words: arachidonic acid • heat shock protein 90 • phosphorylation






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Copyright © 2008 by the Society for Leukocyte Biology.