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Published online before print June 11, 2008

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(Journal of Leukocyte Biology. 2008;84:798-806.)
© 2008 by Society for Leukocyte Biology

Regulation of cytosolic phospholipase A₂ 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 and Christina C. Leslie^*,,1

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

¹ Correspondence: Department of Pediatrics, National Jewish Medical and Research Center, 1400 Jackson St., Denver, CO 80206, USA. E-mail: lesliec{at}njc.org

In resident mouse peritoneal macrophages, group IVA cytosolic phospholipase A₂ (cPLA₂) 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 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-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 in in-gel kinase assays and was associated with cPLA₂ 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. The results demonstrate a role for hsp90 in regulating cPLA₂-mediated AA release that involves association of a p54 kinase with cPLA₂ upon OA stimulation.

Key Words: arachidonic acid • heat shock protein 90 • phosphorylation • cytosolic phospholipase A₂