Regulation of Cytosolic Prostaglandin E Synthase

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Biosynthesis of prostaglandin E_2 (PGE_2), the most common prostanoid with potent and various biological activities, is regulated by three sequential steps of cyclooxygenase (COX) pathway. We reported the molecular identification of cytosolic prostaglandin E synthase (cPGES), a terminal enzyme of the COX-mediated PGE_2 biosynthetic pathway. Of interest, it is identical to the co-chaperone p23 that binds to heat shock protein 90 (Hsp90). Incubation of recombinant cPGES/p23 and Hsp90 resulted in a remarkable increase in PGES activity in vitro. Furthermore, A23187-induced PGE_2 generation in 3Y1 cells was suppressed by Hsp90 inhibitors, which destabilized the cPGES/p23-Hsp90 complex, and reduced cPGES/p23 activity and PGE_2 production to basal levels. Next, we found that cPGES/p23 underwent serine phosphorylation, which was accelerated transiently after cell activation. In activated cells, cPGES/p23 phosphorylation occurred in parallel with increased cPGES/p23 enzymic activity and PGE_2 production from exogenous and endogenous arachidonic acid, and these processes were facilitated by Hsp90 that formed a tertiary complex with cPGES/p23 and protein kinase CK2. Treatment of cells with inhibitors of CK2 and Hsp90 and with a dominant-negative CK2 attenuated the formation of the cPGES/p23-CK2-Hsp90 complex and attendant cPGES/p23 phosphorylation and activation. Mutations of either of two predicted CK2 phosphorylation sites on cPGES/p23 (Ser^<113> and Ser^<118>) abrogated its phosphorylation and activation both in vitro and in vivo. These results provide the first evidence that the cellular function of this eicosanoid-biosynthetic enzyme is under the control of a molecular chaperone and its client protein kinase.
2007-06-01

著者

Nakatani Yoshihito
Department Of Health Chemistry School Of Pharmaceutical Sciences Showa University

Regulation of Cytosolic Prostaglandin E Synthase

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