Regulatory mechanisms for cytosolic prostaglandin E synthase, cPGES/p23

Abstract

We reported the molecular identification of cytosolic prostaglandin E synthase (cPGES), a terminal enzyme of the cyclooxygenase-mediated PGE₂ biosynthetic pathway. Of interest, it is identical to the co-chaperone p23 that binds to heat shock protein 90 (Hsp90). Association of cPGES/p23 and Hsp90 resulted in a remarkable increase in PGES activity in vitro. 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 PGE₂ 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 (Ser¹¹³ and Ser¹¹⁸) abrogated its phosphorylation and activation both in vitro and in vivo. These results provide the evidence that the cellular function of this eicosanoid-biosynthetic enzyme is under the control of a molecular chaperone and its client protein kinase.