Current evidence suggests that two forms of prostaglandin (PG) E synthase (PGES), cytosolic PGES and membrane-bound PGES (mPGES) -1, preferentially lie downstream of cyclooxygenase (COX) -1 and -2, respectively, in the PGE 2 biosynthetic pathway. In this study, we examined the expression and functional aspects of the third PGES enzyme, mPGES-2, in mammalian cells and tissues. mPGES-2 was synthesized as a Golgi membrane-associated protein, and spontaneous cleavage of the N-terminal hydrophobic domain led to the formation of a truncated mature protein that was distributed in the cytosol with a trend to be enriched in the perinuclear region. In several cell lines, mPGES-2 promoted PGE 2 production via both COX-1 and COX-2 in the immediate and delayed responses with modest COX-2 preference. In contrast to the marked inducibility of mPGES-1, mPGES-2 was constitutively expressed in various cells and tissues and was not increased appreciably during tissue inflammation or damage. Interestingly, a considerable elevation of mPGES-2 expression was observed in human colorectal cancer. Collectively, mPGES-2 is a unique PGES that can be coupled with both COXs and may play a role in the production of the PGE 2 involved in both tissue homeostasis and disease.Biosynthesis of prostaglandin (PG) 1 E 2 , which is produced by a variety of cells and tissues and exhibits diverse bioactivities, is mediated by three enzymatic reactions involving phospholipase A 2 (PLA 2 ), cyclooxygenase (COX), and PGE synthase (PGES). In this biosynthetic pathway, arachidonic acid (AA) released from membrane phospholipids by cytosolic or secretory PLA 2 s is converted to PGH 2 by COX-1 or COX-2 and is then isomerized to PGE 2 by terminal PGES enzymes.The constitutive COX-1 mainly promotes immediate PG production elicited by agonists promptly mobilizing intracellular Ca 2ϩ , a situation in which a burst release of AA occurs (1-5).The inducible COX-2 is essential for delayed PG generation induced by proinflammatory stimuli, during which AA is gradually supplied over long periods, and also promotes immediate PG production if it already exists in cells primed by particular stimuli (1-5). Current studies employing isozyme-specific inhibitors and knockout mice have revealed that the two COXs play distinct roles in vivo (6 -10), and segregated utilization of these enzymes at the cellular level has been explained not only by their distinct expression profiles but also by subtle differences in their AA requirement, hydroperoxide sensitivity, and subcellular localization (4, 11-13). In addition, selective coupling with various terminal PG synthases has also been shown to influence crucially the utilization of the two COX isoforms during the different phases of cell activation (14 -16). PGES enzymes, which lie downstream of COXs, occur in multiple forms in mammalian cells (1). Among them, a perinuclear membrane-bound form of PGES belonging to the MAPEG (for membrane-associated proteins involved in eicosanoid and glutathione metabolism) family, which we herein cal...

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