cPGES [cytosolic PG (prostaglandin) E synthase] is constitutively expressed in various cells and can regulate COX (cyclo-oxygenase)-1-dependent immediate PGE2 generation. In the present study, we found that cPGES underwent serine phosphorylation, which was accelerated transiently after cell activation. Several lines of evidence suggest that a cPGES-activating protein kinase is CK-II (casein kinase II). Recombinant cPGES was phosphorylated directly by and associated with CK-II in vitro, resulting in marked reduction of the Km for the substrate PGH2. In activated cells, cPGES phosphorylation occurred in parallel with increased cPGES enzymic activity and PGE2 production from exogenous and endogenous arachidonic acid, and these processes were facilitated by Hsp90 (heat-shock protein 90), a molecular chaperone that formed a tertiary complex with cPGES and CK-II. Treatment of cells with inhibitors of CK-II and Hsp90 and with a dominant-negative CK-II attenuated the formation of the cPGES–CK-II–Hsp90 complex and attendant cPGES phosphorylation and activation. Mutations of either of two predicted CK-II phosphorylation sites on cPGES (Ser113 and Ser118) abrogated its phosphorylation and activation both in vitro and in vivo. Moreover, the CK-II–Hsp90-mediated activation of cPGES was ameliorated by the p38 mitogen-activated protein kinase inhibitor SB20358 or by the anti-inflammatory glucocorticoid dexamethasone. Taken together, the results of the present study have provided 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.
Skip Nav Destination
Article navigation
July 2004
-
Cover Image
Cover Image
- PDF Icon PDF LinkFront Matter
- PDF Icon PDF LinkTable of Contents
- PDF Icon PDF LinkEditorial Board
Research Article|
June 22 2004
Regulation of cytosolic prostaglandin E synthase by phosphorylation
Tsuyoshi KOBAYASHI;
Tsuyoshi KOBAYASHI
*Department of Health Chemistry, School of Pharmaceutical Sciences, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan
Search for other works by this author on:
Yoshihito NAKATANI;
Yoshihito NAKATANI
*Department of Health Chemistry, School of Pharmaceutical Sciences, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan
Search for other works by this author on:
Toshihiro TANIOKA;
Toshihiro TANIOKA
*Department of Health Chemistry, School of Pharmaceutical Sciences, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan
†Laboratory of Cellular Chemistry, RIKEN, 2-1 Wako-shi, Saitama 351-0198, Japan
Search for other works by this author on:
Masafumi TSUJIMOTO;
Masafumi TSUJIMOTO
†Laboratory of Cellular Chemistry, RIKEN, 2-1 Wako-shi, Saitama 351-0198, Japan
Search for other works by this author on:
Shigeo NAKAJO;
Shigeo NAKAJO
‡Laboratory of Biological Chemistry, School of Pharmaceutical Sciences, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan
Search for other works by this author on:
Kazuyasu NAKAYA;
Kazuyasu NAKAYA
‡Laboratory of Biological Chemistry, School of Pharmaceutical Sciences, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan
Search for other works by this author on:
Makoto MURAKAMI;
Makoto MURAKAMI
*Department of Health Chemistry, School of Pharmaceutical Sciences, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan
Search for other works by this author on:
Ichiro KUDO
Ichiro KUDO
1
*Department of Health Chemistry, School of Pharmaceutical Sciences, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan
1To whom correspondence should be addressed (e-mail kudo@pharm.showa-u.ac.jp).
Search for other works by this author on:
Publisher: Portland Press Ltd
Received:
January 21 2004
Revision Received:
March 24 2004
Accepted:
March 25 2004
Accepted Manuscript online:
March 25 2004
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London
2004
Biochem J (2004) 381 (1): 59–69.
Article history
Received:
January 21 2004
Revision Received:
March 24 2004
Accepted:
March 25 2004
Accepted Manuscript online:
March 25 2004
Citation
Tsuyoshi KOBAYASHI, Yoshihito NAKATANI, Toshihiro TANIOKA, Masafumi TSUJIMOTO, Shigeo NAKAJO, Kazuyasu NAKAYA, Makoto MURAKAMI, Ichiro KUDO; Regulation of cytosolic prostaglandin E synthase by phosphorylation. Biochem J 1 July 2004; 381 (1): 59–69. doi: https://doi.org/10.1042/BJ20040118
Download citation file:
Sign in
Don't already have an account? Register
Sign in to your personal account
You could not be signed in. Please check your email address / username and password and try again.
Captcha Validation Error. Please try again.