Published online before print January 19, 2006, doi: 10.1161/01.RES.0000204451.88147.96
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Submitted on June 15, 2005
Revised on December 16, 2005
Accepted on January 5, 2006
A Novel Prostaglandin E Receptor 4-Associated Protein Participates in Antiinflammatory Signaling
Kiyoshi Takayama ;
From the Leducq Center for Cardiovascular Research (K.T., G.K.S., P.L.); and Cardiovascular Division (M.T.C.), Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Mass. Current address for K.T.: Medicinal Research Center, Taisho Pharmaceutical Company, Ltd, Saitama, Japan.
* To whom correspondence should be addressed. E-mail: plibby{at}rics.bwh.harvard.edu.
Prostaglandin E2 exerts an antiinflammatory action by ligation of the heptahelical receptor EP4 in human macrophages. Because the mechanism by which EP4 receptor stimulation suppresses inflammatory activation in macrophages remains undefined, we sought interactors with the carboxyl-terminal cytoplasmic domain of the EP4 receptor. Yeast 2-hybrid screening of the human bone marrow cDNA library with the EP4 receptor as a bait identified a cDNA clone encoding a 669-amino acid protein, designated here as EP4 receptor-associated protein (EPRAP), which contains 8 ankyrin motifs that might recruit other signaling molecules. EPRAP bound to the full-length EP4 receptor in HEK293 cells cotransfected with V5-tagged EPRAP and FLAG-tagged EP4 receptor cDNA, as anti-FLAG antibody coimmunoprecipitated EPRAP with the EP4 receptor from the lysates of cotransfected cells. Human macrophages derived from peripheral blood monocytes expressed an approximately 70-kDa protein detected by Western blotting with a polyclonal anti-EPRAP antibody. Fluorescence immunohistochemistry colocalized EPRAP with the EP4 receptor in human atheromata. Interference with EPRAP function by small interference RNA limited prostaglandin E2-mediated suppression of chemokine expression in macrophages activated with lipopolysaccharide and tumor necrosis factor 
. In conclusion, the antiinflammatory action of prostaglandin E2 in macrophages involves EPRAP that associates directly with the cytoplasmic tail of EP4 receptor.
Key words: macrophage • arteriosclerosis • two-hybrid system techniques • prostaglandin receptor • ankyrin repeat
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