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EP2 Induces p38 Phosphorylation via the Activation of Src in HEK 293 Cells
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  • Journal title : Biomolecules and Therapeutics
  • Volume 23, Issue 6,  2015, pp.539-548
  • Publisher : The Korean Society of Applied Pharmacology
  • DOI : 10.4062/biomolther.2015.043
 Title & Authors
EP2 Induces p38 Phosphorylation via the Activation of Src in HEK 293 Cells
Chun, Kyung-Soo; Shim, Minsub;
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Prostaglandin (), a major product of cyclooxygenase, binds to four different prostaglandin receptors (EP1, EP2, EP3, and EP4) which are G-protein coupled transmembrane receptors (GPCRs). Although GPCRs including EP receptors have been shown to be associated with their specific G proteins, recent evidences suggest that GPCRs can regulate MAPK signaling via non-G protein coupled pathways including Src. EP2 is differentially expressed in various tissues and the expression of EP2 is induced by extracellular stimuli. We hypothesized that an increased level of EP2 expression may affect MAPK signaling. The overexpression of EP2 in HEK 293 cells resulted in significant increase in intracellular cAMP levels response to treatment with butaprost, a specific EP2 agonist, while overexpression of EP2 alone did not increase intracellular cAMP levels. However, EP2 overexpression in the absence of induced an increase in the level of p38 phosphorylation as well as the kinase activity of p38, suggesting that up-regulation of EP2 may promote p38 activation via non-G protein coupled pathway. Inhibition of Src completely blocked EP2-induced p38 phosphorylation and overexpression of Src increased the level of p38 phosphorylation, indicating that Src is upstream kinase for EP2-induced p38 phosphorylation. EP2 overexpression also increased the Src activity and EP2 protein was co-immunoprecipitated with Src. Furthermore, sequential co-immunoprecipitation studies showed that EP2, Src, and -arrestin can form a complex. Our study found a novel pathway in which EP2 is associated with Src, regulating p38 pathway.
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