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Papers In Press, published online ahead of print February 3, 2003
J. Biol. Chem, 10.1074/jbc.M212665200
Submitted on December 12, 2002
Revised on February 3, 2003
Accepted on February 3, 2003

Prostaglandin E2 induced functional expression of early growth response factor-1 by EP4, but not EP2, prostanoid receptors via the phosphatidylinositol 3-kinase and extracellular signal-regulated kinases

Hiromichi Fujino, Wei Xu, and John W. Regan

Pharmacology & Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ 85721-0207

Corresponding Author: regan{at}pharmacy.arizona.edu

Prostaglandin E2 (PGE2) mediates its physiological effects by interactions with a subfamily of G-protein coupled receptors known as EP receptors. These receptors consist of four primary subtypes named EP1, EP2, EP3 and EP4. The EP2 and EP4 subtypes are known to couple to G{alphas} and stimulate intracellular cyclic 3, 5-adenosine monophosphate formation, while the EP1 and EP3 receptors are known to couple to G{alphaq} and G{alphai}, respectively. Recently we found that EP2 and EP4 receptors can activate T-cell factor signaling; however, EP2 receptors did this primarily through a protein kinase A dependent pathway, whereas EP4 receptors primarily utilized a phosphatidylinositol 3-kinase (PI3K) dependent pathway (Fujino et al. (2002) J. Biol. Chem. 277, 2614-2619). We now report that PGE2 stimulation of EP4 receptors, but not EP2 receptors, leads to phosphorylation of the extracellular signal-regulated kinases (ERKs) through a PI3K dependent mechanism. Furthermore, this activation of PI3K/ERKs signaling by the EP4 receptors induces the functional expression of early growth response factor-1 (EGR-1). Under the same conditions induction of EGR-1 protein expression was not observed following PGE2 stimulation of EP2 receptors. These findings point to important differences in the signaling potential of the EP2 and EP4 receptors which could be significant with respect to the potential involvement of EP4 receptors in inflammation and cancer.


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