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

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 Gα_s and stimulate intracellular cyclic 3,5-adenosine monophosphate formation, whereas the EP₁ and EP₃ receptors are known to couple to Gα_q and Gα_i, respectively. Recently we found that EP₂ and EP₄ receptors can activate T-cell factor signaling; however, EP₂ receptors did this primarily through a cAMP-dependent protein kinase-dependent pathway, whereas EP₄ receptors primarily utilized a phosphatidylinositol 3-kinase (PI3K)-dependent pathway (Fujino, H., West, K. A., and Regan, J. W. (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/ERK 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.