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 E(2) (PGE(2)) 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 EP(1), EP(2), EP(3), and EP(4). The EP(2) and EP(4) subtypes are known to couple to Galpha(s) and stimulate intracellular cyclic 3,5- adenosine monophosphate formation, whereas the EP(1) and EP(3) receptors are known to couple to Galpha(q) and Galpha(i), respectively. Recently we found that EP(2) and EP(4) receptors can activate T-cell factor signaling; however, EP(2) receptors did this primarily through a cAMP-dependent protein kinase-dependent pathway, whereas EP(4) 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 PGE(2) stimulation of EP(4) receptors, but not EP(2) 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 EP(4) 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 PGE(2) stimulation of EP(2) receptors. These findings point to important differences in the signaling potential of the EP(2) and EP(4) receptors, which could be significant with respect to the potential involvement of EP(4) receptors in inflammation and cancer.
Fujino
Hiromichi
H
Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, Arizona 85721-0207, USA.
Xu
Wei
W
Regan
John W
JW
D000730:Androstadienes / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000235:genetics*; D015232:Dinoprostone / Q000494:pharmacology*; D051766:Early Growth Response Protein 1; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D006801:Humans; D017874:Immediate-Early Proteins; D007668:Kidney / Q000166:cytology; D020935:MAP Kinase Signaling System / Q000502:physiology; D048057:Mitogen-Activated Protein Kinase 10; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D018078:Receptors, Prostaglandin E / Q000378:metabolism*; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D014157:Transcription Factors / Q000235:genetics*; D000077191:Wortmannin; D048051:p38 Mitogen-Activated Protein Kinases
D000730:Androstadienes; D004268:DNA-Binding Proteins; D015232:Dinoprostone; D051766:Early Growth Response Protein 1; D004791:Enzyme Inhibitors; D017874:Immediate-Early Proteins; D048057:Mitogen-Activated Protein Kinase 10; D020928:Mitogen-Activated Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011505:Protein-Tyrosine Kinases; D018078:Receptors, Prostaglandin E; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D014157:Transcription Factors; D000077191:Wortmannin; D048051:p38 Mitogen-Activated Protein Kinases; C497325:EGR1 protein, human; C545644:PTGER2 protein, human; C545650:PTGER4 protein, human