RT Journal Article
SR Electronic
T1 Signal Transduction for Proteinase-Activated Receptor-2-Triggered Prostaglandin E<sub>2</sub> Formation in Human Lung Epithelial Cells
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 576
OP 589
DO 10.1124/jpet.105.089490
VO 315
IS 2
A1 Naoyuki Kawao
A1 Mami Nagataki
A1 Keita Nagasawa
A1 Satoko Kubo
A1 Kelly Cushing
A1 Tetsuyuki Wada
A1 Fumiko Sekiguchi
A1 Seiji Ichida
A1 Morley D. Hollenberg
A1 Wallace K. MacNaughton
A1 Hiroyuki Nishikawa
A1 Atsufumi Kawabata
YR 2005
UL http://jpet.aspetjournals.org/content/315/2/576.abstract
AB We investigated proteinase-activated receptor-2 (PAR2)-triggered signal transduction pathways causing increased prostaglandin E2 (PGE2) formation in human lung-derived A549 epithelial cells. The PAR2 agonist, SLIGRL-NH2 (Ser-Leu-Ile-Gly-Arg-Leu-amide), evoked immediate cytosolic Ca2+ mobilization and delayed (0.5-3 h) PGE2 formation. The PAR2-triggered PGE2 formation was attenuated by inhibition of the following signal pathway enzymes: cyclooxygenases 1 and 2 (COX-1 and COX-2, respectively), cytosolic Ca2+-dependent phospholipase A2 (cPLA2), the mitogen-activated protein kinases (MAPKs), mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK)-extracellular signal-regulated kinase (ERK) and p38 MAPK, Src family tyrosine kinase, epidermal growth factor (EGF) receptor tyrosine kinase (EGFRK), and protein kinase C (PKC), but not by inhibition of matrix metalloproteinases. SLIGRL-NH2 caused prompt (5 min) and transient ERK phosphorylation, blocked in part by inhibitors of PKC and tyrosine kinases but not by an EGFRK inhibitor. SLIGRL-NH2 also evoked a relatively delayed (15 min) and persistent (30 min) phosphorylation of p38 MAPK, blocked by inhibitors of Src and EGFRK but not by inhibitors of COX-1 or COX-2. SLIGRL-NH2 elicited a Src inhibitor-blocked prompt (5 min) and transient phosphorylation of the EGFRK. SLIGRL-NH2 up-regulated COX-2 protein and/or mRNA levels that were blocked by inhibition of p38 MAPK, EGFRK, Src, and COX-2 but not MEK-ERK. SLIGRL-NH2 also caused COX-1-dependent up-regulation of microsomal PGE synthase-1 (mPGES-1). We conclude that PAR2-triggered PGE2 formation in A549 cells involves a coordinated up-regulation of COX-2 and mPGES-1 involving cPLA2, increased cytosolic Ca2+, PKC, Src, MEK-ERK, p38 MAPK, Src-mediated EGF receptor trans-activation, and also metabolic products of both COX-1 and COX-2. The American Society for Pharmacology and Experimental Therapeutics