title: Signal transduction for proteinase-activated receptor-2-triggered prostaglandin E2 formation in human lung epithelial cells.
abstract: We investigated proteinase-activated receptor-2 (PAR(2))-triggered signal transduction pathways causing increased prostaglandin E(2) (PGE(2)) formation in human lung-derived A549 epithelial cells. The PAR(2) agonist, SLIGRL-NH(2) (Ser-Leu-Ile-Gly-Arg-Leu-amide), evoked immediate cytosolic Ca(2+) mobilization and delayed (0.5-3 h) PGE(2) formation. The PAR(2)-triggered PGE(2) formation was attenuated by inhibition of the following signal pathway enzymes: cyclooxygenases 1 and 2 (COX-1 and COX-2, respectively), cytosolic Ca(2+)-dependent phospholipase A(2) (cPLA(2)), 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-NH(2) 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-NH(2) 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-NH(2) elicited a Src inhibitor-blocked prompt (5 min) and transient phosphorylation of the EGFRK. SLIGRL-NH(2) 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-NH(2) also caused COX-1-dependent up-regulation of microsomal PGE synthase-1 (mPGES-1). We conclude that PAR(2)-triggered PGE(2) formation in A549 cells involves a coordinated up-regulation of COX-2 and mPGES-1 involving cPLA(2), increased cytosolic Ca(2+), PKC, Src, MEK-ERK, p38 MAPK, Src-mediated EGF receptor trans-activation, and also metabolic products of both COX-1 and COX-2.
authors.affiliation: Division of Physiology and Pathophysiology, School of Pharmaceutical Sciences, Kinki University, Higashi-Osaka, Japan.
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Kawao
authors.forename: Mami
authors.initials: M
authors.lastname: Nagataki
authors.forename: Keita
authors.initials: K
authors.lastname: Nagasawa
authors.forename: Satoko
authors.initials: S
authors.lastname: Kubo
authors.forename: Kelly
authors.initials: K
authors.lastname: Cushing
authors.forename: Tetsuyuki
authors.initials: T
authors.lastname: Wada
authors.forename: Fumiko
authors.initials: F
authors.lastname: Sekiguchi
authors.forename: Seiji
authors.initials: S
authors.lastname: Ichida
authors.forename: Morley D
authors.initials: MD
authors.lastname: Hollenberg
authors.forename: Wallace K
authors.initials: WK
authors.lastname: MacNaughton
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Nishikawa
authors.forename: Atsufumi
authors.initials: A
authors.lastname: Kawabata
mesh_terms: D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D051545:Cyclooxygenase 1 / Q000096:biosynthesis; D051546:Cyclooxygenase 2 / Q000096:biosynthesis; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D015232:Dinoprostone / Q000096:biosynthesis*; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008168:Lung / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology; D010766:Phosphorylation; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D044463:Receptor, PAR-1 / Q000819:agonists; D044464:Receptor, PAR-2 / Q000819:agonists / Q000502:physiology*; D011960:Receptors, Estrogen / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D012333:RNA, Messenger; D044463:Receptor, PAR-1; D044464:Receptor, PAR-2; D011960:Receptors, Estrogen; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D066246:ErbB Receptors; D048051:p38 Mitogen-Activated Protein Kinases; D015232:Dinoprostone; D002118:Calcium