Mitogenic activity and signaling mechanism of 2-(14,15- epoxyeicosatrienoyl)glycerol, a novel cytochrome p450 arachidonate metabolite.
Arachidonic acid is an essential constituent of cell membranes that is esterified to the sn-2 position of glycerophospholipids and is released from selected phospholipid pools by tightly regulated phospholipase cleavage. Metabolism of the released arachidonic acid by the cytochrome P450 enzyme system (cP450) generates biologically active compounds, including epoxyeicosatrienoic acids (EETs) and hydroxyeicosatetraenoic acids. Here we report that 2-(14,15-epoxyeicosatrienoyl)glycerol (2-14,15-EG), a novel cP450 arachidonate metabolite produced in the kidney, is a potent mitogen for renal proximal tubule cells. This effect is mediated by activation of tumor necrosis factor alpha-converting enzyme (ADAM17), which cleaves membrane-bound transforming growth factor alpha (proTGF-alpha) and releases soluble TGF-alpha as a ligand that binds and activates epidermal growth factor receptor (EGFR). The present studies additionally demonstrate that the structurally related 14,15-EET stimulates release of soluble heparin-binding EGF-like growth factor as an EGFR ligand by activation of ADAM9, another member of the ADAM family. Thus, in addition to the characterization of 2-14,15-EG's mitogenic activity and signaling mechanism, our study provides the first example that two structurally related biologically active lipid mediators can activate different metalloproteinases and release different EGFR ligands in the same cell type to activate EGFR and stimulate cell proliferation.
Chen
Jianchun
J
C-3121 Medical Center North, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Chen
Jian-Kang
JK
Falck
John R
JR
Guthi
Jagadeesh Setti
JS
Anjaiah
Siddam
S
Capdevila
Jorge H
JH
Harris
Raymond C
RC
D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism; D000072198:ADAM17 Protein; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism*; D002460:Cell Line; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects; D066246:ErbB Receptors / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D005990:Glycerol / Q000737:chemistry / Q000494:pharmacology*; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000187:drug effects; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008934:Mitogens / Q000494:pharmacology*; D008954:Models, Biological; D050178:Monoglycerides / Q000737:chemistry / Q000494:pharmacology*; D034741:RNA, Small Interfering; D043882:Receptors, Cannabinoid / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013552:Swine; D016211:Transforming Growth Factor alpha / Q000378:metabolism
C519406:2-(14,15-epoxyeicosatrienoyl)glycerol; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D008934:Mitogens; D050178:Monoglycerides; D034741:RNA, Small Interfering; D043882:Receptors, Cannabinoid; D016211:Transforming Growth Factor alpha; D016718:Arachidonic Acid; D004815:Epidermal Growth Factor; C046782:14,15-epoxy-5,8,11-eicosatrienoic acid; D003577:Cytochrome P-450 Enzyme System; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases; D051722:ADAM Proteins; D000072198:ADAM17 Protein; D015126:8,11,14-Eicosatrienoic Acid; D005990:Glycerol