Mitogenic activity and signaling mechanism of 2-(14,15- epoxyeicosatrienoyl)glycerol, a novel cytochrome p450 arachidonate metabolite.

Chen J, Chen JK, Falck JR, Guthi JS, Anjaiah S, Capdevila JH, Harris RC
Mol Cell Biol. 2007 27 (8): 3023-34

PMID: 17283047 · PMCID: PMC1899952 · DOI:10.1128/MCB.01482-06

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.

MeSH Terms (27)

8,11,14-Eicosatrienoic Acid ADAM17 Protein ADAM Proteins Animals Arachidonic Acid Cell Line Cytochrome P-450 Enzyme System Down-Regulation Enzyme Activation Epidermal Growth Factor Epithelial Cells ErbB Receptors Extracellular Signal-Regulated MAP Kinases Gene Expression Regulation, Enzymologic Glycerol Heparin-binding EGF-like Growth Factor Intercellular Signaling Peptides and Proteins Kidney Tubules, Proximal Membrane Proteins Mitogens Models, Biological Monoglycerides Receptors, Cannabinoid RNA, Small Interfering Signal Transduction Swine Transforming Growth Factor alpha

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