Mitogenic activity and signaling mechanism of 2-(14,15-epoxyeicosatrienoyl) glycerol, a novel cytochrome P450 arachidonate metabolite

Jianchun Chen, Jiankang Chen, John R. Falck, Siddam Anjaiah, Jorge H. Capdevila, Raymond C. Harris

Research output: Contribution to journalArticle

25 Scopus citations

Abstract

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 α (proTGF-α) and releases soluble TGF-α 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.

Original languageEnglish (US)
Pages (from-to)3023-3034
Number of pages12
JournalMolecular and Cellular Biology
Volume27
Issue number8
DOIs
StatePublished - Apr 2007

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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