MCB Accepts, published online ahead of print on 5 February 2007

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Mol. Cell. Biol. doi:10.1128/MCB.01482-06
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Mitogenic Activity and Signaling Mechanism of 2-(14,15-epoxyeicosatrienoyl)glycerol, a Novel cP450 Arachidonate Metabolite

Jianchun Chen, Jian-Kang Chen, John R. Falck, Siddam Anjaiah, Jorge H. Capdevila, and Raymond C. Harris^*

Departments of Medicine and Biochemistry, Vanderbilt University, Nashville, TN 37232; and Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390

^* To whom correspondence should be addressed. Email: ray.harris{at}vanderbilt.edu.

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 (HETEs). 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 (TACE, ADAM17), which cleaves membrane bound transforming growth factor-alpha (proTGF- ) and releases soluble TGF- as a ligand that binds and activates EGFR. The present studies additionally demonstrate that the structurally-related 14,15-epoxyeicosatrienoic acid (14,15-EET) stimulates release of soluble heparin-binding epidermal growth factor-like growth factor (HB-EGF) 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.

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