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Molecular and Cellular Biology, April 2007, p. 3023-3034, Vol. 27, No. 8
0270-7306/07/$08.00+0     doi:10.1128/MCB.01482-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Mitogenic Activity and Signaling Mechanism of 2-(14,15- Epoxyeicosatrienoyl)Glycerol, a Novel Cytochrome P450 Arachidonate Metabolite{triangledown} ,{dagger}

Jianchun Chen,1 Jian-Kang Chen,1 John R. Falck,3 Siddam Anjaiah,3 Jorge H. Capdevila,1,2 and Raymond C. Harris1*

Departments of Medicine,1 Biochemistry Vanderbilt University, Nashville, Tennessee 37232,2 Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 753903

Received 9 August 2006/ Returned for modification 27 October 2006/ Accepted 22 January 2007

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.

* Corresponding author. Mailing address: C-3121 Medical Center North, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232. Phone: (615) 343-0030. Fax: (615) 343-7156. E-mail: ray.harris{at}vanderbilt.edu

{triangledown} Published ahead of print on 5 February 2007.

{dagger} Supplemental material for this article may be found at http//:mcb.asm.org/.

Molecular and Cellular Biology, April 2007, p. 3023-3034, Vol. 27, No. 8
0270-7306/07/$08.00+0     doi:10.1128/MCB.01482-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Spector, A. A. (2009). Arachidonic acid cytochrome P450 epoxygenase pathway. J. Lipid Res. 50: S52-S56 [Abstract] [Full Text]  
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