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Originally published In Press as doi:10.1074/jbc.M307827200 on September 9, 2003
J. Biol. Chem., Vol. 278, Issue 47, 46261-46269, November 21, 2003
Dependence of Peroxisome Proliferator-activated Receptor Ligand-induced Mitogen-activated Protein Kinase Signaling on Epidermal Growth Factor Receptor Transactivation*
Olivia S. Gardner  ,
Brian J. Dewar,
H. Shelton Earp¶||,
James M. Samet**, and
Lee M. Graves¶||
From the
Curriculum in Toxicology, the ¶Lineberger Comprehensive Cancer Center, the ||Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599 and the **Human Studies Division, National Health Effects and Environmental Research Laboratory, United States Environmental Protection Agency, Research Triangle Park, North Carolina 27711
Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors that function as ligand-activated transcription factors regulating lipid metabolism and homeostasis. In addition to their ability to regulate PPAR-mediated gene transcription, PPAR and  ligands have recently been shown to induce activation of mitogen-activated protein kinases (MAPKs), which in turn phosphorylate PPARs, thereby affecting transcriptional activity. However, the mechanism for PPAR ligand-dependent MAPK activation is unclear. In the current study, we demonstrate that various PPAR (nafenopin) and (ciglitazone and troglitazone) agonists rapidly induced extracellular signal-regulated kinase (Erk) and/or p38 phosphorylation in rat liver epithelial cells (GN4). The selective epidermal growth factor receptor (EGFR) kinase inhibitors, PD153035 and ZD1839 (Iressa), abolished PPAR and agonist-dependent Erk activation. Consistent with this, PPAR agonists increased tyrosine autophosphorylation of the EGFR as well as phosphorylation at a putative Src-specific site, Tyr845. Experiments with the Src inhibitor, PP2, and the antioxidant N-acetyl-L-cysteine revealed critical roles for Src and reactive oxygen species as upstream mediators of EGFR transactivation in response to PPAR ligands. Moreover, PPAR and ligands increased Src autophosphorylation as well as kinase activity. EGFR phosphorylation, in turn, led to Ras-dependent Erk activation. In contrast, p38 activation by PPAR and ligands occurred independently of Src, oxidative stress, the EGFR, and Ras. Interestingly, PPAR and agonists caused rapid activation of proline-rich tyrosine kinase or Pyk2; Pyk2 as well as p38 phosphorylation was reduced by intracellular Ca2+ chelation without an observable effect on EGFR and Erk activation, suggesting a possible role for Pyk2 as an upstream activator of p38. In summary, PPAR and ligands activate two distinct signaling cascades in GN4 cells leading to MAPK activation.
Received for publication, July 18, 2003
, and in revised form, September 5, 2003.
* This work was supported in part by the National Institute of Health with Public Health Service Grants ES04325 and CA81503 and Environmental Protection Agency Science to Achieve Results Award R-82921401-0. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
 Supported by the Susan G. Komen Foundation.
To whom correspondence should be addressed. Tel.: 919-966-0915; Fax: 919-966-5640; E-mail: lmg{at}med.unc.edu.
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Copyright © 2003 by the American Society for Biochemistry and Molecular Biology.
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