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J. Biol. Chem., Vol. 281, Issue 34, 24575-24587, August 25, 2006

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Peroxisome Proliferator-activated Receptor Promotes Epithelial to Mesenchymal Transformation by Rho GTPase-dependent Activation of ERK1/2^*

From the Department of Cancer Biology, Mayo Clinic Comprehensive Cancer Center, Jacksonville, Florida 32224

Peroxisome proliferator-activated receptor (PPAR) causes epithelial to mesenchymal transformation (EMT) in intestinal epithelial cells, as evidenced by reorganization of the actin cytoskeleton, acquisition of a polarized, mesenchymal cellular morphology, increased cellular motility, and colony scattering. This response is due to activation of Cdc42, resulting in p21-activated kinase-dependent phosphorylation and activation of MEK1 Ser²⁹⁸ and activation of ERK1/2. Dominant negative MEK1, MEK2, and ERK2 block PPAR-induced EMT, whereas constitutively active MEK1 and MEK2 induce a mesenchymal phenotype similar to that evoked by PPAR. PPAR also stimulates ERK1/2 phosphorylation in the intestinal epithelium in vivo. PPAR induces the p110 subunit of phosphoinositide 3-kinase (PI3K), and inhibition of PI3K blocks PPAR-dependent phosphorylation of MEK1 Ser²⁹⁸, activation of ERK1/2, and EMT. We conclude that PPAR regulates the motility of intestinal epithelial cells through a mitogen-activated protein kinase cascade that involves PI3K, Cdc42, p21-activated kinase, MEK1, and ERK1/2. Regulation of cellular motility through Rho family GTPases has not been previously reported for nuclear receptors, and elucidation of the mechanism that accounts for the role of PPAR in regulating motility of intestinal epithelial cells provides fundamental new insight into the function of this receptor during renewal of the intestinal epithelium.

Received for publication, May 1, 2006 , and in revised form, June 29, 2006.

^* This work was supported in part by a grant from Sankyo Co., LTD and by National Institutes of Health Grants CA24347 and CA121349 (to E. A. T.). 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.

¹ To whom correspondence should be addressed: 4500 San Pablo Rd. Griffin Cancer Research Bldg., RM 304, Jacksonville, FL 32224. Tel.: 904-953-6226; E-mail: thompson.aubrey{at}mayo.edu.

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