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Papers In Press, published online ahead of print June 30, 2006
Mayo Clinic, Jacksonville, FL 32224
Corresponding Author: thompson.aubrey{at}mayo.edu
Peroxisome proliferator-activated recep-tor-gamma (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 re-sponse is due to activation of Cdc42, re-sulting in p21-activated kinase (PAK)-dependent phosphorylation and activation of MEK1 S298 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 phospho-inositide-3 kinase (PI3K) and inhibition of PI3K blocks PPAR-dependent phos-phorylation of MEK1 S298, activation of ERK1/2, and EMT. We conclude that PPAR regulates motility of intestinal epithelial cells through a MAPK cascade that involves PI3K, Cdc42, PAK, MEK1, and ERK1/2. Regulation of cellular motil-ity through Rho family GTPases has not been previously reported for nuclear re-ceptors, and elucidation of the mecha-nism 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.
J. Biol. Chem, 10.1074/jbc.M604147200
Submitted on May 1, 2006
Revised on June 29, 2006
Accepted on June 30, 2006
Peroxisome proliferator-activated receptor-gamma (PPAR
) promotes epithelial to mesenchymal transformation by Rho GTPase activation of ERK1/2
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