Peroxisome proliferator-activated receptor γ promotes epithelial to mesenchymal transformation by Rho GTPase-dependent activation of ERK1/2

Lu Chen, Brian M. Necela, Weidong Su, Masahiro Yanagisawa, Panagiotis Z Anastasiadis, Alan P Fields, E Aubrey Thompson

Research output: Contribution to journalArticle

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Abstract

Peroxisome proliferator-activated receptor γ (PPARγ) 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 Ser 298 and activation of ERK1/2. Dominant negative MEK1, MEK2, and ERK2 block PPARγ-induced EMT, whereas constitutively active MEK1 and MEK2 induce a mesenchymal phenotype similar to that evoked by PPARγ. PPARγ also stimulates ERK1/2 phosphorylation in the intestinal epithelium in vivo. PPARγ induces the p110α subunit of phosphoinositide 3-kinase (PI3K), and inhibition of PI3K blocks PPARγ-dependent phosphorylation of MEK1 Ser298, activation of ERK1/2, and EMT. We conclude that PPARγ 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 PPARγ in regulating motility of intestinal epithelial cells provides fundamental new insight into the function of this receptor during renewal of the intestinal epithelium.

Original languageEnglish (US)
Pages (from-to)24575-24587
Number of pages13
JournalJournal of Biological Chemistry
Volume281
Issue number34
DOIs
StatePublished - Aug 25 2006

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rho GTP-Binding Proteins
Peroxisome Proliferator-Activated Receptors
Epithelial-Mesenchymal Transition
Chemical activation
Phosphorylation
1-Phosphatidylinositol 4-Kinase
Phosphatidylinositols
p21-Activated Kinases
Gastrointestinal Motility
Phosphotransferases
Epithelial Cells
Intestinal Mucosa
GTP Phosphohydrolases
Cytoplasmic and Nuclear Receptors
Mitogen-Activated Protein Kinases
Actin Cytoskeleton
Actins
Scattering
Phenotype

ASJC Scopus subject areas

  • Biochemistry

Cite this

Peroxisome proliferator-activated receptor γ promotes epithelial to mesenchymal transformation by Rho GTPase-dependent activation of ERK1/2. / Chen, Lu; Necela, Brian M.; Su, Weidong; Yanagisawa, Masahiro; Anastasiadis, Panagiotis Z; Fields, Alan P; Thompson, E Aubrey.

In: Journal of Biological Chemistry, Vol. 281, No. 34, 25.08.2006, p. 24575-24587.

Research output: Contribution to journalArticle

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