title: The Ras inhibitors caveolin-1 and docking protein 1 activate peroxisome proliferator-activated receptor γ through spatial relocalization at helix 7 of its ligand-binding domain.
abstract: Peroxisome proliferator-activated receptor γ (PPARγ) is a transcription factor that promotes differentiation and cell survival in the stomach. PPARγ upregulates and interacts with caveolin-1 (Cav1), a scaffold protein of Ras/mitogen-activated protein kinases (MAPKs). The cytoplasmic-to-nuclear localization of PPARγ is altered in gastric cancer (GC) patients, suggesting a so-far-unknown role for Cav1 in spatial regulation of PPARγ signaling. We show here that loss of Cav1 accelerated proliferation of normal stomach and GC cells in vitro and in vivo. Downregulation of Cav1 increased Ras/MAPK-dependent phosphorylation of serine 84 in PPARγ and enhanced nuclear translocation and ligand-independent transcription of PPARγ target genes. In contrast, Cav1 overexpression sequestered PPARγ in the cytosol through interaction of the Cav1 scaffolding domain (CSD) with a conserved hydrophobic motif in helix 7 of PPARγ's ligand-binding domain. Cav1 cooperated with the endogenous Ras/MAPK inhibitor docking protein 1 (Dok1) to promote the ligand-dependent transcriptional activity of PPARγ and to inhibit cell proliferation. Ligand-activated PPARγ also reduced tumor growth and upregulated the Ras/MAPK inhibitors Cav1 and Dok1 in a murine model of GC. These results suggest a novel mechanism of PPARγ regulation by which Ras/MAPK inhibitors act as scaffold proteins that sequester and sensitize PPARγ to ligands, limiting proliferation of gastric epithelial cells.
authors.affiliation: Department of Medicine II, Universitätsklinikum Mannheim, Universität Heidelberg, Mannheim, Germany. elke.burgermeister@lrz.tum.de
authors.forename: Elke
authors.initials: E
authors.lastname: Burgermeister
authors.forename: Teresa
authors.initials: T
authors.lastname: Friedrich
authors.forename: Ivana
authors.initials: I
authors.lastname: Hitkova
authors.forename: Ivonne
authors.initials: I
authors.lastname: Regel
authors.forename: Henrik
authors.initials: H
authors.lastname: Einwächter
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Zimmermann
authors.forename: Christoph
authors.initials: C
authors.lastname: Röcken
authors.forename: Aurel
authors.initials: A
authors.lastname: Perren
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Wright
authors.forename: Roland M
authors.initials: RM
authors.lastname: Schmid
authors.forename: Rony
authors.initials: R
authors.lastname: Seger
authors.forename: Matthias P A
authors.initials: MP
authors.lastname: Ebert
mesh_terms: D000818:Animals; D001665:Binding Sites; D051242:Caveolin 1 / Q000502:physiology*; D049109:Cell Proliferation; D004268:DNA-Binding Proteins / Q000502:physiology*; D004847:Epithelial Cells / Q000473:pathology; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D047495:PPAR gamma / Q000737:chemistry / Q000378:metabolism*; D010750:Phosphoproteins / Q000502:physiology*; D016601:RNA-Binding Proteins / Q000502:physiology*; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000473:pathology; D018631:ras Proteins / Q000037:antagonists & inhibitors*
chemical_list: D051242:Caveolin 1; D004268:DNA-Binding Proteins; C489560:DOK1 protein, human; D047495:PPAR gamma; D010750:Phosphoproteins; D016601:RNA-Binding Proteins; D018631:ras Proteins