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

Peroxisome proliferator-activated receptor gamma (PPAR gamma) is a transcription factor that promotes differentiation and cell survival in the stomach. PPAR gamma upregulates and interacts with caveolin-1 (Cav1), a scaffold protein of Ras/mitogen-activated protein kinases (MAPKs). The cytoplasmic-to-nuclear localization of PPAR gamma is altered in gastric cancer (GC) patients, suggesting a so-far-unknown role for Cav1 in spatial regulation of PPAR gamma 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 PPAR gamma and enhanced nuclear translocation and ligand-independent transcription of PPAR gamma target genes. In contrast, Cav1 overexpression sequestered PPAR gamma in the cytosol through interaction of the Cav1 scaffolding domain (CSD) with a conserved hydrophobic motif in helix 7 of PPA gamma's ligand-binding domain. Cav1 cooperated with the endogenous Ras/MAPK inhibitor docking protein 1 (Dok1) to promote the ligand-dependent transcriptional activity of PPAR gamma and to inhibit cell proliferation. Ligand-activated PPAR gamma 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 PPAR gamma regulation by which Ras/MAPK inhibitors act as scaffold proteins that sequester and sensitize PPAR gamma to ligands, limiting proliferation of gastric epithelial cells.