Docking complexes comprising mitogen-activated protein kinase kinase-1 (MEK1) and Ras-inhibitory scaffold/adapter proteins, caveolin-1 (Cav1) and docking protein-1 (Dok1), regulate subcellular compartmentalization and activity of the ligand-driven nuclear hormone receptor and transcription factor peroxisome proliferator-activated receptor-gamma (PPARg).This spatio-temporal control is achieved by sequestration to or release from membranes and the cytosol and exclusion from the nucleus. We found that Cav1 and Dok1 counteract the MEK1-dependent cytosolic retention of PPARg. Expression of Cav1 and Dok1 was lost in tissues and cell lines derived from patients with primary gastric cancer (GC), but regained in GC metastases. Consistent with this stage-specific expression in GC, Cav1 inhibited proliferation but increased hallmarks of GC progression: migration, anchorage-independent growth and drug resistance. Cav1-deficient mice suffered from gastric hyperplasia and enhanced sensitivity to gastric ulceration. Murine GC inApc1638N/+andCEA-SV40 T-antigen mice also showed loss of Cav1 and Dok1 similar to human primary GC. The PPARg-agonist rosiglitazone reactivated intratumoral expression of PPARg, Cav1 and Dok1 and inhibited growth of GC in vivo. In contrast, chemotherapeutic drugs up-regulated Cav1, Pleiotrophin and Wnt6 as novel chemoresistance factors in human and murine GC cells. Thus, specific docking complexes on the 3D-surface of PPARg were identified as the molecular determinants of its down-stream effector functions in GC. Intervention with these docking complexes may provide novel perspectives for therapy of human GC.