Weidner P Söhn M Schroeder T Helm L Hauber V Gutting T Betge J Röcken C Rohrbacher FN Pattabiraman VR Bode JW Seger R Saar D Nunes-Alves A Wade RC Ebert MPA Burgermeister E 2020 Peroxisome proliferator-activated receptor-gamma (PPARγ) is a transcription factor drugable by agonists approved for treatment of type 2 diabetes, but also inhibits carcinogenesis and cell proliferation in vivo. Activating mutations in the Kirsten rat sarcoma viral oncogene homologue (KRAS) gene mitigate these beneficial effects by promoting a negative feedback-loop comprising extracellular signal-regulated kinase 1/2 (ERK1/2) and mitogen-activated kinase kinase 1/2 (MEK1/2)-dependent inactivation of PPARγ. To overcome this inhibitory mechanism, we searched for novel post-translational regulators of PPARγ. Phosphoinositide phosphatase Myotubularin-Related-Protein-7 (MTMR7) was identified as cytosolic interaction partner of PPARγ. Synthetic peptides were designed resembling the regulatory coiled-coil (CC) domain of MTMR7, and their activities studied in human cancer cell lines and C57BL6/J mice. MTMR7 formed a complex with PPARγ and increased its transcriptional activity by inhibiting ERK1/2-dependent phosphorylation of PPARγ. MTMR7-CC peptides mimicked PPARγ-activation in vitro and in vivo due to LXXLL motifs in the CC domain. Molecular dynamics simulations and docking predicted that peptides interact with the steroid receptor coactivator 1 (SRC1)-binding site of PPARγ. Thus, MTMR7 is a positive regulator of PPARγ, and its mimicry by synthetic peptides overcomes inhibitory mechanisms active in cancer cells possibly contributing to the failure of clinical studies targeting PPARγ. application/pdf https://sonar.ch/global/documents/238687 eng info:eu-repo/semantics/altIdentifier/doi/10.1038/s41389-020-0238-8 info:eu-repo/semantics/altIdentifier/pmid/32522977 info:eu-repo/semantics/openAccess Oncogenesis. - 2020 Cancer Research Molecular Biology Myotubularin-related protein 7 activates peroxisome proliferator-activated receptor-gamma. http://purl.org/coar/resource_type/c_6501