Myotubularin-related protein 7 activates peroxisome proliferator-activated receptor-gamma.
- Weidner P Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
- Söhn M Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
- Schroeder T Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
- Helm L Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
- Hauber V Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
- Gutting T Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
- Betge J Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
- Röcken C Department of Pathology, Christian-Albrechts University, Kiel, Germany.
- Rohrbacher FN Department of Organic Chemistry, ETH Zürich, Zürich, Switzerland.
- Pattabiraman VR Department of Organic Chemistry, ETH Zürich, Zürich, Switzerland.
- Bode JW Department of Organic Chemistry, ETH Zürich, Zürich, Switzerland.
- Seger R Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel.
- Saar D Heidelberg Institute for Theoretical Studies (HITS), Heidelberg, Germany.
- Nunes-Alves A Heidelberg Institute for Theoretical Studies (HITS), Heidelberg, Germany.
- Wade RC Heidelberg Institute for Theoretical Studies (HITS), Heidelberg, Germany.
- Ebert MPA Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
- Burgermeister E Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany. elke.burgermeister@medma.uni-heidelberg.de.
- 2020-06-12
Published in:
- Oncogenesis. - 2020
English
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.
- Language
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- English
- Open access status
- gold
- Identifiers
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- DOI 10.1038/s41389-020-0238-8
- PMID 32522977
- Persistent URL
- https://sonar.ch/global/documents/238687
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