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Myotubularin-related protein 7 activates peroxisome proliferator-activated receptor-gamma

Philip Weidner1, Michaela Söhn1, Torsten Schroeder1

  • 1Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.

Oncogenesis
|June 12, 2020
PubMed

Insights

Myotubularin-Related-Protein-7 (MTMR7) activates Peroxisome proliferator-activated receptor-gamma (PPARγ), a key factor in diabetes and cancer. Synthetic peptides mimicking MTMR7 overcome cancer-related inhibition, offering new therapeutic potential.

Area of Science:

  • Molecular Biology
  • Oncology
  • Endocrinology

Background:

  • Peroxisome proliferator-activated receptor-gamma (PPARγ) agonists treat type 2 diabetes but are hindered in cancer treatment by KRAS mutations.
  • Activating KRAS mutations induce a feedback loop (ERK1/2/MEK1/2) that inactivates PPARγ, limiting its anti-cancer effects.

Purpose of the Study:

  • To identify novel post-translational regulators of PPARγ.
  • To develop strategies to overcome KRAS-mediated inhibition of PPARγ for potential cancer therapy.

Main Methods:

  • Identified Myotubularin-Related-Protein-7 (MTMR7) as a PPARγ interaction partner.
  • Designed and tested synthetic MTMR7 coiled-coil (CC) domain peptides.
  • Utilized molecular dynamics simulations and docking to predict peptide-PPARγ interactions.

Main Results:

  • MTMR7 forms a complex with PPARγ, enhancing its transcriptional activity by inhibiting ERK1/2-dependent phosphorylation.
  • MTMR7-CC peptides mimic PPARγ activation in vitro and in vivo, independent of KRAS-driven inhibition.
  • Peptides bind to the PPARγ SRC1-binding site, suggesting a mechanism for enhanced activity.

Conclusions:

  • MTMR7 is a positive regulator of PPARγ.
  • Synthetic MTMR7-CC peptides can overcome inhibitory mechanisms in cancer cells.
  • This approach may address limitations observed in clinical studies targeting PPARγ for cancer treatment.

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