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

ABSTRACT: Peroxisome proliferator-activated receptor-gamma (PPAR?) 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 PPAR?. To overcome this inhibitory mechanism, we searched for novel post-translational regulators of PPAR?. Phosphoinositide phosphatase Myotubularin-Related-Protein-7 (MTMR7) was identified as cytosolic interaction partner of PPAR?. 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 PPAR? and increased its transcriptional activity by inhibiting ERK1/2-dependent phosphorylation of PPAR?. MTMR7-CC peptides mimicked PPAR?-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 PPAR?. Thus, MTMR7 is a positive regulator of PPAR?, and its mimicry by synthetic peptides overcomes inhibitory mechanisms active in cancer cells possibly contributing to the failure of clinical studies targeting PPAR?.

SUBMITTER: Weidner P 

PROVIDER: S-EPMC7286916 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature