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Menin and PRMT5 suppress GLP1 receptor transcript and PKA-mediated phosphorylation of FOXO1 and CREB

Abdul Bari Muhammad1,2, Bowen Xing3, Chengyang Liu4

  • 1Abramson Family Cancer Research Institute, Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.

American Journal of Physiology. Endocrinology and Metabolism
|March 9, 2017
PubMed

Insights

Menin and PRMT5 suppress GLP1R transcript levels and key signaling pathways. A menin inhibitor reverses this suppression, potentially promoting pancreatic beta-cell proliferation for diabetes treatment.

Area of Science:

  • Endocrinology
  • Molecular Biology
  • Diabetes Research

Background:

  • Menin (encoded by MEN1) is a scaffold protein regulating gene transcription and suppressing pancreatic beta-cell proliferation.
  • Glucagon-like-peptide-1 (GLP1) influences beta-cell mass and glucose homeostasis, but its interaction with menin is unclear.
  • Menin's role in diabetes pathogenesis and its potential modulation for therapeutic benefit warrant investigation.

Purpose of the Study:

  • To investigate the crosstalk between menin and GLP1 signaling in pancreatic beta-cells.
  • To determine if menin influences GLP1 receptor (GLP1R) expression and downstream signaling pathways.
  • To evaluate the therapeutic potential of menin inhibition in promoting beta-cell proliferation.

Main Methods:

  • Assessed menin and PRMT5 effects on GLP1R transcript levels.
  • Investigated GLP1-induced phosphorylation of FOXO1 and CREB, and menin's role in this process.
  • Utilized a small-molecule menin inhibitor to reverse menin-mediated suppression.
  • Examined the impact of menin inhibition on beta-cell proliferation marker Ki67 in pancreatic islets.

Main Results:

  • Menin and PRMT5 were found to suppress GLP1R transcript levels.
  • Menin inhibits GLP1-induced and PKA-mediated phosphorylation of FOXO1 and CREB.
  • Menin inhibition reversed suppression of FOXO1 and CREB phosphorylation, increasing FOXO1 levels and affecting CREB target genes.
  • Ex vivo treatment with a menin inhibitor increased Ki67 levels in mouse and human pancreatic islets.

Conclusions:

  • Menin and PRMT5 suppress GLP1R expression and key signaling pathways (FOXO1, CREB phosphorylation) involved in beta-cell function.
  • A menin inhibitor can reverse menin-mediated suppression, suggesting a therapeutic strategy to induce beta-cell proliferation.
  • Targeting menin offers a potential approach for managing diabetes by enhancing beta-cell mass.
Keywords:
diabetesglucagon-like-peptide-1 receptorisletsmeninprotein arginine methyltransferase 5

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