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

• Published in: American journal of physiology: endocrinology and metabolism 2017-08, Vol.313 (2), p.E148-E166
• Main Authors: Muhammad, Abdul Bari, Xing, Bowen, Liu, Chengyang, Naji, Ali, Ma, Xiaosong, Simmons, Rebecca A, Hua, Xianxin
• Format: Article
• Language: English
• Subjects: Adenosine triphosphatase; Animal models; Animals; Arginine; Cell proliferation; Cells, Cultured; Clonal deletion; Cyclic AMP response element-binding protein; Cyclic AMP Response Element-Binding Protein - metabolism; Cyclic AMP-Dependent Protein Kinases - metabolism; Diabetes; Diabetes mellitus; Down-Regulation - genetics; Epigenetics; Forkhead Box Protein O1 - metabolism; Forkhead protein; FOXO1 protein; Gene deletion; Glucagon; Glucagon-Like Peptide-1 Receptor - genetics; Glucagon-Like Peptide-1 Receptor - metabolism; Homeostasis; Hormones; Humans; Inhibitors; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Multiple endocrine neoplasia; Pancreas; Peptides; Phosphorylation; Protein arginine methyltransferase; Protein kinase A; Protein-Arginine N-Methyltransferases - physiology; Proteins; Proto-Oncogene Proteins - physiology; Signal Transduction; Tamoxifen; Transcription
• ISSN: 0193-1849; 1522-1555
• DOI: 10.1152/ajpendo.00241.2016

Menin is a scaffold protein that interacts with several epigenetic mediators to regulate gene transcription, and suppresses pancreatic β-cell proliferation. Tamoxifen-inducible deletion of multiple endocrine neoplasia type 1 ( ) gene, which encodes the protein menin, increases β-cell mass in multiple murine models of diabetes and ameliorates diabetes. Glucagon-like-peptide-1 (GLP1) is another key physiological modulator of β-cell mass and glucose homeostasis. However, it is not clearly understood whether menin crosstalks with GLP1 signaling. Here, we show that menin and protein arginine methyltransferase 5 (PRMT5) suppress GLP1 receptor (GLP1R) transcript levels. Notably, a GLP1R agonist induces phosphorylation of forkhead box protein O1 (FOXO1) at S253, and the phosphorylation is mediated by PKA. Interestingly, menin suppresses GLP1-induced and PKA-mediated phosphorylation of both FOXO1 and cAMP response element binding protein (CREB), likely through a protein arginine methyltransferase. Menin-mediated suppression of FOXO1 and CREB phosphorylation increases FOXO1 levels and suppresses CREB target genes, respectively. A small-molecule menin inhibitor reverses menin-mediated suppression of both FOXO1 and CREB phosphorylation. In addition, ex vivo treatment of both mouse and human pancreatic islets with a menin inhibitor increases levels of proliferation marker Ki67. In conclusion, our results suggest that menin and PRMT5 suppress GLP1R transcript levels and PKA-mediated phosphorylation of FOXO1 and CREB, and a menin inhibitor may reverse this suppression to induce β-cell proliferation.