title: Menin and PRMT5 suppress GLP1 receptor transcript and PKA-mediated phosphorylation of FOXO1 and CREB.
abstract: 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 (MEN1) 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.
authors.affiliation: Abramson Family Cancer Research Institute, Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.|Institute for Diabetes, Obesity, and Metabolism Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Abdul Bari
authors.initials: AB
authors.lastname: Muhammad
authors.affiliation: Shenzen University School of Medicine, Institute of Diabetes Research, Shenzhen, Guangdong, China.
authors.forename: Bowen
authors.initials: B
authors.lastname: Xing
authors.affiliation: Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Chengyang
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.|Institute for Diabetes, Obesity, and Metabolism Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Ali
authors.initials: A
authors.lastname: Naji
authors.affiliation: Shenzen University School of Medicine, Institute of Diabetes Research, Shenzhen, Guangdong, China.
authors.forename: Xiaosong
authors.initials: X
authors.lastname: Ma
authors.affiliation: Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; and.|Division of Neonatology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Simmons
authors.affiliation: Abramson Family Cancer Research Institute, Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; huax@mail.med.upenn.edu.|Institute for Diabetes, Obesity, and Metabolism Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Xianxin
authors.initials: X
authors.lastname: Hua
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D015536:Down-Regulation / Q000235:genetics; D000071161:Forkhead Box Protein O1 / Q000378:metabolism*; D000067757:Glucagon-Like Peptide-1 Receptor / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010766:Phosphorylation; D011484:Protein-Arginine N-Methyltransferases / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D015398:Signal Transduction
chemical_list: C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D000071161:Forkhead Box Protein O1; C467200:Foxo1 protein, mouse; C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; C484898:Men1 protein, mouse; D011518:Proto-Oncogene Proteins; C498518:Prmt5 protein, mouse; D011484:Protein-Arginine N-Methyltransferases; D017868:Cyclic AMP-Dependent Protein Kinases
keywords: diabetes; glucagon-like-peptide-1 receptor; islets; menin; protein arginine methyltransferase 5