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 p... More
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.
