Menin and PRMT5 suppress GLP1 receptor transcript and PKA-mediated phosphorylation of FOXO1 and CREB.
Am J Physiol Endocrinol Metab
; 313(2): E148-E166, 2017 08 01.
Article
en En
| MEDLINE
| ID: mdl-28270438
ABSTRACT
Menin is a scaffold protein that interacts with several epigenetic mediators to regulate gene transcription, and suppresses pancreatic ß-cell proliferation. Tamoxifen-inducible deletion of multiple endocrine neoplasia type 1 (MEN1) gene, which encodes the protein menin, increases ß-cell mass in multiple murine models of diabetes and ameliorates diabetes. Glucagon-like-peptide-1 (GLP1) is another key physiological modulator of ß-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 ß-cell proliferation.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Asunto principal:
Proteína-Arginina N-Metiltransferasas
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Proteínas Proto-Oncogénicas
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Proteína de Unión a Elemento de Respuesta al AMP Cíclico
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Proteínas Quinasas Dependientes de AMP Cíclico
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Receptor del Péptido 1 Similar al Glucagón
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Proteína Forkhead Box O1
Límite:
Animals
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Humans
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Male
Idioma:
En
Revista:
Am J Physiol Endocrinol Metab
Asunto de la revista:
ENDOCRINOLOGIA
/
FISIOLOGIA
/
METABOLISMO
Año:
2017
Tipo del documento:
Article