GLP-1 signaling suppresses menin's transcriptional block by phosphorylation in ß cells.
J Cell Biol
; 218(3): 855-870, 2019 03 04.
Article
en En
| MEDLINE
| ID: mdl-30792230
ABSTRACT
Both menin and glucagon-like peptide 1 (GLP-1) pathways play central yet opposing role in regulating ß cell function, with menin suppressing, and GLP-1 promoting, ß cell function. However, little is known as to whether or how GLP-1 pathway represses menin function. Here, we show that GLP-1 signaling-activated protein kinase A (PKA) directly phosphorylates menin at the serine 487 residue, relieving menin-mediated suppression of insulin expression and cell proliferation. Mechanistically, Ser487-phosphorylated menin gains increased binding affinity to nuclear actin/myosin IIa proteins and gets sequestrated from the Ins1 promoter. This event leads to reduced binding of repressive epigenetic histone modifiers suppressor variegation 3-9 homologue protein 1 (SUV39H1) and histone deacetylases 1 (HDAC1) at the locus and subsequently increased Ins1 gene transcription. Ser487 phosphorylation of menin also increases expression of proproliferative cyclin D2 and ß cell proliferation. Our results have uncovered a previously unappreciated physiological link in which GLP-1 signaling suppresses menin function through phosphorylation-triggered and actin/myosin cytoskeletal protein-mediated derepression of gene transcription.
Texto completo:
1
Colección:
01-internacional
Asunto principal:
Factores de Transcripción
/
Transcripción Genética
/
Transducción de Señal
/
Activación Transcripcional
/
Células Secretoras de Insulina
/
Péptido 1 Similar al Glucagón
Límite:
Animals
/
Humans
Idioma:
En
Revista:
J Cell Biol
Año:
2019
Tipo del documento:
Article
País de afiliación:
China