GLP-1 signaling suppresses menin's transcriptional block by phosphorylation in β cells

The Journal of Cell Biology
Bowen XingX Hua

Abstract

Both menin and glucagon-like peptide 1 (GLP-1) pathways play central yet opposing role in regulating β cell function, with menin suppressing, and GLP-1 promoting, β 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 β 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.

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Datasets Mentioned

BETA
GSE106653

Methods Mentioned

BETA
x-ray crystallography
nucleotide exchange
coimmunoprecipitation
pull-down
immunoprecipitation
ELISA
PCR
acetylation
ChIP
coIP

Software Mentioned

Zen
ImageJ
NIS Elements
LAS AF
SPSS Statistics
Genescript
GraphPad Prism
GraphPad

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