Insulin regulates menin expression, cytoplasmic localization, and interaction with FOXO1

Abstract

Menin is the ubiquitously expressed nuclear protein product of the MEN1 gene, which interacts with PKB/Akt in the cytoplasm to inhibit its activity. This study describes a novel insulin-dependent mechanism of menin regulation and interaction with other metabolic proteins. We show that insulin downregulated menin in a time-dependent manner via the human insulin receptor. Inhibition analysis indicated a critical role for the protein kinase Akt in regulation of menin expression and localization. Insulin-mediated decrease in menin expression was abrogated by the PI3K/Akt inhibitor LY-294002 at early time points, from 2 to 7 h. Furthermore, exposure to insulin resulted in the cytoplasmic localization of menin and increased interaction with FOXO1. Fasting followed by refeeding modulates serum insulin levels, which corresponded to an increase in menin interaction with FOXO1 in the liver. Liver-specific hemizygous deletion of menin resulted in increased expression of FOXO1 target genes, namely IGFBP-1, PGC-1α, insulin receptor, Akt, and G-6-Pase. This study provides evidence that menin expression and localization are regulated by insulin signaling and that this regulation triggers an increase in its interaction with FOXO1 via Akt with metabolic consequences.

Menin Is Required for Optimal Processing of the MicroRNA let-7a

“…A recent report described insulin-mediated down-regulation of menin and localization in the cytoplasm in a time-dependent manner via the human insulin receptor (55). It is conceivable that activation of the insulin signaling pathway by insulin leads to reduction in menin levels particularly in the nucleus, consequently resulting in decreased processing of pri-let-7a and increased Irs2 expression.…”

MEN1, MEN4, and Carney Complex: Pathology and Molecular Genetics

“…Menin binds to cytoskeletal proteins, e.g. vimentin [108], and cytoplasmic cell signalling mediators including Akt1/protein kinase B (PKB) and forkhead box protein O1 (FoxO1) [109, 110]. Some of the known menin interaction partners are depicted in Fig.…”

Tumor suppressor Menin acts as a corepressor of LXRα to inhibit hepatic lipogenesis

“…Therefore, our study suggests that Menin could act as a novel co-repressor of LXRa in the liver. Interestingly, recent studies also found that Menin could interact with FOXO1, in response to insulin signaling [13]. Liver-specific hemizygous deletion of menin led to increased expression of FOXO1 target genes, such as IGFBP-1, PGC-1a, insulin receptor, and G6Pase [13].…”