GLP-1 signaling suppresses menin’s transcriptional block by phosphorylation in β cells
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...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Rockefeller University Press
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6400573/ https://www.ncbi.nlm.nih.gov/pubmed/30792230 http://dx.doi.org/10.1083/jcb.201805049 |
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author | Xing, Bowen Ma, Jian Jiang, Zongzhe Feng, Zijie Ling, Sunbin Szigety, Katy Su, Wen Zhang, Longmei Jia, Ruirui Sun, Yanmei Zhang, Lin Kong, Xiangchen Ma, Xiaosong Hua, Xianxin |
author_facet | Xing, Bowen Ma, Jian Jiang, Zongzhe Feng, Zijie Ling, Sunbin Szigety, Katy Su, Wen Zhang, Longmei Jia, Ruirui Sun, Yanmei Zhang, Lin Kong, Xiangchen Ma, Xiaosong Hua, Xianxin |
author_sort | Xing, Bowen |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-6400573 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Rockefeller University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-64005732019-09-04 GLP-1 signaling suppresses menin’s transcriptional block by phosphorylation in β cells Xing, Bowen Ma, Jian Jiang, Zongzhe Feng, Zijie Ling, Sunbin Szigety, Katy Su, Wen Zhang, Longmei Jia, Ruirui Sun, Yanmei Zhang, Lin Kong, Xiangchen Ma, Xiaosong Hua, Xianxin J Cell Biol Research Articles 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. Rockefeller University Press 2019-03-04 /pmc/articles/PMC6400573/ /pubmed/30792230 http://dx.doi.org/10.1083/jcb.201805049 Text en © 2019 Xing et al. http://www.rupress.org/terms/https://creativecommons.org/licenses/by-nc-sa/4.0/This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/). |
spellingShingle | Research Articles Xing, Bowen Ma, Jian Jiang, Zongzhe Feng, Zijie Ling, Sunbin Szigety, Katy Su, Wen Zhang, Longmei Jia, Ruirui Sun, Yanmei Zhang, Lin Kong, Xiangchen Ma, Xiaosong Hua, Xianxin GLP-1 signaling suppresses menin’s transcriptional block by phosphorylation in β cells |
title | GLP-1 signaling suppresses menin’s transcriptional block by phosphorylation in β cells |
title_full | GLP-1 signaling suppresses menin’s transcriptional block by phosphorylation in β cells |
title_fullStr | GLP-1 signaling suppresses menin’s transcriptional block by phosphorylation in β cells |
title_full_unstemmed | GLP-1 signaling suppresses menin’s transcriptional block by phosphorylation in β cells |
title_short | GLP-1 signaling suppresses menin’s transcriptional block by phosphorylation in β cells |
title_sort | glp-1 signaling suppresses menin’s transcriptional block by phosphorylation in β cells |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6400573/ https://www.ncbi.nlm.nih.gov/pubmed/30792230 http://dx.doi.org/10.1083/jcb.201805049 |
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