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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Rockefeller University Press 2019
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.
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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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