GLP-1 signaling suppresses menin's transcriptional block by phosphorylation in β cells
GLP-1 signaling suppresses menin's transcriptional block by phosphorylation in β cells
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GLP-1 信号通过 β 细胞中的磷酸化抑制 menin 的转录阻断
DOI：
10.1083/jcb.201805049
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发表时间：
2019-03-01
影响因子：
7.8
通讯作者：
Hua, Xianxin
中科院分区：
文献类型：
--
作者：
Xing, Bowen;Ma, Jian;Hua, Xianxin
menin和胰高血糖素样肽1（GLP-1）途径在调节β细胞功能中起着重要但相反的作用，menin抑制β细胞功能，GLP-1促进β细胞功能。然而，关于GLP-1通路是否或如何抑制menin功能知之甚少。在这里，我们发现GLP-1信号激活蛋白激酶A（PKA）直接磷酸化menin的丝氨酸487残基，减轻menin介导的抑制胰岛素表达和细胞增殖。从机制上讲，Ser 487-磷酸化的menin获得增加的结合亲和力，核肌动蛋白/肌球蛋白IIa蛋白，并得到螯合从Ins 1启动子。这一事件导致抑制性表观遗传组蛋白修饰剂抑制杂色3-9同源蛋白1（SUV 39 H1）和组蛋白脱乙酰酶1（HDAC 1）在该位点的结合减少，随后增加Ins 1基因转录。menin的Ser 487磷酸化也增加促增殖细胞周期蛋白D2的表达和β细胞增殖。我们的研究结果揭示了一个以前未被认识到的生理联系，其中GLP-1信号通过磷酸化触发和肌动蛋白/肌球蛋白细胞骨架蛋白介导的基因转录去抑制来抑制menin功能。
Both menin and glucagon-like peptide 1 (GLP-1) pathways play central yet opposing role in regulating beta cell function, with menin suppressing, and GLP-1 promoting, beta 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 beta 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.