Biased G protein-coupled receptor agonism mediates Neu1 sialidase and matrix metalloproteinase-9 crosstalk to induce transactivation of insulin receptor signaling
Biased G protein-coupled receptor agonism mediates Neu1 sialidase and matrix metalloproteinase-9 crosstalk to induce transactivation of insulin receptor signaling
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DOI：
10.1016/j.cellsig.2017.12.006
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发表时间：
2018-03-01
影响因子：
4.8
通讯作者：
Szewczuk, Myron R.
中科院分区：
文献类型：
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作者：
Haxho, Fiona;Haq, Sabah;Szewczuk, Myron R.
G蛋白偶联受体（GPCR）可以参与许多信号转导途径，这一性质导致了GPCR偏激动的概念。激动剂、拮抗剂和变构调节剂可以以不同的方式与GPCR结合，产生独特的构象，通过一种或多种G蛋白差异性地调节信号传导。神经介肽B（NMBR）GPCR信号平台控制哺乳动物神经氨酸酶-1（Neu 1）和基质金属蛋白酶-9（MMP 9）的相互作用，通过修饰胰岛素受体（IR）的糖基化而激活IR。在这里，我们提出，有一个偏见的GPCR激动作为小扩散分子在激活Neu 1介导的胰岛素受体信号。GPCR激动剂蛙皮素，缓激肽，血管紧张素I和血管紧张素II显着和剂量依赖性诱导Neu 1唾液酸酶活性和IR激活的人IR表达大鼠肝癌细胞系（HTC-IR），在胰岛素的情况下。此外，GPCR激动剂诱导的Neul唾液酸酶活性可以被NMBR抑制剂BIM-23127特异性阻断。蛋白质表达分析表明，这些GPCR激动剂显着诱导IR 11和胰岛素受体底物-1（IRS 1）的磷酸化。其中，血管紧张素II是能够促进HTC-112细胞中IRD磷酸化的最有效的GPCR激动剂。有趣的是，用BIM 23127和Neul抑制剂磷酸奥司他韦处理能够在体外阻断HTC细胞中GPCR激动剂诱导的IR活化。此外，我们发现，血管紧张素II受体（1型）存在于与Neu 1，IRO和NMBR在幼稚（未刺激）和刺激的HTC-IR细胞与胰岛素，缓激肽，血管紧张素I和血管紧张素II的多聚体受体复合物。该复合物表明调节细胞表面上这些分子之间的相互作用和信号传导机制的分子连接。这些发现揭示了一个有偏见的GPCR激动剂诱导的IR反式激活信号轴，介导的Neu 1唾液酸酶和胰岛素受体糖基化的修改。
G protein-coupled receptors (GPCR) can participate in a number of signaling pathways, and this property led to the concept of biased GPCR agonism. Agonists, antagonists and allosteric modulators can bind to GPCRs in different ways, creating unique conformations that differentially modulate signaling through one or more G proteins. A unique neuromedin B (NMBR) GPCR-signaling platform controlling mammalian neuraminidase-1 (Neu1) and matrix metalloproteinase-9 (MMP9) crosstalk has been reported in the activation of the insulin receptor (IR) through the modification of the IR glycosylation. Here, we propose that there exists a biased GPCR agonism as small diffusible molecules in the activation of Neu1-mediated insulin receptor signaling. GPCR agonists bombesin, bradykinin, angiotensin I and angiotensin II significantly and dose-dependently induce Neu1 sialidase activity and IR activation in human IR-expressing rat hepatoma cell lines (HTC-IR), in the absence of insulin. Furthermore, the GPCR agonist-induced Neul sialidase activity could be specifically blocked by the NMBR inhibitor, BIM-23127. Protein expression analyses showed that these GPCR agonists significantly induced phosphorylation of IR11 and insulin receptor substrate-1 (IRS1). Among these, angiotensin II was the most potent GPCR agonist capable of promoting IRD phosphorylation in HTC-112 cells. Interestingly, treatment with BIM 23127 and Neul inhibitor oseltamivir phosphate were able to block GPCR agonist-induced IR activation in HTC cells in vitro. Additionally, we found that angiotensin II receptor (type 1) exists in a multimeric receptor complex with Neu1, IRO and NMBR in naive (unstimulated) and stimulated HTC-IR cells with insulin, bradykinin, angiotensin I and angiotensin II. This complex suggests a molecular link regulating the interaction and signaling mechanism between these molecules on the cell surface. These findings uncover a biased GPCR agonist-induced IR transactivation signaling axis, mediated by Neu1 sialidase and the modification of insulin receptor glycosylation.