Activation and nuclear translocation of ERK1/2 by the formyl peptide receptor is regulated by G protein and is not dependent on β-arrestin translocation or receptor endocytosis
Activation and nuclear translocation of ERK1/2 by the formyl peptide receptor is regulated by G protein and is not dependent on β-arrestin translocation or receptor endocytosis
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DOI：
10.1016/j.cellsig.2005.01.006
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发表时间：
2005-10-01
影响因子：
4.8
通讯作者：
Miettinen, HM
中科院分区：
文献类型：
--
作者：
Gripentrog, JM;Miettinen, HM
G蛋白偶联受体（gpcr）在化学引诱剂、脂质、神经递质、气味剂和光线等大量刺激下传递多种细胞信号。经典的信号通路是通过异源三聚体G蛋白，但gpcr也可以通过不依赖于G蛋白的机制传递信号。在哺乳动物细胞中，这种类型的信号传导的关键成分是被称为-抑制素的支架分子家族。它们可以作为丝裂原活化蛋白激酶的激活支架，包括细胞外信号调节激酶1和2 （ERK1/2）。在这项研究中，我们使用野生型和突变型受体检测了G蛋白和β -阻滞蛋白在甲酰基肽受体（FPR）介导的趋化性激活、受体内吞作用和ERK1/2激活中的作用。我们的研究结果表明，与某些不需要G蛋白参与即可激活ERK1/2的其他gpcr不同，FPR需要通过G蛋白介导的途径发出信号。先前的观察表明，ERK1/2通过G蛋白激活，易位到细胞核，在那里刺激转录因子。相反，支架蛋白β -阻滞蛋白保留了细胞质中活化的ERK1/2，使细胞质靶标磷酸化。我们的实验数据表明，野生型FPR和突变型FPR在抑制蛋白结合上存在缺陷，诱导活化的ERK1/2的核易位，其配体浓度依赖性与胞质ERK1/2的活化相似。我们认为fpr介导的ERK1/2激活主要通过G蛋白发生，并且在生理上对确保髓系免疫调节剂（如细胞因子）的转录激活具有重要意义。(c) 2005爱思唯尔公司版权所有。
G protein-coupled receptors (GPCRs) transmit diverse cellular signals in response to a large number of stimuli such as chemoattractants, lipids, neurotransmitters, odorants and light. The classical signaling pathway is through heterotrimeric G proteins, but GPCRs can also transmit signals through mechanisms that are not dependent on G proteins. In mammalian cells, the key component for this type of signaling is the family of scaffolding molecules called beta-arrestins. They can function as scaffolds for activation of mitogen-activated protein kinases, including extracellular signal-regulated kinases 1 and 2 (ERK1/2). In this study we examined the role of G protein and beta-arrestin in formyl peptide receptor (FPR)-mediated activation of chemotaxis, receptor endocytosis and ERK1/2 activation using wild type and mutant receptors. Our findings suggest that, unlike certain other GPCRs that can activate ERK1/2 without the involvement of G protein, FPR requires signaling through a G protein-mediated pathway. Previous observations have shown that ERK1/2, activated through G protein, translocates to the nucleus where it stimulates transcription factors. In contrast, the scaffolding protein beta-arrestin retains the activated ERK1/2 in the cytoplasm to allow phosphorylation of cytoplasmic targets. Our experimental data show that both wild-type FPR and a mutant FPR, defective in arrestin binding, induce nuclear translocation of activated ERK1/2 with similar ligand concentration dependence as seen for activation of cytosolic ERK1/2. We propose that FPR-mediated activation of ERK1/2 takes place primarily through G protein and is physiologically important to ensure transcriptional activation of myeloid immunomodulators, such as cytokines. (c) 2005 Elsevier Inc. All rights reserved.