DeNies Maxwell S, Smrcka Alan V, Schnell Santiago, Liu Allen P
Cellular and Molecular Biology Program, University of Michigan, Ann Arbor, MI, USA.
Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI, USA.
Commun Biol. 2020 Dec 18;3(1):789. doi: 10.1038/s42003-020-01510-2.
It has become increasingly apparent that G protein-coupled receptor (GPCR) localization is a master regulator of cell signaling. However, the molecular mechanisms involved in this process are not well understood. To date, observations of intracellular GPCR activation can be organized into two categories: a dependence on OCT3 cationic channel-permeable ligands or the necessity of endocytic trafficking. Using CXC chemokine receptor 4 (CXCR4) as a model, we identified a third mechanism of intracellular GPCR signaling. We show that independent of membrane permeable ligands and endocytosis, upon stimulation, plasma membrane and internal pools of CXCR4 are post-translationally modified and collectively regulate EGR1 transcription. We found that β-arrestin-1 (arrestin 2) is necessary to mediate communication between plasma membrane and internal pools of CXCR4. Notably, these observations may explain that while CXCR4 overexpression is highly correlated with cancer metastasis and mortality, plasma membrane localization is not. Together these data support a model where a small initial pool of plasma membrane-localized GPCRs are capable of activating internal receptor-dependent signaling events.
越来越明显的是，G蛋白偶联受体（GPCR）的定位是细胞信号传导的主要调节因子。然而，这一过程所涉及的分子机制尚未得到充分理解。迄今为止，细胞内GPCR激活的观察结果可分为两类：对OCT3阳离子通道可渗透配体的依赖性或内吞运输的必要性。以CXC趋化因子受体4（CXCR4）为模型，我们确定了细胞内GPCR信号传导的第三种机制。我们表明，在刺激时，独立于膜可渗透配体和内吞作用，CXCR4的质膜和内部池会进行翻译后修饰，并共同调节早期生长反应蛋白1（EGR1）转录。我们发现β抑制蛋白1（抑制蛋白2）是介导CXCR4质膜和内部池之间通讯所必需的。值得注意的是，这些观察结果可能解释了为什么虽然CXCR4的过表达与癌症转移和死亡率高度相关，但质膜定位却并非如此。这些数据共同支持了一个模型，即一小部分初始质膜定位的GPCR能够激活内部受体依赖性信号事件。
