Gu Yuan-jing, Sun Wu-yi, Zhang Sen, Wu Jing-jing, Wei Wei
Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Antiinflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Hefei 230032, China.
Acta Pharmacol Sin. 2015 Nov;36(11):1277-87. doi: 10.1038/aps.2015.74. Epub 2015 Sep 21.
β-Arrestins and β-arrestin2 are important adaptor proteins and signal transduction proteins that are mainly involved in the desensitization and internalization of G-protein-coupled receptors. Fibrosis is characterized by accumulation of excess extracellular matrix (ECM) molecules caused by chronic tissue injury. If highly progressive, the fibrotic process leads to organ malfunction and, eventually, death. The incurable lung fibrosis, renal fibrosis and liver fibrosis are among the most common fibrotic diseases. Recent studies show that β-arrestins can activate signaling cascades independent of G-protein activation and scaffold many intracellular signaling networks by diverse types of signaling pathways, including the Hedgehog, Wnt, Notch and transforming growth factor-β pathways, as well as downstream kinases such as MAPK and PI3K. These signaling pathways are involved in the pathological process of fibrosis and fibrotic diseases. This β-arrestin-mediated regulation not only affects cell growth and apoptosis, but also the deposition of ECM, activation of inflammatory response and development of fibrotic diseases. In this review, we survey the involvement of β-arrestins in various signaling pathways and highlight different aspects of their regulation of fibrosis. We also discuss the important roles of β-arrestins in the process of fibrotic diseases by regulating the inflammation and deposit of ECM. It is becoming more evident that targeting β-arrestins may offer therapeutic potential for the treatment of fibrotic diseases.
β抑制蛋白和β抑制蛋白2是重要的衔接蛋白和信号转导蛋白，主要参与G蛋白偶联受体的脱敏和内化过程。纤维化的特征是慢性组织损伤导致细胞外基质（ECM）分子过度积累。如果进展迅速，纤维化过程会导致器官功能障碍，最终导致死亡。无法治愈的肺纤维化、肾纤维化和肝纤维化是最常见的纤维化疾病。最近的研究表明，β抑制蛋白可以独立于G蛋白激活而激活信号级联反应，并通过多种信号通路，包括刺猬信号通路、Wnt信号通路、Notch信号通路和转化生长因子-β信号通路，以及丝裂原活化蛋白激酶（MAPK）和磷脂酰肌醇-3激酶（PI3K）等下游激酶，构建许多细胞内信号网络。这些信号通路参与了纤维化和纤维化疾病的病理过程。这种由β抑制蛋白介导的调节不仅影响细胞生长和凋亡，还影响ECM的沉积、炎症反应的激活以及纤维化疾病的发展。在这篇综述中，我们调查了β抑制蛋白在各种信号通路中的作用，并强调了它们对纤维化调节的不同方面。我们还讨论了β抑制蛋白通过调节炎症和ECM沉积在纤维化疾病过程中的重要作用。越来越明显的是，靶向β抑制蛋白可能为纤维化疾病的治疗提供潜在的治疗方法。
