Keenan Research Centre for Biomedical Science of the St. Michael's Hospital and Department of Surgery, University of Toronto, Toronto, ON M5B 1W8, Canada.
Int J Mol Sci. 2019 Nov 12;20(22):5655. doi: 10.3390/ijms20225655.
Claudin-2 is expressed in the tight junctions of leaky epithelia, where it forms cation-selective and water permeable paracellular channels. Its abundance is under fine control by a complex signaling network that affects both its synthesis and turnover in response to various environmental inputs. Claudin-2 expression is dysregulated in many pathologies including cancer, inflammation, and fibrosis. Claudin-2 has a key role in energy-efficient ion and water transport in the proximal tubules of the kidneys and in the gut. Importantly, strong evidence now also supports a role for this protein as a modulator of vital cellular events relevant to diseases. Signaling pathways that are overactivated in diseases can alter claudin-2 expression, and a good correlation exists between disease stage and claudin-2 abundance. Further, loss- and gain-of-function studies showed that primary changes in claudin-2 expression impact vital cellular processes such as proliferation, migration, and cell fate determination. These effects appear to be mediated by alterations in key signaling pathways. The specific mechanisms linking claudin-2 to these changes remain poorly understood, but adapters binding to the intracellular portion of claudin-2 may play a key role. Thus, dysregulation of claudin-2 may contribute to the generation, maintenance, and/or progression of diseases through both permeability-dependent and -independent mechanisms. The aim of this review is to provide an overview of the properties, regulation, and functions of claudin-2, with a special emphasis on its signal-modulating effects and possible role in diseases.
紧密连接蛋白 2 表达于渗漏性上皮细胞的紧密连接处，在此形成阳离子选择性和水通透的细胞旁通道。其丰度受精细调控，复杂的信号网络可影响其合成和周转，以响应各种环境输入。紧密连接蛋白 2 的表达在许多病理学中失调，包括癌症、炎症和纤维化。紧密连接蛋白 2 在肾脏近端小管和肠道中的能量高效离子和水转运中起关键作用。重要的是，现在有强有力的证据支持该蛋白作为与疾病相关的重要细胞事件调节剂的作用。在疾病中过度激活的信号通路可以改变紧密连接蛋白 2 的表达，并且疾病阶段与紧密连接蛋白 2 的丰度之间存在良好的相关性。此外，失活和功能获得研究表明，紧密连接蛋白 2 表达的主要变化会影响增殖、迁移和细胞命运决定等重要细胞过程。这些效应似乎是通过关键信号通路的改变介导的。将紧密连接蛋白 2 与这些变化联系起来的具体机制仍知之甚少，但与紧密连接蛋白 2 细胞内部分结合的衔接蛋白可能起关键作用。因此，通过渗透性依赖和非依赖性机制，紧密连接蛋白 2 的失调可能导致疾病的发生、维持和/或进展。本综述的目的是概述紧密连接蛋白 2 的特性、调节和功能，特别强调其信号调节作用及其在疾病中的可能作用。
