Critchley William R, Pellet-Many Caroline, Ringham-Terry Benjamin, Harrison Michael A, Zachary Ian C, Ponnambalam Sreenivasan
Endothelial Cell Biology Unit, School of Molecular & Cellular Biology, University of Leeds, Leeds LS2 9JT, UK.
Centre for Cardiovascular Biology & Medicine, Rayne Building, University College London, London WC1E 6PT, UK.
Cells. 2018 Mar 15;7(3):22. doi: 10.3390/cells7030022.
Receptor tyrosine kinases (RTKs) are membrane-based sensors that enable rapid communication between cells and their environment. Evidence is now emerging that interdependent regulatory mechanisms, such as membrane trafficking, ubiquitination, proteolysis and gene expression, have substantial effects on RTK signal transduction and cellular responses. Different RTKs exhibit both basal and ligand-stimulated ubiquitination, linked to trafficking through different intracellular compartments including the secretory pathway, plasma membrane, endosomes and lysosomes. The ubiquitin ligase superfamily comprising the E1, E2 and E3 enzymes are increasingly implicated in this post-translational modification by adding mono- and polyubiquitin tags to RTKs. Conversely, removal of these ubiquitin tags by proteases called de-ubiquitinases (DUBs) enables RTK recycling for another round of ligand sensing and signal transduction. The endocytosis of basal and activated RTKs from the plasma membrane is closely linked to controlled proteolysis after trafficking and delivery to late endosomes and lysosomes. Proteolytic RTK fragments can also have the capacity to move to compartments such as the nucleus and regulate gene expression. Such mechanistic diversity now provides new opportunities for modulating RTK-regulated cellular responses in health and disease states.
受体酪氨酸激酶（RTKs）是基于膜的传感器，可实现细胞与其环境之间的快速通讯。现在有证据表明，相互依存的调节机制，如膜运输、泛素化、蛋白水解和基因表达，对RTK信号转导和细胞反应有重大影响。不同的RTK表现出基础的和配体刺激的泛素化，这与通过不同的细胞内区室运输有关，包括分泌途径、质膜、内体和溶酶体。由E1、E2和E3酶组成的泛素连接酶超家族通过向RTK添加单泛素和多泛素标签，越来越多地参与这种翻译后修饰。相反，被称为去泛素酶（DUBs）的蛋白酶去除这些泛素标签，可使RTK循环利用，进行新一轮的配体感知和信号转导。基础的和活化的RTK从质膜的内吞作用与运输并递送至晚期内体和溶酶体后的可控蛋白水解密切相关。蛋白水解的RTK片段也有能力转移到细胞核等区室并调节基因表达。这种机制的多样性现在为在健康和疾病状态下调节RTK调节的细胞反应提供了新的机会。
