Dusaban Stephanie S, Brown Joan Heller
Department of Pharmacology, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Biomedical Sciences Graduate Program, University of California, San Diego, La Jolla, CA 92093, USA.
Department of Pharmacology, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Adv Biol Regul. 2015 Jan;57:17-23. doi: 10.1016/j.jbior.2014.09.014. Epub 2014 Oct 5.
Phospholipase C-ε (PLCε) integrates signaling from G-protein coupled receptors (GPCRs) to downstream kinases to regulate a broad range of biological and pathophysiological responses. Relative to other PLCs, PLCε is unique in that it not only serves a catalytic function in phosphoinositide hydrolysis but also functions as an exchange factor small the low molecular weight G-protein Rap1. PLCε is selectively stimulated by agonists for GPCRs that couple to RhoA, which bind directly to the enzyme to regulate its activity. Rap1 also regulates PLCε activity by binding to its RA2 domain and this generates a feedback mechanism allowing sustained signaling. As a result of its regulation by inflammatory ligands for GPCRs and its ability to promote chronic signals, PLCε has been implicated in diseases ranging from cancer to ischemia/reperfusion injury. This review will discuss the regulation of PLCε, molecular mechanisms that contribute to sustained signaling, and the role of the enzyme in various disease contexts.
磷脂酶C-ε(PLCε)将来自G蛋白偶联受体(GPCR)的信号整合到下游激酶,以调节广泛的生物学和病理生理反应。相对于其他磷脂酶,PLCε的独特之处在于它不仅在磷酸肌醇水解中起催化作用,还作为小分子低分子量G蛋白Rap1的交换因子发挥作用。PLCε被与RhoA偶联的GPCR激动剂选择性激活,RhoA直接与该酶结合以调节其活性。Rap1也通过与PLCε的RA2结构域结合来调节其活性,这产生了一种反馈机制,允许持续信号传导。由于其受GPCR炎症配体的调节以及促进慢性信号的能力,PLCε已被认为与从癌症到缺血/再灌注损伤等多种疾病有关。本综述将讨论PLCε的调节、促成持续信号传导的分子机制以及该酶在各种疾病背景下的作用。