Yu Olivia M, Brown Joan Heller
Department of Pharmacology (O.Y., J.H.B.) and Biomedical Sciences Graduate Program, University of California at San Diego, La Jolla, California (O.Y.).
Department of Pharmacology (O.Y., J.H.B.) and Biomedical Sciences Graduate Program, University of California at San Diego, La Jolla, California (O.Y.)
Mol Pharmacol. 2015 Jul;88(1):171-80. doi: 10.1124/mol.115.097857. Epub 2015 Apr 22.
The low molecular weight G protein RhoA (rat sarcoma virus homolog family member A) serves as a node for transducing signals through G protein-coupled receptors (GPCRs). Activation of RhoA occurs through coupling of G proteins, most prominently, G12/13, to Rho guanine nucleotide exchange factors. The GPCR ligands that are most efficacious for RhoA activation include thrombin, lysophosphatidic acid, sphingosine-1-phosphate, and thromboxane A2. These ligands also stimulate proliferation, differentiation, and inflammation in a variety of cell and tissues types. The molecular events underlying these responses are the activation of transcription factors, transcriptional coactivators, and downstream gene programs. This review describes the pathways leading from GPCRs and RhoA to the regulation of activator protein-1, NFκB (nuclear factor κ-light-chain-enhancer of activated B cells), myocardin-related transcription factor A, and Yes-associated protein. We also focus on the importance of two prominent downstream transcriptional gene targets, the inflammatory mediator cyclooxygenase 2, and the matricellular protein cysteine-rich angiogenic inducer 61 (CCN1). Finally, we describe the importance of GPCR-induced activation of these pathways in the pathophysiology of cancer, fibrosis, and cardiovascular disease.
低分子量G蛋白RhoA（大鼠肉瘤病毒同源家族成员A）作为通过G蛋白偶联受体（GPCR）转导信号的节点。RhoA的激活通过G蛋白（最主要的是G12/13）与Rho鸟嘌呤核苷酸交换因子的偶联而发生。对RhoA激活最有效的GPCR配体包括凝血酶、溶血磷脂酸、鞘氨醇-1-磷酸和血栓素A2。这些配体还在多种细胞和组织类型中刺激增殖、分化和炎症。这些反应背后的分子事件是转录因子、转录共激活因子和下游基因程序的激活。本综述描述了从GPCR和RhoA到激活蛋白-1、NFκB（活化B细胞核因子κ轻链增强子）、心肌相关转录因子A和Yes相关蛋白调控的信号通路。我们还重点关注两个突出的下游转录基因靶点，即炎症介质环氧化酶2和基质细胞蛋白富含半胱氨酸的血管生成诱导因子61（CCN1）的重要性。最后，我们描述了GPCR诱导的这些信号通路激活在癌症、纤维化和心血管疾病病理生理学中的重要性。
