Abstract
The low molecular weight G-protein RhoA 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 (LPA), sphingosine-1-phosphate (S1P) and thromboxane A2 (TXA2). These ligands also stimulate proliferation, differentiation and inflammation in a variety of cell and tissues types. Most of these pleiotropic effects of GPCRs and RhoA can be dissociated from the cytoskeletal changes classically associated with RhoA signaling. Instead, the molecular events underlying these responses are the activation of transcription factors, transcriptional co-activators and downstream gene programs. This review describes the pathways leading from GPCRs and RhoA to the regulation of activator protein-1 (AP-1), nuclear factor kappa-light-chain-enhancer of activated B cells (NFkB), myocardin-related transcription factor-A (MRTF-A) and Yes associated protein (YAP). We also focus on the importance of two prominent downstream transcriptional gene targets, the inflammatory mediator cyclooxygenase-2 (COX-2) and the matricellular protein cysteine-rich angiogenic inducer 61 (CCN-1/Cyr61). Finally we describe the importance of GPCR induced activation of these pathways in the pathophysiology of cancer, fibrosis, and cardiovascular disease.
- G12,13;other G's
- GEFs (non-receptor)
- Rho
- Protein kinase D
- AP-1
- NFkappaB
- Transcriptional coactivators
- Cyclooxygenases
- Neuroinflammation
- The American Society for Pharmacology and Experimental Therapeutics