G protein-coupled receptor connectivity to NF-kappaB in inflammation and cancer.

Complex intracellular network interactions regulate gene expression and cellular behavior. Whether at the site of inflammation or within a tumor, individual cells are exposed to a plethora of signals. The transcription factor nuclear factor-kappaB (NF-kappaB) regulates genes that control key cellular activities involved in inflammatory diseases and cancer. NF-kappaB is regulated by several distinct signaling pathways that may be activated individually or simultaneously. Multiple ligands and heterologous cell-cell interactions have an impact on NF-kappaB activity. The G protein-coupled receptor (GPCR) superfamily makes up the largest class of transmembrane receptors in the human genome and has multiple molecularly distinct natural ligands. GPCRs regulate proliferation, differentiation, and chemotaxis and play a major role in inflammatory diseases and cancer. Both GPCRs and NF-kappaB have been, and continue to be, major targets for drug discovery. A clear understanding of network interactions between GPCR signaling pathways and those that control NF-kB may be valuable for the development of better drugs and drug combinations.