Regulation of Mitogen-Activated Protein Kinase Signaling Networks by G Protein-Coupled Receptors

The family of receptors that transmit signals through the activation of heterotrimeric GTP-binding proteins (G proteins) constitutes the largest group of cell surface proteins involved in signal transduction. These receptors participate in a broad range of important biological functions and are implicated in a number of disease states. More than half of all drugs currently available influence G protein-coupled receptors (GPCRs). These receptors affect the generation of small molecules that act as intracellular mediators or second messengers, and can regulate a highly interconnected network of biochemical routes controlling the activity of several members of the mitogen-activated protein kinase (MAPK) superfamily. They include extracellular signal-regulated kinase 1 (ERK1) and ERK2 (or p44(MAPK) and p42(MAPK)), c-Jun NH(2)-terminal kinases (JNKs), ERK5 (or BMK), and p38 MAPKs, including p38alpha (or CSBP-1), p38beta, p38gamma (or SAPK3 or ERK6), and p38delta?(or SAPK4). This review will focus on the molecular mechanisms by which GPCRs signal to the nucleus through this intricate network of second messenger-generating systems and MAPK signaling pathways, thereby affecting the expression of genes whose products influence many biological processes, including normal and aberrant cell growth.