G protein-coupled receptors (GPCRs) constitute the largest family of cell surface molecules involved in signal transmission. These receptors play key physiological roles, with their dysfunction resulting in a number of disease states. Indeed, these receptors are the target of over 50% of the current therapeutic agents on the market, including more than a quarter of the 100 top-selling drugs with benefits in the range of several billion US dollars. Our paper provides a review of the mechanisms whereby GPCRs affect normal and aberrant cell growth, with emphasis on the most recently identified molecular routes. It also provides graphic representations of this wealth of information, which are invaluable for understanding the emerging principles in the field. Our review aims to serve as a guiding tool for those involved in basic, translational and clinical research in this fascinating area, as well as for those actively engaged in drug discovery efforts.

Recently, it has been discovered that many of the cellular responses mediated by GPCRs go beyond the stimulation of conventional second messenger generating systems, and result from the functional integration of an intricate network of intracellular signaling pathways. The review highlights the participation of these routes in GPCR-regulated normal cell growth and cancer, as well as summarizes the newly recognized effectors for GPCRs that are independent of G proteins, thus changing the conventional view of "G protein-coupled receptor/heterotrimeric G protein associated effector".

A myriad of key biological processes, including vision, smell and taste, the action of neurotransmitters in the brain, the regulation of angiogenesis, blood pressure control and cardiac function, the motility of white blood cells and their response to invading microorganisms, the function of endocrine and exocrine glands, as well as fundamental processes governing development during embryogenesis, cell survival or death, hypertrophy, and normal cell growth and cancer, are all controlled by cell surface receptors that transmit signals inside the cells though the activation of heterotrimeric G proteins (GPCRs). The recent advances in our understanding of how GPCRs regulate intracellular signaling networks are now helping to elucidate the most basic mechanism by which these receptors exert their numerous physiological roles, as well as why the perturbation of their function results in many pathological conditions. This emerging body of information may provide a golden opportunity to identify novel approaches for pharmacological intervention in a number of disease states.

Certain alterations of proteins involved in mitogenic signaling are known to exert profound effects on cellular behavior, including malignant transformation. The vast majority of the studies on the basic mechanisms whereby growth factors control normal cell proliferation and cancer have been focused on the function of receptor protein tyrosine kinases. Instead, we were fascinated by the potent mitogenic response to a large number of growth factors that act on G protein coupled receptors, and chose to approach the study of cancer through research on the normal and aberrant function of molecules transmitting proliferative signals by this large receptor family. These efforts have helped uncover a number of novel signaling routes, whose contribution to tumor initiation and progression and as targets for cancer therapy are under current active investigation.