Contribution of receptor/G protein signaling to cell growth and transformation.

While the effects of receptor/G protein systems on intermediary metabolism have been intensively studied, it has only recently been appreciated that G protein-coupled receptors and G proteins (heterotrimeric GTP-binding proteins) play important roles in the regulation of cell growth, differentiation and even transformation. Naturally occurring mutations both in G protein-coupled receptors and in G protein alpha-subunits lead to autonomous cell growth resulting in human disease. One mechanism to transduce mitogenic signals from the cell membrane to the nucleus is the engagement of the extracellular signal-regulated kinase (ERK)mitogen-activated protein kinase (MAPK) cascade. Multiple distinct signal transduction pathways have been characterized which link G proteins with the ERK cascade. Receptor and non-receptor tyrosine kinases play central roles in these pathways. Mitogenic signaling by receptor/G protein systems is realized as a complex interplay between signals emanating from different classes of cell surface receptors. The characterization of receptor-, G protein- and tyrosine kinase-specific contributions to mitogenic signaling in a particular cell may ultimately allow for the rational design and application of pharmaceuticals to treat diseases involving uncontrolled cell proliferation.