Multiple pathways of ERK activation by G protein-coupled receptors.

It has only recently been fully realized that G protein-coupled receptors and G proteins play crucial roles in the regulation of cell growth, differentiation and even tumour formation. Naturally occurring mutations in G protein-coupled receptors and in G protein alpha subunits result in uncontrolled cellular proliferation resulting in distinct human diseases. One important mechanism to transduce mitogenic signals from the cell membrane to the cell nucleus is the engagement of the extracellular signal-regulated kinase (ERK)-mitogen-activated protein kinase (MAPK) cascade. A multitude of distinct signal transduction pathways have been deciphered which connect G proteins with the ERK cascade. Both receptor and non-receptor tyrosine kinases play pivotal roles in these signalling pathways. Mitogenic signalling by G protein-coupled receptors can be regarded as a complex interplay between signals emanating from different classes of cell surface receptors which ultimately converge upon a small subset of central signalling proteins in the cell. The characterization of receptor-, G protein- and tyrosine kinase-specific contributions to mitogenic signalling in a particular cell and the identification of proteins serving as a point of convergence in the mitogenic signalling cascade may ultimately allow the design of novel pharmacological approaches to treat diseases involving unrestricted cell proliferation.