Signaling by G protein coupled receptors and G proteins: A perspective

Cell surface receptors belonging to the family of G protein coupled receptors (GPCRs) ± also known as seven-transmembrane, heptahelical or serpentine, receptors ± are involved in the regulation of diverse signaling processes. Heterotrimeric G proteins, consisting of a, b, and g-subunits provide the signal coupling mechanisms to this superfamily of receptors. The role of the heptahelical receptors and their G proteins in signaling mechanisms involving sensory transduction as well as cell homeostasis has been known for almost three decades. However, only in the recent days, their critical role in the regulation of cell growth has been identi®ed. The identi®cation of newer heptahelical receptors as well as G protein subunits has contributed towards the greater understanding of the novel mechanisms through which these receptors recruit G proteins and small GTPases in regulating cell growth. The compendium of reviews presented here focuses on the mechanisms by which the dierent components of the heptahelical receptors signaling unit, namely the receptors, the G protein subunits, and their eectors regulate the critical signaling events involved in cell growth, dierentiation, and apoptosis. In the reviews presented here, the authors bring their unique perspective to describe the possible mechanisms by which signaling pathways regulated by G protein coupled receptors and G proteins contribute to signal networking involved in cell growth, dierentiation and apoptosis. Signaling by GPCRs is initiated by a speci®c ligand b that binds and activates the receptor inducing a conformational change in the receptor. The receptor, thus activated, stimulates a speci®c G protein by catalyzing the exchange of guanine nucleotides in the a-subunit. The GTP-bound a-subunit and the ba subunits disassociate from the receptor and activate their respective down-stream eector proteins. The ®rst six articles from this compendium analyse the signaling events from the vantage point of the GPCRs. The following two articles describe the variations of the common theme exhibited by two novel families of GPCRs namely, the PAR and the virally encoded GPCRs. Two articles that discuss the intracellular communication networking initiated by GPCRs involving receptor tyrosine kinases, non-receptor tyrosine kinases, and STATs follow this. As the signal from GPCR progresses to the G proteins, the next series of seven reviews discusses the mechanisms by which dierent G proteins transduce the signals from the receptors to the downstream eector molecules. The review by Lefkowitz and coworkers describe the novel mechanisms by which GPCRs activate the extracellular-signal regulated kinases (ERKs) and Jun N-terminal kinases (JNK) through the recruitment of receptoras well as non-receptor associated kinases. In the article by Kraneburg and Moolenaar, the mechanism by which lysophosphatidic receptors selectively coupling to speci®c G proteins to recruit the small GTPase Ras in activating the ERK signaling pathway. In contrast, the role of Rho-family of GTPases in cellular transformation induced by the novel GPCRs are described by Channing Der and his colleagues. The role of such GPCRs in angiogenesis and the possible role of this pathway in metastasis are discussed by Jacques PouysseÂ gur and his co-workers. In the next article, Lynn Heasley reviews the autocrine and paracrine signaling pathways stimulated by neuropeptide receptors and their possible role in human cancers. In the following article, Lawrence Brass and coworkers summarize novel mechanisms by which the PAR-family of GPCRs are activated. Recent studies have shown that some human pathogenic viruses utilize either endogenous or virally encoded GPCRs for their growth and survival pathways. Schwartz and his colleagues discuss the novel aspects of these virally encoded GPCRs. Critical signaling pathways involved in cell proliferation, dierentiation, and apoptosis is regulated by multiple signaling input. More often than not, these multiple signaling inputs are generated from signaling pathways originating from dierent signaling loci. A potent transforming, dierentiating, or apoptotic signal involves the activation of these multiple signaling pathways. The article by Axel Ullrich and his colleagues describe the mechanism through which GPCRs can transactivate the receptor tyrosine kinase EGFR to promote cell proliferation. Similarly the article by Ram and Iyengar describe the mechanism(s) by which GPCRs especially the receptors that couple Oncogene (2001) 20, 1530 ± 1531 a 2001 Nature Publishing Group All rights reserved 0950 ± 9232/01 $15.00