Ste 11 Ste 7 Fus 3 Ste 5 scaffold Ste 12 FUS 1 promoter His 3 transcription Activated receptor Ligand Receptor

Background: Heterotrimeric G proteins are important for numerous signaling events in eukaryotes, serving primarily to transduce signals that are initiated by G protein-coupled receptors. It has recently become clear that nonreceptor activators can regulate the level of heterotrimeric G protein signaling and, in some cases, drive cycles of receptor-independent G protein activation. In this study, we used a yeast expression cloning strategy to identify novel nonreceptor activators of heterotrimeric G proteins in a human adipocyte cDNA library. Results: The human transcription factor E2F8 was found to activate heterotrimeric G proteins, suggesting a specific biological role for this recently described member of the E2F family. Epistasis studies showed that E2F8 acted at the level of G proteins and was specific for Gαi over Gpa1. E2F8 augmented receptor-driven signaling, but also activated G proteins in the absence of a receptor. The GTPase-activating protein RGS4 antagonized the effect of E2F8, showing that E2F8's effect on Gα involved nucleotide turnover. The entire E2F8 protein was required for full activity, but the majority of the signaling activity appeared to reside in the first 200 residues. Conclusion: In yeast, E2F8 is a guanine nucleotide exchange factor (GEF) for the α subunit of heterotrimeric G proteins. The molecular mechanism and biological significance of this effect remain to be determined. Background Cells use heterotrimeric G proteins to transduce a wide variety of signals, including polypeptide hormones, small molecules, odorants, and light. They are thus one of the primary means by which cells gather information about their environment [1]. In the conventional paradigm for G protein signaling, a ligand-activated G protein-coupled receptor (GPCR) is responsible for catalyzing the exchange of GTP for GDP on the heterotrimer's α subunit. This exchange results in the dissociation of the heterotrimer, releasing the α and βγ moieties to exert celland context-dependent downstream effects. It has generally been thought that activated receptors are the primary source of guanine nucleotide exchange factor (GEF) activity for heterotrimeric G proteins. However, in recent years it has become apparent that several nonreceptor GEFs also exist, providing cells with a further level of control over G protein activity. One of the earliest nonreceptor GEFs to be identified was GAP-43, also known as B-50 or neuromodulin. GAP-43 is abundant in neuron growth cones and promotes axonal pathfinding during development and regeneration [2]. Investigating the function of GAP-43, Fishman and cowPublished: 30 March 2007 Journal of Molecular Signaling 2007, 2:3 doi:10.1186/1750-2187-2-3 Received: 10 January 2007 Accepted: 30 March 2007 This article is available from: http://www.jmolecularsignaling.com/content/2/1/3 © 2007 Hagemann et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.