GEFs: master regulators of G-protein activation.

What is a GEF? GEF stands for guanine-nucleotide exchange factor, any of a large and diverse group of proteins that catalyze the release of GDPand the subsequent uptake of GTPby members of the Ras and heterotrimeric G-protein superfamilies (referred to here collectively as G proteins). When bound to GTP, G proteins are in the active conformation. Upon hydrolysis of this bound GTP, by virtue of their own intrinsic GTPase activities, G proteins are inactivated. GDP release is the rate-limiting step for the GTPase reaction in vitro; in vivo, this kinetic barrier is reduced by GEFs. Certain GEFs have also been called guanine-nucleotide release factors (GRFs) or guanine-nucleotide dissociation factors (GDFs). GEFs are not to be confused with guanine-nucleotide dissociation inhibitors (GDIs), which trap G proteins in an inactive GDP-bound state, nor with GTPase activating proteins (GAPs), which accelerate the rate of GTPhydrolysis (i.e. augment the intrinsic GTPase activity of the G protein) and thereby terminate G-protein signaling. GEFs constitute a highly diverse group of proteins in the cell. All GEFs contain one or more G-protein interaction domain that manifests exchange activity; most also contain other proteininteraction and regulatory domains.