Cells use all sorts of tricks to make the signal transduction pathways that tailor the cells' physiology to the changing environment. One feature used repeatedly is the protein switch, flicked on and off by the nucleotide guanosine 5′-triphosphate (GTP). When GTP is bound, two families of proteins—heterotrimeric guanine nucleotide-binding proteins (G proteins) and their distant relatives, the small molecular weight guanosine triphosphatases (GTPases)—are “on” and can activate the element immediately downstream to send a signal further down the line. But each of these proteins is also a GTPase, containing within the molecule itself the ability to hydrolyze GTP to guanosine diphosphate (GDP) and so turn off the switch.

Small GTPases control fundamental cell properties—polarity, shape, and the commitment to divide or differentiate. The larger G proteins usually regulate more specialized signals—the production of second messengers like cyclic AMP and calcium. Two members of the G protein family, G 12 and G 13, are unusual in that they promote cell cycle progression and reorganization of the actin cytoskeleton, changes that are typically associated with the small GTPases. Now an impressive piece of detective work, described on pages 2109 and 2112 of this issue, unites the two distantly related families through these unique G proteins. Kozasa et al. and Hart et al. show that G 13 directly activates a guanine nucleotide exchange factor, which in turn promotes GDP dissociation from the small GTPase Rho, allowing it to be activated again by GTP (1, 2). At least in this instance, a G protein triggers action in its distant cousin, the small GTPase Rho.