Signaling from Ras to Rac and beyond: not just a matter of GEFs

Members of a family of intracellular molecular switches, the small GTPases, sense modifications of the extracellular environment and transduce them in to a variety of homeostatic signals. Among small GTPases, Ras and the Rho f amily of proteins hierarchically and/or coordinately regulate signaling pat hways leading to phenotypes as important as proliferation, differentiation and apoptosis, Ras and Rho-GTPases are organized in a complex network of fu nctional interactions, whose molecular mechanisms are being elucidated. Sta rting from the simple concept of linear cascades of events (GTPase-->activa tor-->GTPase), the work of several laboratories is uncovering an increasing ly complex scenario in which upstream regulators of GTPases also function a s downstream effecters and influence the precise biological outcome. Furthe rmore, small GTPases assemble into macromolecular machineries that include upstream activators, downstream effecters, regulators and perhaps even fina l biochemical targets, We are starting to understand how these macromolecul ar complexes work and how they are regulated and targeted to their proper s ubcellular localization. Ultimately, the acquisition of a cogent picture of the various levels of integration and regulation in small GTPase-mediated signaling should define the physiology of early signal transduction events and the pathological implication of its subversion.