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

Abstract

Members of a family of intracellular molecular switches, the small GTPases, sense modifications of the extracellular environment and transduce them into a variety of homeostatic signals. Among small GTPases, Ras and the Rho family of proteins hierarchically and/or coordinately regulate signaling pathways leading to phenotypes as important as proliferation, differentiation and apoptosis. Ras and Rho-GTPases are organized in a complex network of functional interactions, whose molecular mechanisms are being elucidated. Starting from the simple concept of linear cascades of events (GTPase-->activator--> GTPase), the work of several laboratories is uncovering an increasingly complex scenario in which upstream regulators of GTPases also function as downstream effectors and influence the precise biological outcome. Furthermore, small GTPases assemble into macromolecular machineries that include upstream activators, downstream effectors, regulators and perhaps even final biochemical targets. We are starting to understand how these macromolecular complexes work and how they are regulated and targeted to their proper subcellular 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.

Fig. 1. Signaling from Ras to Rac and relationships among Rho-GTPases. Activation of Rho-GTPases by growth factors (G.F.) can be achieved by pathways requiring the activation of PI3-K, either directly through binding of its regulatory subunit, p85, to the activated receptor, or indirectly through activation of Ras and formation of a Ras-GTP–p110 complex. The phosphoinositides generated by PI3-K are thought to regulate the activity and/or the localization of Rac-specific GEFs (Vav, Sos-1 and Tiam-1). The formation of a multimolecular complex (Eps8–E3b1–Sos-1) in addition to PI3-K activation is required for proper signaling in the case of Sos-1-mediated Rac activation. Tyrosine phosphorylation of GEFs, as in the case of Vav, might also be required in synergy with PI3-K action. Linear cascades coordinate the activity of the Rho GTPases Cdc42, Rac and Rho leading to actin remodeling and other phenotypes. See the text for further details. [Insets showing Rho GTPase-mediated actin remodeling are reprinted with permission from Hall (1998). Copyright 1998 American Association for Advancement of Science. Figure courtesy of Kate Nobes).]