Ras and Rho GTPases A Family Reunion

Rap1, is required to define the position of the new bud. 1997). In vitro, this interaction is not sufficient to stimulate the GEF activity of Cdc24p, and one functional out-and Molecular Biology University College London come of this interaction in vivo, therefore, is likely to be the localization of Cdc24p to the presumptive bud site London WC1E 6BT United Kingdom (Zheng et al., 1995). In S. pombe, normal cell morphology is dependent on both ras1 and cdc42 functions and genetic and biochemical analysis has revealed that ras1 interacts directly with scd1, the GEF for cdc42 (Chang et al., 1994). In animal cells, it has been recognized for Introduction GTPases of the Ras superfamily act as molecular quite some time that Ras and Rho GTPases regulate an overlapping set of cellular responses, the best charac-switches to control a wide range of essential biochemical pathways in all eukaryotic cells. Among the 60 terized of which are gene expression, cellular proliferation , and actin-based cell motility. However, the elucida-or so that have been identified so far in mammalian cells, the Ras and the Rho families are of special interest tion of the molecular basis for the cross-talk between Ras and Rho GTPases has awaited the delineation of since they couple intracellular signal transduction pathways to changes in the external environment. Like all the signaling events controlled by each family. With this knowledge in hand, it is now feasible to begin to define GTPases, they exist in an inactive (GDP-bound) and an active (GTP-bound) conformation. Guanine nucleotide the biochemical and physiological links between these two families. exchange factors (GEFs) catalyze the release of GDP, allowing GTP to bind (its intracellular concentration is higher than that of GDP). In their active, GTP-bound Molecular Mechanisms of Cross-Talk state, Ras and Rho GTPases interact with target proteins Although diverse in nature, the molecular events identi-to promote a cellular response. Finally, an intrinsic fied thus far as mediators of cross-talk between Ras GTPase activity, catalyzed further by GTPase activating and Rho GTPases can be broadly classified into two proteins (GAPs), completes the cycle and the GTPase mechanistic frameworks: the branching of upstream sig-returns to its inactive, GDP-bound state. Figure 1 shows nals, referred to here as signal divergence, and coordi-some of the upstream GEFs, downstream targets, and nated regulation of downstream functions, referred to GAPs for two examples, Ras itself, and Rac, a member here as signal convergence …