Ras and Rho GTPases: A Family Reunion

• Published in: Cell 2000-10, Vol.103 (2), p.227-238
• Main Authors: Bar-Sagi, Dafna, Hall, Alan
• Format: Article
• Language: English
• Subjects: Animals; Cell Movement; erk kinase; Models, Biological; rac protein; ras Proteins - metabolism; Receptor Cross-Talk; rho GTP-Binding Proteins - metabolism; rho1 protein; Signal Transduction; Transcriptional Activation
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/S0092-8674(00)00115-X

The functional analysis of GTP binding proteins has most often led to the identification of a single, signal transduction pathway as being of particular importance; Gs regulates adenylyl cyclase and cAMP levels, Ras regulates the ERK/MAP kinase cascade and cell proliferation, and Rho GTPases regulate actin polymerization and the organization of the actin cytoskeleton. The identification of multiple target proteins for many of these GTPases (Rac has 12 so far) has, however, made this idea of simple linear pathways untenable and there is now little doubt that members of the Ras and Rho GTPase families each control multiple intracellular pathways. Some of the potential biological implications of this have been most clearly revealed in S. cerevisiae, where Rho1p, for example, coordinately controls three distinct biochemical pathways, each of which contributes to the growth of a new bud during cell division. Similarly, in mammalian cells, the ability of Ras to regulate several pathways, not just ERK MAP kinase, explains why it is so efficient at inducing a malignant phenotype. We have focused this review specifically on examples of cross-talk between Ras and Rho GTPases in animal cells. While the biochemical details by which this is achieved are still poorly understood, there is much experimental work that points to the importance of combinatorial activities controlled by these two families in promoting complex biological responses such as cell proliferation, cell transformation, and cell migration. Coordinated regulation of nucleotide exchange factors ensures that distinct subsets of GTPases are activated in response to a given agonist, while the specific recruitment of GAPs can provide a mechanism by which one GTPase leads to inactivation of another. The multiple pathways downstream of Ras and Rho GTPases can act in parallel to provide distinct biochemical activities and they can act synergistically such that activation of one pathway is dependent on the activation of another. So far, examples of each of these scenarios have been observed, although this is probably only the tip of the iceberg. Only as we learn more about the cellular roles of the twenty or so GTPases that constitute the mammalian Ras and Rho families will the biological versatility of these regulatory molecules be fully appreciated.