Signaling by Rho Family GTPases

The GTPase family of small GTP-binding proteins comprises a group of signaling molecules that are activated by growth factors, cytokines, adhesion molecules, hormones and integrins. They regulate a wide range of biological processes, including reorganization of the actin cytoskeleton, transcriptional regulation, vesicle trafficking, morphogenesis, neutrophil activation, phagocytosis, mitogenesis, apoptosis and tumorigenesis. The mammalian GTPase family currently consists of three subfamilies: Rho, Rac and Cdc42. Each controls the formation of a distinct cytoskeletal element in mammalian cells. Activation of Rac induces actin polymerization to form lamellipodia, whereas activation of Cdc42 stimulates the polymerization of actin to filopodia or microspikes. In contrast, Rho regulates bundling of actin filaments into stress fibers and the formation of focal adhesion complexes. The small GTPases act as molecular switches, cycling between an active GTP-bound state and an inactive GDP-bound state, a process that is regulated by Guanine nucleotide exchange factors (GEF) and GTPase activating proteins (GAP).A number of proteins have been identified as targets of Rho with ROCK being a prominent target. ROCK phosphorylates MLC which plays an important role in actomyosin contractility. ROCK also activates LIMK, which results in Cofilin inactivation and leads to actin polymerization. Both Rac and Rho bind to and activate PIP5K which then activates ERM proteins. ROCK also phosphorylates intermediate filaments such as vimentin and desmin. These effects of ROCK have been linked to reorganization of intermediate filaments at cytokinesis.Similar to Rho, Rac and Cdc42 also affect numerous downstream molecules that mediate effects on the cytoskeleton and gene expression. Rac releases active WAVE, which promotes actin polymerization in lamellipodia through activation of the ARP2/3 complex. Rac and Cdc42 bind and activate PAK family members. PAKs have multiple substrates, including LIMK and OP18/Stathmin. Rac and Cdc42 also bind to the actin-binding protein IQGAP, which is implicated in regulation of cell-cell adhesion and microtubule orientation. Rac and Cdc42 also bind to PI3K, thus activating the PI3K/AKT signaling pathway.Signaling pathways that are regulated by GTPase family members play an important role in several pathological conditions, including cancer, inflammation, and bacterial infections. Although substantial evidence indicates that the balance between the two nucleotide-bound states of these proteins correlates well with their ability to promote biological responses, the precise mechanism by which this balance is regulated is still largely unknown. Moreover, although it is clear that a discrete 'on-off' switch is too simple a mechanism to account for the current experimental evidence, whether the regulated intracellular translocation of GTPases plays a role still needs to be elucidated.