ReviewThe role of Rho GTPases in disease development
Introduction
The family of Rho GTPases comprise a large subfamily of the Ras-superfamily of GTPases. Among all Rho GTPases, Rac1 (Ras-related C3 botulinum toxin substrate 1), Cdc42 (cell division cycle 42) and RhoA (Ras homologous member A) have been studied most extensively. Through the work of many laboratories the role, that Rho GTPases play in cellular processes as diverse as polarization, cell-cell and cell-matrix adhesion, membrane trafficking, cytoskeletal and transcriptional regulation and cell proliferation has made them a group of crucial regulators with a very general relevance (comprehensively reviewed in Hall, 1998, Van Aelst and D'Souza-Schorey, 1997).
As is the case for small GTPases in general, Rho GTPases are guanine nucleotide binding proteins, which cycle between an active GTP-bound and an inactive GDP-bound state, and are subject to distinct control mechanisms. In the inactive state, Rho GTPases are associated with a class of negative regulators, the Rho DP issociation nhibitors (GDIs), that stabilize the GDP-bound form of the GTPase and sequester them in the cytoplasm. Their active state is promoted by positive regulators called DP/TP xchange actors (GEFs) that (a) tether a given GTPase to a distinct subcellular location and (b) by virtue of their signature tandem Dbl homology (DH)/pleckstrin homology (PH) domain exchange GDP moieties associated with the inactive GTPases for GTP. As a consequence, a conformational switch is induced. This in turn renders the GTPase active and allows it to initiate a productive signaling complex with one of several effector proteins. This instigates an information flow to different cellular destinations via different molecular pathways with different physiological outcomes. The active GTP-bound state is counteracted by negative regulators, the TPase ctivating roteins (GAPs), that catalyze the intrinsic ability of a small GTPase to hydrolyze the bound GTP-moiety to GDP (hence the name uanosine ri-hosphat). Thus, effector binding is reversed and signaling activity halted, causing the biochemical system to come full circle. Understanding this biochemical basis for the function of GTPases has greatly benefited research and lead to the development of constitutively active (GTPase-deficient) and dominant negative (nucleotide exchange-defective) mutants that lock a respective GTPase in the GTP- or GDP-bound state. The introduction of such mutants into diverse experimental systems allows for either overactivation or functional deletion of a specific GTPase.
There is a growing list of disease-causing mutations in genes that have been associated with Rho GTPase signaling by means of functional prediction or insights obtained by direct biochemical analysis. These include GEFs, GAPs and effector proteins that appear to be part of quite diverse signaling networks. Surprisingly, though, aberrations in only a single gene encoding a Rho GTPase itself, namely the RhoH gene, have been described thus far to be a putative cause of lymphoma development (see below). Other mutations that may inactivate a Rho gene or lead to an overactive version of the resulting protein due to a lack of extensive screening or functional redundancy have either escaped detection or simply are lethal. This latter possibility is underscored by the fact, that mouse embryos whose Rac1 or Cdc42 genes have been deleted by gene-targeted mutation die early in development (Sugihara et al., 1998, Chen et al., 2000). It may also reflect the multifunctional nature of Rho GTPases. Loss-of-function or constitutive gain-of-function mutations in many Rho GTPases thus may interfere with a number of different cellular processes. Based on our current understanding and dependent on the precise physiological circumstances and cell-types under investigation, a single Rho GTPase can affect a diverse array of phenomena implicated in a cell's specific biology. In addition, there is also continued speculation that Rho-type GTPases need to cycle between their active and inactive states in order to exert their complete physiological potential (discussed by Symons and Settleman, 2000).
On the other hand, it is likely that regulators and effectors of Rho GTPases are expressed and act in a more specific manner, be it in the context of a specific cell-type, tissue-type or developmental process. Genetic loss-of-function mutations in these regulators or effectors, even in form of a germline mutation, may result in a weaker impairment than loss of the respective GTPase itself. The continuing revelation of novel genetic lesions in genes encoding Rho regulators and effectors fully supports this possibility.
The following sections summarize examples of disease processes whose underlying genetic alterations affect the normal function and regulation of Rho GTPases. We examine the importance of such mutations in cancer progression, mental disabilities and other disorders.
Section snippets
Rho GTPases in cancer progression
The evidence that directly implicates aberrant Rho-signaling activity in cancer has been obtained either by means of mutations uncovered in various genes encoding Rho-signaling components, or by screening and interference protocols that focus on specific aspects of cancer biology. For a detailed summary of the biological understanding of the pivotal role of Rho-type GTPases in cancer-related processes such as cell-proliferation, migration, invasion and metastasis, we refer the reader to some
An emerging role for Rho GTPases in neurodegenerative disorders
Rho GTPases are currently gaining increasing attention for their involvement in different classes of neurodegenerative disorders that reflect vital functions of Rho GTPases in diverse aspects of the nervous system. Over the past few years, Rho GTPases have been implicated in neuronal processes including neuronal migration and polarization, axon guidance and dendrite formation, as well as synaptic organization and plasticity (comprehensively reviewed in (Luo, 2000). Given the large number of
FGD1 (faciogenital dysplasia)
By conventional means of forward genetics, the FGD gene has been cloned and revealed to be the mutated locus causing faciogenital dysplasia, also known as Aarskog–Scott syndrome (Pasteris et al., 1994). The discovery of additional mutant FGD-alleles since then has confirmed the role of the gene in the development of the disease (Orrico et al., 2000, Schwartz et al., 2000). Faciogenital dysplasia is an X-linked developmental disorder and individuals are of disproportionately short stature and
Conclusions and future perspectives
Given the complexity of Rho GTPase signaling and the multiple cellular and developmental aspects involving and requiring the function of Rho GTPases, there is a very strong possibility that many more disease-causing mutations in genes encoding Rho-related signaling molecules will be uncovered in the future. The available annotated genome sequences suggest a vast number of genes for Rho GTPase-specific regulators, but many of them remain biologically unexplored to date. Emerging areas of
Acknowledgements
We would like to thank Sarah Newey and Eve-Ellen Govek for their comments on the manuscript. B.B. is a fellow of the ‘Gesellschaft der Naturforscher Leopoldina’. Linda Van Aelst is supported by grants from the NIH, the U.S. Army, and the NF Foundation Inc. Due to the complexity of the subject under review, we would like to apologize to those colleagues whose contributions have not been included.
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