Overview of Rho GTPase History
It is estimated that approximately 1% of the human genome encodes proteins that either regulate or are regulated by direct interaction with members of the Rho (Ras-homologous) family of small GTPases (Jaffe and Hall 2005). Rho GTPases are low molecular weight proteins (21–28 kDa) that control complex biological processes. The most widely studied and best-characterized members are the three “classical” members, RhoA, Rac1, and Cdc42, and much of our current concepts of Rho GTPase function are based on their properties (Aspenstrom et al. 2007; Wennerberg and Der 2004). They act as bi-molecular switches that cycle between two conformational states: GDP-bound (“inactive” state) and GTP-bound (“active” state) and they hydrolyze GTP. In the “active” GTP-bound state, Rho is able to activate downstream effectors. There are 20 human family members (Fig. 1.1) that receive extracellular ligand-stimulated signals from upstream cell surface receptors including tyrosine kinase, cytokine, adhesion, integrin, and G-protein-coupled receptors (GPCRs). They transmit signals to a plethora of cytoplasmic effectors that regulate essentially all aspects of normal cell physiology (Etienne-Manneville and Hall 2002). These include the regulation of cell proliferation and survival, cell polarity and morphogenesis, adhesion, migration, growth, gene transcription, and vesicular trafficking. Moreover, a causal role for the aberrant regulation of Rho GTPases has been found for human disease, including cancer, and in neurological and developmental disorders (Govek et al. 2005; Sahai and Marshall 2002). Rho GTPases are also targeted by pathogenic bacteria to facilitate their infection of human cells (Finlay 2005; Munter et al. 2006). In this chapter, we provide a historical overview of some of the key discoveries that provide the foundation for our current knowledge of Rho GTPase regulation and function, with an emphasis on the importance of deregulated Rho GTPase function in human disease.
KeywordsActin Stress Fiber CAAX Motif Actin Cytoskeletal Organization
We thank Kent Rossman for help with preparation of the dendrogram of the Rho family GTPases and Lanika DeGrafenreid for assistance in manuscript preparation. We apologize to all colleagues whose work could not be cited due to space limitations. Our studies are supported by NIH grants CA063071 and CA67771.
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