Hindawi Publishing Corporation Journal of Signal Transduction Volume 2012, Article ID 365769, 9 pages doi:10.1155/2012/365769 Review Article The Interplay between ROS and Ras GTPases: Physiological and Pathological Implications Elisa Ferro,1 Luca Goitre,2 Saverio Francesco Retta,2 and Lorenza Trabalzini1 1 Department of Biotechnology, University of Siena, Via Fiorentina 1, 53100 Siena, Italy 2 Department of Clinical and Biological Sciences, University of Torino, Regione Gonzole 10, 10043 Orbassano, Italy Correspondence should be addressed to Lorenza Trabalzini, trabalzinil@unisi.it Received 14 July 2011; Accepted 18 October 2011 Academic Editor: Paola Chiarugi Copyright © 2012 Elisa Ferro et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The members of the RasGTPase superfamily are involved in various signaling networks responsible for fundamental cellular processes. Their activity is determined by their guanine nucleotide-bound state. Recent evidence indicates that some of these proteins may be regulated by redox agents. Reactive oxygen species (ROSs) and reactive nitrogen species (RNSs) have been historically considered pathological agents which can react with and damage many biological macromolecules including DNA, proteins, and lipids. However, a growing number of reports have suggested that the intracellular production of ROS is tightly regulated and that these redox agents serve as signaling molecules being involved in a variety of cell signaling pathways. Numerous observations have suggested that some Ras GTPases appear to regulate ROS production and that oxidants function as eﬀector molecules for the small GTPases, thus contributing to their overall biological function. Thus, redox agents may act both as upstream regulators and as downstream eﬀectors of Ras GTPases. Here we discuss current understanding concerning mechanisms and physiopathological implications of the interplay between GTPases and redox agents. 1. Introduction The Ras GTPase superfamily includes low molecular weight GTP-binding and hydrolyzing (GTPases) proteins that act as molecular switches by coupling extracellular signals to diﬀerent cellular responses, thus controlling cellular signal- ing pathways responsible for growth, migration, adhesion, cytoskeletal integrity, survival, and diﬀerentiation. The three human Ras proteins, H-Ras, N-Ras, and K-Ras, are the founding members of this large superfamily of small GTPases comprising over 150 human members with evolutionarily conserved orthologs found in Drosophila, C. elegans, S. cere- visiae, S. pombe, Dictyostelium, and plants. This superfamily is divided into families and subfamilies on the basis of sequence and functional similarities (Table 1). The ﬁve major families are Ras, Rho, Rab, Arf, and Ran [1]. In addition to the diﬀerent Ras isoforms, the Ras family includes Rap, R-Ras, Ral, and Rheb proteins, also regulating signaling networks. Rho GTPase family includes the well-characterized family members Rac1, RhoA, and Cdc42, each of which is associated with unique phenotypes and functions [2–4]. Rab proteins comprise the largest branch of superfamily and regulate intracellular vesicular transport and traﬃcking of proteins. Like the Rab proteins, Arf family proteins are involved in regulation of vesicular transport. The Ran protein is the most abundant small GTPase in the cell and is best known for its function in nucleocytoplasmic transport of both RNA and proteins [1]. Although being similar to the heterotrimeric G protein α subunit in biochemical mechanism and function, Ras GTPases function as monomeric GTP-binding proteins. The functional diversity of these proteins is based on variations in structure, posttranslational modiﬁcations that dictate spe- ciﬁc subcellular localizations, and proteins that act as reg- ulators and eﬀectors [1, 5]. Signal transduction through Ras proteins occurs by re- versible binding of GTP, while the inactive form is bound to GDP. Switching between these two states is regulated by three distinct types of protein modulator agents: Guanine nucleotide Exchange Factors (GEFs) catalyze the exchange of GDP with GTP to promote Ras activation, whereas GTPase- Activating Proteins (GAPs) deactivate the Ras protein by