2 Ras H-Ras K-Ras N-Ras E-Ras TC21 R-Ras M-Ras Rap1A Rap1B Rap2A Rap2B RalA RalB Others Rab Rab1A Rab1B Rab2 Rab3A Rab3B Rab4 Rab5A Rab5B Rab6 Rab7 Rab8 Rab9 Rab10 Others Rho RhoA RhoB RhoC RhoD RhoE Rnd1 Rnd2 RhoG Rac1 Rac2 Rac3 Cdc42 TC10 TTF Others Sec N-Sec1 S-Sec1 Sec4 Sly1p Others Arf Arf1 Arf2 Arf3 Arf4 Arf5 Arf6 Arf7 Others Rad Rad Gem Kir Rem1 Rem2 Others Table 1: The Ras superfamily of small GTPases. The RasGTPase superfamily is divided into 9 families of small GTP-binding proteins on the basis of sequence and functional similarities (modiﬁed from [7]). Journal of Signal Transduction Ran Ran/TC4 Dexras1 Others RheS Rhes Others Rit Rit Rin Ric Others stimulating hydrolysis of bound GTP to GDP. Deactivation can also be achieved by association with Guanine Nucleotide Dissociation Inhibitors (GDIs), which prevent membrane association, and GDP dissociation. All of these regulatory proteins are themselves aﬀected by diverse upstream signals, which serve to activate or inactivate Ras GTPase signaling pathways. The transition of Ras proteins between the GDP- and GTP-bound states is accompanied by a conformational change that greatly enhances their aﬃnity for downstream eﬀectors [6]. The interaction between the active GTP-bound GTPase and the eﬀector molecule leads to activation of downstream signal transduction pathways. In addition to these protein regulatory factors, many of the Ras superfamily small GTPases have been shown to be redox sensitive, and their known conserved redox-sensitive sequences have been termed the NKCD, GXXXXGK(S/T)C, and CGNKXD motifs. The action of redox agents on these redox-sensitive GTPases is similar to that of guanine nu- cleotide exchange factors in that they perturb GTPase nu- cleotide-binding interactions that result in the enhancement of the guanine nucleotide exchange of small GTPases [7]. For many years, the generation of intracellular redox agents such as reactive oxygen species (ROS) and reactive ni- trogen species (RNS) was viewed solely as the unregulated by-product of aerobic metabolism and other enzymatic processes, and redox agents have been historically considered pathological agents which can react with and damage many biological macromolecules including DNA, proteins, and lipids. However, over the last years a growing number of reports have suggested that mammalian cells can rapidly respond to ligand stimulation with a change in intracellular ROS thus indicating that the production of intracellular ROS is tightly regulated and that these redox agents serve as intracellular signaling molecules being involved in a variety of cell signaling pathways, including growth factor signaling [8, 9], inﬂammation [10], engagement of integrins [11, 12], and adhesion to extracellular matrix [13]. The precise means of regulation is not completely understood. However, numerous observations have suggested that the Ras GTPases appear to regulate ROS production and that oxidants func- tion as eﬀector molecules for the small GTPases, thus con- tributing to their overall biological function [14]. Here we discuss current understanding concerning the interplay between GTPases and redox agents. The discussion also takes into account pathological implications of alter- ations of both ROS regulation by small GTPases and small GTPases regulation by ROS. 2. ROS Regulation by RasGTPases Among the major source of ROS, NADPH oxidases have been demonstrated to play a fundamental role in the com- partmentalization of ROS production and redox signaling [15]. Besides NADPH oxidase, an important role in the spatio-temporal regulation of ROS production is also played by enzymes involved in arachidonic acid (AA) metabolism, such as phospholipase A2 (PLA2), lipooxygenases (LOXs), and cyclooxygenases (COXs), suggesting that a complex reg- ulatory network may take place for proper modulation of re- dox signaling [16]. The NADPH oxidase (NOX) complex was originally identiﬁed in phagocytic leukocytes as an enzymatic defense system against infections required for the oxidative burst- dependent microbial killing [17–19]. It is composed of membrane-associated and cytosolic components, which assembly to form the active NOX enzymatic complex in response to appropriate stimuli. Speciﬁcally, this complex consists of membrane-associated cytochrome b558, com- prising the catalytic gp91phox (also known as NOX2) and regulatory p22phox subunits, and four cytosolic regulatory components, including p40phox, p47phox, p67phox, and the small GTPase Rac1 [17]. The neutrophil expresses two diﬀerent Rac isoforms, including the phagocyte-speciﬁc Rac2 and the more ubiquitously expressed Rac1. Detailed