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First published online December 15, 2003
doi: 10.1242/10.1242/jcs.00937

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GTPases and reactive oxygen species: switches for killing and signaling

Department of Cell Biology R455, Emory University, Whitehead Biomedical Research Building, 615 Michael Street, Atlanta GA 30322, USA

View larger version (34K): [in a new window]   Fig. 1. Multiple domain interactions drive assembly and function of the NADPH oxidase. The diagram depicts the protein domains and motifs in all the oxidases subunits involved in assembly. The domain localization is approximate and does not exclude additional possible interactions between the subunits. For clarity, the lettering color changes from black to white when the domain is involved in a functional interaction in each state. In the resting state (A), the tandem SH3 domains of p47phox form a groove that binds the poly-basic region in the C-terminal domain. Following signaling from soluble ligands and from phagocytosis, assembly is triggered and the domain interactions change (B). Phosphorylation in the C-terminal domain of p47phox and phosphoinositides binding to PX domains drive the interaction of the tandem SH3 domains with the PRD domain of p22phox and the PRD interaction with an SH3 domain of p67phox. Concurrently, Rac translocates to the membrane and interacts with p67phox and possibly gp91phox in a GTP-dependent fashion.

View larger version (25K): [in a new window]   Fig. 2. NADPH oxidase localization in neutrophils. Diagram based on published information (Borregaard and Cowland, 1997). Approximately 10% of the oxidase is located at the plasma membrane and 90% is located in two separate compartments: the secretory vesicles and specific granules. Secretory vesicles contain several proteins [including complement receptor (CR-1), integrin ß2, N-formyl-methionylleucyl-phenylalanine receptor (fMLP-R)] and are rapidly translocated to the plasma membrane upon regulated exocitosis. Another fraction of gp91phox is included in specific granules, which can either fuse with the phagosome or eventually with the plasma membrane.

View larger version (31K): [in a new window]   Fig. 3. Rac changes the redox state of the cell through the engagement of multiple superoxide sources to modulate signal transduction. Downstream of several cell-surface receptors, Rac is activated to shift the intracellular redox state by triggering superoxide generation from several alternative sources. Tyrosine phosphatases are one of the known targets for superoxide, which are inactivated upon oxidation of a catalytic cysteine residue, thus increasing phosphotyrosine content of several effector proteins in Rac-mediated signal transduction pathways.