RHO GTPases Activate NADPH Oxidases

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Homo sapiens
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NADPH oxidases (NOX) are membrane-associated enzymatic complexes that use NADPH as an electon donor to reduce oxygen and produce superoxide (O2-) that serves as a secondary messenger (Brown and Griendling 2009).

NOX2 complex consists of CYBB (NOX2), CYBA (p22phox), NCF1 (p47phox), NCF2 (p67phox) and NCF4 (p40ohox). RAC1:GTP binds NOX2 complex in response to VEGF signaling by directly interracting with CYBB and NCF2, leading to enhancement of VEGF-signaling through VEGF receptor VEGFR2, which plays a role in angiogenesis (Ushio-Fukai et al. 2002, Bedard and Krause 2007). RAC2:GTP can also activate the NOX2 complex by binding to CYBB and NCF2, leading to production of superoxide in phagosomes of neutrophils which is necessary fo the microbicidal activity of neutrophils (Knaus et al. 1991, Roberts et al. 1999, Kim and Dinauer 2001, Jyoti et al. 2014).

NOX1 complex (composed of NOX1, NOXA1, NOXO1 and CYBA) and NOX3 complex (composed of NOX3, CYBA, NCF1 amd NCF2 or NOXA1) can also be activated by binding to RAC1:GTP to produce superoxide (Cheng et al. 2006, Miyano et al. 2006, Ueyama et al. 2006).

Literature References
PubMed ID Title Journal Year
23875749 Interaction of inducible nitric oxide synthase with rac2 regulates reactive oxygen and nitrogen species generation in the human neutrophil phagosomes: implication in microbial killing

Chandra, T, Dubey, M, Kumar, S, Keshari, RS, Jyoti, A, Verma, A, Saluja, R, Kumar, A, Singh, AK, Bajpai, VK, Dikshit, M, Barthwal, MK

Antioxid. Redox Signal. 2014
19628035 Nox proteins in signal transduction

Griendling, KK, Brown, DI

Free Radic. Biol. Med. 2009
12480817 Novel role of gp91(phox)-containing NAD(P)H oxidase in vascular endothelial growth factor-induced signaling and angiogenesis

Alexander, RW, Quinn, MT, Fujimoto, M, Ma, Y, Dikalov, SI, Johnson, C, Ushio-Fukai, M, Fukai, T, Pagano, PJ, Tang, Y

Circ. Res. 2002
16762923 Direct involvement of the small GTPase Rac in activation of the superoxide-producing NADPH oxidase Nox1

Takeya, R, Miyano, K, Sumimoto, H, Ueno, N

J. Biol. Chem. 2006
1660188 Regulation of phagocyte oxygen radical production by the GTP-binding protein Rac 2

Bokoch, GM, Curnutte, JT, Evans, T, Knaus, UG, Heyworth, PG

Science 1991
16636067 Nox1-dependent reactive oxygen generation is regulated by Rac1

Lambeth, JD, Diebold, BA, Hughes, Y, Cheng, G

J. Biol. Chem. 2006
16507994 Involvement of Rac1 in activation of multicomponent Nox1- and Nox3-based NADPH oxidases

Geiszt, M, Ueyama, T, Leto, TL

Mol. Cell. Biol. 2006
11145705 Rac2 is an essential regulator of neutrophil nicotinamide adenine dinucleotide phosphate oxidase activation in response to specific signaling pathways

Kim, C, Dinauer, MC

J. Immunol. 2001
17237347 The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology

Bedard, K, Krause, KH

Physiol. Rev. 2007
10072071 Deficiency of the hematopoietic cell-specific Rho family GTPase Rac2 is characterized by abnormalities in neutrophil function and host defense

Kim, C, Zhen, L, Kapur, R, Dinauer, MC, Petryniak, B, Williams, DA, Roberts, AW, Spaetti, A, Pollock, JD, Lowe, JB, Borneo, JB, Bradford, GB, Atkinson, SJ

Immunity 1999
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