NOXO1, Regulation of Lipid Binding, Localization, and Activation of Nox1 by the Phox Homology (PX) Domain

Cheng, Guangjie; Lambeth, J. David

doi:10.1074/jbc.m305968200

Cited by 189 publications

(198 citation statements)

References 44 publications

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“…Finally, plasma membrane targeting of Noxo1β-GFP is dramatically disrupted with the Noxo1β(R40Q)-GFP mutant (Fig. 2C), which correlates with the lower Nox1 activity supported by this mutant [25]. These observations are consistent with the co-localization of Noxo1β and Nox1 on the plasma membrane of HEK293 cells, which is seen even without cell stimulation [25].…”

Section: Discussionsupporting

confidence: 74%

“…Nox1 activity depends on at least three cytoplasmic proteins: Noxo1 and Noxa1 (homologs of p47 phox and p67 phox , respectively) and the small GTPase, Rac1 [13][14][15][17][18][19]25]. GTP-bound Rac1 appears to regulate Nox1 through its binding partner, Noxa1, which is in turn dependent on Noxo1 to associate with the plasma membrane [17].…”

Section: Discussionmentioning

confidence: 99%

“…Several groups described structural variants of human Noxo1, which were proposed to result from alternative splicing of mRNA sequences encoding their PX domains [14,15,25,26]. We characterized Noxo1α and showed that it supports Nox1 activity in several transfected cell models (Genbank™ accession no.…”

Section: Introductionmentioning

confidence: 99%

“…AY255768) [14]. Most reports studied Noxo1β (human or mouse), the most common isoform [9,13,15,17,25]. Noxo1β and Noxo1γ isoforms were compared recently for their abilities to support Nox1 and Nox3-based oxidases [26].…”

Section: Introductionmentioning

confidence: 99%

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Subcellular localization and function of alternatively spliced Noxo1 isoforms

Ueyama

Lekstrom

Tsujibe

et al. 2007

Free Radical Biology and Medicine

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Nox organizer 1 (Noxo1), a p47 phox homolog, is produced as four isoforms with unique N-terminal PX domains derived by alternative mRNA splicing. We compared the subcellular distribution of these isoforms or their isolated PX domains produced as GFP fusion proteins, as well as their ability to support Nox1 activity in several transfected models. Noxo1α, β, γ, and δ show different subcellular localization patterns, determined by their PX domains. In HEK293 cells, Noxo1β exhibits prominent plasma membrane binding, Noxo1γ shows plasma membrane and nuclear associations, Noxo1α and δ localize primarily on intracellular vesicles or cytoplasmic aggregates, but not the plasma membrane. Nox1 activity correlates with Noxo1 plasma membrane binding in HEK293 cells, since Noxo1β supports the highest activity and Noxo1γ and Noxo1α support moderate or low activities, respectively. In COS-7 cells, where Noxo1α localizes on the plasma membrane, the activities supported by the three isoforms (α, β, and γ) do not differ significantly. The PX domains of β and γ bind the same phospholipids, including phosphatidic acid. These results indicate the variant PX domains are unique determinants of Noxo1 localization and Nox1 function. Finally, the overexpressed Noxo1 isoforms do not affect p22 phox localization, although Nox1 is needed to transport p22 phox to the plasma membrane.

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Section: Discussionsupporting

confidence: 74%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Subcellular localization and function of alternatively spliced Noxo1 isoforms

Ueyama

Lekstrom

Tsujibe

et al. 2007

Free Radical Biology and Medicine

View full text Add to dashboard Cite

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“…However, rotenone did not affect ROS generation (data not shown), indicating that mitochondrial mechanisms are not involved in K-Ras-induced ROS generation. As Nox1 activity is regulated by the cytosolic regulatory subunit p47 phox or its homolog NOXO1, 22,23 cells were treated with siRNAs targeting p47 phox or NOXO1 (Supplementary Figure S2B). Downregulation of p47 phox inhibited K-Ras V12 -induced ROS generation and anchorage-independent colony formation, whereas siRNAs targeting NOXO1 did not (Figures 2c and d), suggesting that p47 phox has a crucial role in K-Ras V12 -induced activation of Nox1.…”

Section: Resultsmentioning

confidence: 99%

Novel signaling axis for ROS generation during K-Ras-induced cellular transformation

et al. 2014

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Reactive oxygen species (ROS) are well known to be involved in oncogene-mediated cellular transformation. However, the regulatory mechanisms underlying ROS generation in oncogene-transformed cells are unclear. In the present study, we found that oncogenic K-Ras induces ROS generation through activation of NADPH oxidase 1 (NOX1), which is a critical regulator for the K-Ras-induced cellular transformation. NOX1 was activated by K-Ras-dependent translocation of p47 phox , a subunit of NOX1 to plasma membrane. Of note, PKCd, when it was activated by PDPK1, directly bound to the SH3-N domain of p47 phox and catalyzed the phosphorylation on Ser348 and Ser473 residues of p47 phox C-terminal in a K-Ras-dependent manner, finally leading to its membrane translocation. Notably, oncogenic K-Ras activated all MAPKs (JNK, ERK and p38); however, only p38 was involved in p47 phox -NOX1-dependent ROS generation and consequent transformation. Importantly, K-Ras-induced activation of p38 led to an activation of PDPK1, which then signals through PKCd, p47 phox and NOX1. In agreement with the mechanism, inhibition of p38, PDPK1, PKCd, p47 phox or NOX1 effectively blocked K-Ras-induced ROS generation, anchorage-independent colony formation and tumor formation. Taken together, our findings demonstrated that oncogenic K-Ras activates the signaling cascade p38/ PDPK1/PKCd/p47 phox /NOX1 for ROS generation and consequent malignant cellular transformation.

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Aspects of Nox/Duox Signaling

Ushio‐Fukai

2009

Redox Signaling and Regulation in Biology and Medicine

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NOXO1, Regulation of Lipid Binding, Localization, and Activation of Nox1 by the Phox Homology (PX) Domain

Cited by 189 publications

References 44 publications

Subcellular localization and function of alternatively spliced Noxo1 isoforms

Subcellular localization and function of alternatively spliced Noxo1 isoforms

Novel signaling axis for ROS generation during K-Ras-induced cellular transformation

Aspects of Nox/Duox Signaling

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