Molecular regulation of NADPH oxidase 5 via the MAPK pathway

Pandey, D.; Fulton, D. J. R.

doi:10.1152/ajpheart.01163.2010

Cited by 55Redox biology and oxidative stressProtein Kinase Regulation and GTPase SignalingNeutrophil, Myeloperoxidase and Oxidative Mechanisms

Molecular regulation of NADPH oxidase 5 via the MAPK pathway

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Pandey, D., Fulton, D. J. R.·2011·American Journal of Physiology-Heart and Circulatory Physiology

DOI 10.1152/ajpheart.01163.2010PMC PMC3075021

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Abstract

The mechanisms controlling the activity of NADPH oxidase 5 (Nox5) are unique in that they are independent of the protein: protein interactions that coordinate the activation of other Nox isoforms. Instead, the primary driving force for Nox5 activity is calcium. However, in a previous study we reported that the protein kinase C (PKC)-agonist PMA could induce a sustained activation of Nox5 that was independent of calcium changes. This apparent calcium-independent activation was found to be mediated by the PKC-dependent phosphorylation of specific serine and threonine residues on Nox5 which increased the calcium sensitivity of the enzyme and enabled activation at resting levels of calcium. However, the specific kinase(s) mediating the phosphorylation and activation of Nox5 are not known. As PKC can activate the MEK/ERK1/2 signaling pathway, we hypothesized that Nox5 is activated by the coordinated phosphorylation of both MAPK and PKC pathways. The inhibition of MEK1 using PD-98059 and U-0126 significantly reduced the phosphorylation and activity of Nox5 in response to PMA but not to the calcium-mobilizing stimulus ionomycin. Dominant negative MEK1 and knockdown of endogenous MEK1/2 using a specific small interfering RNA also inhibited Nox5 activity in response to PMA. The mutation of S498 to a nonphosphorylatable residue and to a lesser degree T494 blocked the ability of ERK to stimulate Nox5 activity. However, a constitutively active form of MEK1 failed to increase Nox5 activity in the absence of PMA stimulation. These results suggest that the MEK/ERK1/2 pathway is necessary but not sufficient to regulate the PMA-dependent activation of Nox5.

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Production of NO in basal conditions is largely regulated by the activity of endothelial NOS (eNOS) in the vascular endothelium.
“The production of NO in basal conditions is largely regulated by the activity of endothelial NOS (eNOS) in the vascular endothelium”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [716]

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Authors: Pandey, D., & Fulton, D. J. R.
Affiliations: Center for Vascular Biology Research (US)
Augusta University (US)
Corresponding author: Fulton, D. J. R.
ORCID: Fulton, D. J. R.
Venue: American Journal of Physiology-Heart and Circulatory Physiology
Publisher: American Physiological Society
Published: 2011-04
Volume: 300
Issue: 4
Pages: H1336-H1344
ISSN: 0363-6135 (ISSN-L)
1522-1539
DOI: 10.1152/ajpheart.01163.2010
PMC: PMC3075021
OpenAlex: W2132021477
Cited by: 55
References: 50
Citations by year: 2026: 1 · 2025: 1 · 2023: 2 · 2022: 2 · 2021: 4 · 2020: 5 · 2019: 6 · 2018: 3 · 2017: 3 · 2016: 3 · 2015: 7 · 2014: 6 · 2013: 3 · 2012: 7
FWCI: 2.33
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: American Journal of Physiology-Heart and Circulatory Physiology (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: National Heart, Lung, and Blood Institute (R01HL085827, HL092446, HL 085827, R01HL092446)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Life Sciences › Immunology and Microbiology › Immunology › Neutrophil, Myeloperoxidase and Oxidative Mechanisms
Keywords: NADPH oxidase 5, MAPK signaling, MEK/ERK1/2 pathway, protein kinase C, PMA, protein phosphorylation, calcium-independent activation, calcium sensitivity, MEK1, ERK, oxidative stress, cardiomyocytes
MeSH terms: NADPH Oxidase 5, Butadienes, Calcium, Cell Line, Enzyme Inhibitors, Flavonoids, Humans, Ionophores, Membrane Proteins, Nitriles, Phorbols, Phosphorylation, Protein Kinase C, Ionomycin, NADPH Oxidases, Mitogen-Activated Protein Kinases, RNA, Small Interfering, MAP Kinase Kinase 1, MAP Kinase Kinase 2

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Molecular regulation of NADPH oxidase 5 via the MAPK pathway

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