The Myeloperoxidase-Derived Oxidant HOSCN Inhibits Protein Tyrosine Phosphatases and Modulates Cell Signalling via the Mitogen-Activated Protein Kinase (MAPK) Pathway in Macrophages
Open accessAbstract
MPO (myeloperoxidase) catalyses the oxidation of chloride, bromide and thiocyanate by hydrogen peroxide to HOCl (hypochlorous acid), HOBr (hypobromous acid) and HOSCN (hypothiocyanous acid) respectively. Specificity constants indicate that SCN- is a major substrate for MPO. HOSCN is also a major oxidant generated by other peroxidases including salivary, gastric and eosinophil peroxidases. While HOCl and HOBr are powerful oxidizing agents, HOSCN is a less reactive, but more specific, oxidant which targets thiols and especially low pKa species. In the present study we show that HOSCN targets cysteine residues present in PTPs (protein tyrosine phosphatases) with this resulting in a loss of PTP activity for the isolated enzyme, in cell lysates and intact J774A.1 macrophage-like cells. Inhibition also occurs with MPO-generated HOCl and HOBr, but is more marked with MPO-generated HOSCN, particularly at longer incubation times. This inhibition is reversed by dithiothreitol, particularly at early time points, consistent with the reversible oxidation of the active site cysteine residue to give either a cysteine-SCN adduct or a sulfenic acid. Inhibition of PTP activity is associated with increased phosphorylation of p38a and ERK2 (extracellular-signal-regulated kinase 2) as detected by Western blot analysis and phosphoprotein arrays, and results in altered MAPK (mitogen-activated protein kinase) signalling. These data indicate that the highly selective targeting of some protein thiols by HOSCN can result in perturbation of cellular phosphorylation and altered cell signalling. These changes occur with (patho)physiological concentrations of SCN- ions, and implicate HOSCN as an important mediator of inflammation-induced oxidative damage, particularly in smokers who have elevated plasma levels of SCN-.
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Signaling cascades including MAPKs (p38, ERK1/2) are sensitive to HOCl exposure, attributed in part to tyrosine phosphatase modulation through cysteine-oxidation.
“Likewise, signaling cascades including MAPKs (p38, ERK1/2) are sensitive to HOCl exposure attributed in part to tyrosine phosphatase modulation through cysteine-oxidation (139, 140).”
From Hypochlorous Acid: From Innate Immune Factor and Environmental Toxicant to Chemopreventive Agent Targeting Solar UV-Induced Skin Cancer (2022) · cites this paper as [140]
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- Authors
- Lane, A. E., Tan, J. T. M., Hawkins, C. L., Heather, A. K., & Davies, M. J.
- Affiliations
- The Heart Research Institute (AU)
- University of Technology Sydney (AU)
- The University of Sydney (AU)
- Corresponding author
- Davies, Michael J.
- Venue
- Biochemical Journal
- Publisher
- Portland Press Ltd.
- Published
- 2010-07-28
- Volume
- 430
- Issue
- 1
- Pages
- 161-169
- ISSN
- 0264-6021 (ISSN-L)
- 1470-8728
- PMC
- PMC2911680
- OpenAlex
- W2055280915
- Cited by
- 86
- References
- 51
- Citations by year
- 2026: 4 · 2025: 2 · 2024: 5 · 2023: 3 · 2022: 5 · 2021: 5 · 2020: 7 · 2019: 7 · 2018: 2 · 2017: 5 · 2016: 5 · 2015: 4 · 2014: 3 · 2013: 12 · 2012: 9
- FWCI
- 3.65
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Biochemical Journal (publishedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- UTS ePRESS (University of Technology Sydney) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Life Sciences › Immunology and Microbiology › Immunology › Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Keywords
- hypothiocyanous acid, myeloperoxidase, protein tyrosine phosphatase, thiocyanate, cysteine oxidation, sulfenic acid, MAPK signaling, p38 MAPK, ERK2, macrophages, oxidative stress, inflammation, smoking, thiols
- MeSH terms
- Animals, Antioxidants, Cell Line, Macrophages, Peroxidase, Phosphorylation, Thiocyanates, Transcription Factors, Protein Tyrosine Phosphatases, Apoptosis, Mitogen-Activated Protein Kinase 1, MAP Kinase Signaling System, Mitogen-Activated Protein Kinase 14, Mice, Protein Tyrosine Phosphatase, Non-Receptor Type 1
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