Redox cycling of 9,10-phenanthrenequinone activates epidermal growth factor receptor signaling through <i>S</i>-oxidation of protein tyrosine phosphatase 1B

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  • Luong Nho Cong
    Doctoral Program in Biomedical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba Faculty of Pharmacy, Hue University of Medicine and Pharmacy, Hue University, Vietnam
  • Abiko Yumi
    Doctoral Program in Biomedical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba Faculty of Medicine, University of Tsukuba
  • Shibata Takahiro
    Graduate School of Bioagricultural Sciences, Nagoya University
  • Uchida Koji
    Graduate School of Bioagricultural Sciences, Nagoya University Graduate School of Agricultural and Life Sciences, The University of Tokyo
  • Warabi Eiji
    Doctoral Program in Biomedical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba Faculty of Medicine, University of Tsukuba
  • Suzuki Midori
    Graduate School of Pharmaceutical Sciences, Tohoku University
  • Noguchi Takuya
    Graduate School of Pharmaceutical Sciences, Tohoku University
  • Matsuzawa Atsushi
    Graduate School of Pharmaceutical Sciences, Tohoku University
  • Kumagai Yoshito
    Doctoral Program in Biomedical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba Faculty of Medicine, University of Tsukuba

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  • Redox cycling of 9,10-phenanthrenequinone activates epidermal growth factor receptor signaling through S-oxidation of protein tyrosine phosphatase 1B

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<p>9,10-Phenanthrenequinone (9,10-PQ) is a polycyclic aromatic hydrocarbon quinone contaminated in diesel exhaust particles and particulate matter 2.5. It is an efficient electron acceptor that induces redox cycling with electron donors, resulting in excessive reactive oxygen species and oxidized protein production in cells. The current study examined whether 9,10-PQ could activate epidermal growth factor receptor (EGFR) signaling in A431 cells through S-oxidation of its negative regulators such as protein tyrosine phosphatase (PTP) 1B. 9,10-PQ oxidized recombinant human PTP1B at Cys215 and inhibited its catalytic activity, an effect that was blocked by catalase (CAT), whereas cis-9,10-dihydroxy-9,10-dihydrophenanthrene (DDP), which lacks redox cycling activity, had no effect on PTP1B activity. Exposure of A431 cells to 9,10-PQ, but not DDP, activated signaling through EGFR and its downstream extracellular signal-regulated kinase 1/2 (ERK1/2), coupled with a decrease of cellular PTP activity. Immunoprecipitation and UPLC-MSE revealed that PTP1B easily undergoes oxidation during exposure of A431 cells to 9,10-PQ. Pretreatment with polyethylene glycol conjugated with CAT (PEG-CAT) abolished 9,10-PQ–generated H2O2 production and significantly blocked the activation of EGFR-ERK1/2 signaling by 9,10-PQ, indicating the involvement of H2O2 in the activation because scavenging agents for hydroxyl radicals had no effect on the redox signal activation. These results suggest that such an air pollutant producing H2O2, activates EGFR-ERK1/2 signaling, presumably through the S-oxidation of PTPs such as PTP1B, and activation of the signal cascade may contribute, at least in part, to cellular responses in A431 cells.</p>

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