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

Nho Cong Luong, Yumi Abiko, Takahiro Shibata, Koji Uchida, Eiji Warabi, Midori Suzuki, Takuya Noguchi, Atsushi Matsuzawa, Yoshito Kumagai

Research output: Contribution to journalArticle

Abstract

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 inhibit-ed its catalytic activity, an effect that was blocked by catalase (CAT), whereas cis-9,10-dihydroxy-9,10-di-hydrophenanthrene (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. Immunopre-cipitation 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 H2 O2 production and significantly blocked the activation of EGFR-ERK1/2 signaling by 9,10-PQ, indicating the involvement of H2 O2 in the activation because scavenging agents for hydroxyl radi-cals had no effect on the redox signal activation. These results suggest that such an air pollutant producing H2 O2, 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.

Original languageEnglish
Pages (from-to)349-363
Number of pages15
JournalJournal of Toxicological Sciences
Volume45
Issue number6
DOIs
Publication statusPublished - 2020

Keywords

  • 9,10-Phenanthrenequinone
  • Epidermal growth factor receptor
  • Hydrogen peroxide
  • Protein tyrosine phosphatases
  • Reactive oxygen species
  • Redox signaling

ASJC Scopus subject areas

  • Toxicology

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