Covalent N-arylation by the pollutant 1,2-naphthoquinone activates the EGF receptor

Kengo Nakahara, Kyohei Hamada, Tomoki Tsuchida, Nobumasa Takasugi, Yumi Abiko, Kazuhiko Shien, Shinichi Toyooka, Yoshito Kumagai, Takashi Uehara

Research output: Contribution to journalArticlepeer-review

Abstract

The epidermal growth factor receptor (EGFR) is the most intensively investigated receptor tyrosine kinase. Several EGFR mutations and modifications have been shown to lead to abnormal self-activation, which plays a critical role in carcinogenesis. Environmental air pollutants, which are associated with cancer and respiratory diseases, can also activate EGFR. Specifically, the environmental electrophile 1,2- naphthoquinone (1,2-NQ), a component of diesel exhaust particles and particulate matter more generally, has previously been shown to impact EGFR signaling. However, the detailed mechanism of 1,2-NQ function is unknown. Here, we demonstrate that 1,2-NQ is a novel chemical activator of EGFR but not other EGFR family proteins. We found that 1,2-NQ forms a covalent bond, in a reaction referred to as N-arylation, with Lys80, which is in the ligand-binding domain. This modification activates the EGFR-Akt signaling pathway, which inhibits serum deprivation-induced cell death in a human lung adenocarcinoma cell line. Our study reveals a novel mode of EGFR pathway activation and suggests a link between abnormal EGFR activation and environmental pollutant- associated diseases such as cancer.

Original languageEnglish
Article number100524
JournalJournal of Biological Chemistry
Volume296
DOIs
Publication statusPublished - Jan 1 2021

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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