Effects of environmental chemicals on EGFR signaling via protein modification

Abstract

Environmental electrophiles are known to covalently bind to nucleophilic residues such as cysteine, serine, and histidine in proteins. Modification of protein by electrophiles is predicted to play some pivotal roles in the homeostasis and development of disorders. Previously, we demonstrated that the environmental electrophile 1,2-naphthoquinone (1,2-NQ) is a novel chemical activator of EGFR but not other EGFR family proteins. We have 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. Subsequently, we next focused on methyl vinyl ketone (MVK) found in cigarette smoke and exhaust gas. Interestingly, MVK suppressed phosphatidylinositol-3 kinase (PI3K)–Akt signaling. We persued that MVK directly modified Cys656 in the SH2 domain of the PI3K p85 subunit and inhibited the interaction between the epidermal growth factor (EGF) receptor and PI3K in vitro and in human A549 adenocarcinoma cells. These results provide some models for future studies analyzing environmental reactive species. In this symposium, we will discuss the roles of environmental electrophiles via protein modifications.