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.
Highlights
Contributes to cancer [4]
Few studies have indicated that chemical modification of proteins by air pollutants may lead to carcinogenesis
We showed that a component of environmental air pollutants, 1,2-NQ, can activate epidermal growth factor receptor (EGFR) via N-arylation at Lys80
Summary
1,2-NQ activates Akt via the PI3K/phosphoinositide-dependent protein kinase-1 pathway. EGFR kinase inhibitor tyrphostin A25 suppressed 1,2-NQinduced phosphorylation of Akt in a concentration-dependent manner (Fig. 1J and Fig. S2H) These data indicate that 1,2-NQ may modify PTP1B and directly activate EGFR. These results indicate that 1,2-NQ can stimulate only the phosphorylation of EGFR and the formation of homodimer (EGFR) in A549 cells Protein nucleophiles, such as cysteine thiolates, histidine imidazoles, and lysine amines, are reactive to form S- or N-aryl bonds with electrophiles with α,β-unsaturated carbonyl groups, including 1,2-NQ. These results strongly suggested that 1,2-NQ attenuated serum deprivation– induced apoptotic cell death through activation of EGFR–Akt pathway. Our data indicate that 1,2-NQ induces activation of the EGFR–Akt signaling pathway via binding directly to EGFR and that this modification renders cancer cells resistant to apoptotic stimuli
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
