Aryl Hydrocarbon Receptor Defect Attenuates Mitogen-Activated Signaling through Leucine-Rich Repeats and Immunoglobulin-like Domains 1 (LRIG1)-Dependent EGFR Degradation.

Han-Lin Hsu,Yu-Cheng Lee,Hong-Kai Chen,Chi-Hao Tsai,Ching-Hao Li,Chen-Chen Lee,Po-Lin Liao,Yen-Ju Chan

doi:10.3390/ijms22189988

Abstract

Aryl hydrocarbon receptor (AHR) genomic pathway has been well-characterized in a number of respiratory diseases. In addition, the cytoplasmic AHR protein may act as an adaptor of E3 ubiquitin ligase. In this study, the physiological functions of AHR that regulate cell proliferation were explored using the CRISPR/Cas9 system. The doubling-time of the AHR-KO clones of A549 and BEAS-2B was observed to be prolonged. The attenuation of proliferation potential was strongly associated with either the induction of p27Kip1 or the impairment in mitogenic signal transduction driven by the epidermal growth factor (EGF) and EGF receptor (EGFR). We found that the leucine-rich repeats and immunoglobulin-like domains 1 (LRIG1), a repressor of EGFR, was induced in the absence of AHR in vitro and in vivo. The LRIG1 tends to degrade via a proteasome dependent manner by interacting with AHR in wild-type cells. Either LRIG1 or a disintegrin and metalloprotease 17 (ADAM17) were accumulated in AHR-defective cells, consequently accelerating the degradation of EGFR, and attenuating the response to mitogenic stimulation. We also affirmed low AHR but high LRIG1 levels in lung tissues of chronic obstructive pulmonary disease (COPD) patients. This might partially elucidate the sluggish tissue repairment and developing inflammation in COPD patients.

Highlights

The activities of epithelial cells respond to a subset of growth factors in their surrounding environment
By using a coimmunoprecipitation assay, we demonstrated the protein–protein interactions among Aryl hydrocarbon receptor (AHR), EGF receptor (EGFR), and LRIG1 in A549 wt
Tobacco smoke, allergens, microorganisms, and ozone are thought to induce airway inflammation and injure airway epithelium. Some of these factors are AHR active and can impair airway homeostasis via the AHR genomic pathway [19,27]. These factors might ablate the AHR content [27], which is frequently seen in aging [28] and chronic obstructive pulmonary disease (COPD) [29,30]

Summary

Introduction

The activities of epithelial cells respond to a subset of growth factors in their surrounding environment. EGFR belongs to the erbB receptor tyrosine kinase (RTK) family, and is ubiquitously expressed in epithelial, mesenchymal, and neuronal cells. Upon the binding of soluble EGF peptide to the extracellular domain, the EGFR preferentially dimerizes with their cognate receptor, the erbB2, which is constitutively active without any identifiable ligand binding. The dimerization of EGFR and erb is an essential step for the autophosphorylation of key tyrosine residues within the cytoplasmic portion of EGFR. This activates the tyrosine kinase activity and initiates intracellular signaling pathways involving mitogen-activated protein kinase (MEK)/mitogen-activated protein kinase (MAPK) pathway, phosphoinositide-3 kinase/protein kinase B (Akt) pathway, and Janus kinase (Jak)/signal transducer and activator of transcription (STAT) pathway. EGFR mutations are found in 40% of lung cancers [2], suggesting that EGFR might be identified as a selective target during cancer chemotherapy

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Conclusion