TY - JOUR
T1 - Aryl hydrocarbon receptor defect attenuates mitogen‐activated signaling through leucine‐rich repeats and immunoglobulin‐like domains 1 (Lrig1)‐dependent egfr degradation
AU - Hsu, Han Lin
AU - Chen, Hong Kai
AU - Tsai, Chi Hao
AU - Liao, Po Lin
AU - Chan, Yen Ju
AU - Lee, Yu Cheng
AU - Lee, Chen Chen
AU - Li, Ching Hao
N1 - Funding Information:
This study was financed in part by grants 108TMU?WFH?15 (funded by Taipei Medical University?Wan Fang Hospital), MOST 109?2320?B?038?012?MY2, MOST 109?2320?B?038?023, MOST 109?2320?B?038?031 (funded by the Ministry of Science and Technology, Taiwan), and CMU109?MF? 84 (funded by Chinese Medical University).
Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2021/9
Y1 - 2021/9
N2 - 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 leucinerich 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.
AB - 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 leucinerich 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.
KW - A disintegrin and metalloprotease 17 (ADAM17)
KW - Aryl hydrocarbon receptor (AHR)
KW - Cell proliferation
KW - Chronic obstructive pulmonary disease (COPD)
KW - Epidermal growth factor receptor (EGFR)
KW - Leucinerich repeats and immunoglobulin‐like domains 1 (LRIG1)
UR - http://www.scopus.com/inward/record.url?scp=85114881286&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85114881286&partnerID=8YFLogxK
U2 - 10.3390/ijms22189988
DO - 10.3390/ijms22189988
M3 - Article
C2 - 34576152
AN - SCOPUS:85114881286
SN - 1661-6596
VL - 22
JO - International Journal of Molecular Sciences
JF - International Journal of Molecular Sciences
IS - 18
M1 - 9988
ER -