TY - JOUR
T1 - Amphiregulin confers regulatory T cell suppressive function and tumor invasion via the EGFR/GSK-3β/Foxp3 axis
AU - Wang, Sihua
AU - Zhang, Yuan
AU - Wang, Yan
AU - Ye, Ping
AU - Li, Jun
AU - Li, Huabin
AU - Ding, Qingqing
AU - Xia, Jiahong
N1 - Publisher Copyright:
© 2016 by The American Society for Biochemistry and Molecular Biology, Inc.
PY - 2016/9/30
Y1 - 2016/9/30
N2 - Previous studies mainly focused on the role of the epidermal growth factor receptor (EGFR) in tumor cells, whereas the effects of the EGFR on immune responses has not been determined. Our study shows that the EGFR signaling pathway play a role in the regulation of regulatory T cells (Treg cells) in cancer patients. The EGF-like growth factor Amphiregulin (AREG) protein was frequently up-regulated in a tissue microarray, which was associated with worse overall survival. Additionally, in sera, tissue specimens, and effusions of lung or gastric cancer patients, up-regulated AREG protein enhanced the suppressive function of Treg cells. AREG maintained the Treg cell suppressive function via the EGFR/GSK-3β/Foxp3 axis in vitro and in vivo. Furthermore, inhibition of EGFR by the tyrosine kinase inhibitor gefitinib restored the activity of GSK-3β and attenuated Treg cell function. β-TrCP was involved in GSK-3β-mediated Foxp3 degradation, and mass spectrometry identified Lys356 as the ubiquitination site of Foxp3 by β-TrCP. These findings demonstrate the posttranslational regulation of Foxp3 expression by AREG in cancer patients through AREG/EGFR/GSK-3β signaling, which could lead to Foxp3 protein degradation in Treg cells and a potential therapeutic target for cancer treatment.
AB - Previous studies mainly focused on the role of the epidermal growth factor receptor (EGFR) in tumor cells, whereas the effects of the EGFR on immune responses has not been determined. Our study shows that the EGFR signaling pathway play a role in the regulation of regulatory T cells (Treg cells) in cancer patients. The EGF-like growth factor Amphiregulin (AREG) protein was frequently up-regulated in a tissue microarray, which was associated with worse overall survival. Additionally, in sera, tissue specimens, and effusions of lung or gastric cancer patients, up-regulated AREG protein enhanced the suppressive function of Treg cells. AREG maintained the Treg cell suppressive function via the EGFR/GSK-3β/Foxp3 axis in vitro and in vivo. Furthermore, inhibition of EGFR by the tyrosine kinase inhibitor gefitinib restored the activity of GSK-3β and attenuated Treg cell function. β-TrCP was involved in GSK-3β-mediated Foxp3 degradation, and mass spectrometry identified Lys356 as the ubiquitination site of Foxp3 by β-TrCP. These findings demonstrate the posttranslational regulation of Foxp3 expression by AREG in cancer patients through AREG/EGFR/GSK-3β signaling, which could lead to Foxp3 protein degradation in Treg cells and a potential therapeutic target for cancer treatment.
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U2 - 10.1074/jbc.M116.717892
DO - 10.1074/jbc.M116.717892
M3 - Article
C2 - 27432879
AN - SCOPUS:84988926738
SN - 0021-9258
VL - 291
SP - 21085
EP - 21095
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 40
ER -