Effect of Sialylation on EGFR Function and Resistance to Tyrosine Kinase Inhibitor Gefitinib
Date Issued
2014
Date
2014
Author(s)
Yen, Hsin-Yung
Abstract
Epidermal growth factor receptor (EGFR) is a heavily glycosylated transmembrane receptor tyrosine kinase. Upon EGF-binding, EGFR commences conformational changes to dimerize, which results in kinase activation and auto-phosphorylation, and the activation of downstream signaling. Previously, we have demonstrated the suppression effect of EGFR sialylation on its dimerization and phosphorylation in lung cancer cells. To further investigate the mechanism of sialylation on EGFR activation and how sialylation regulates EGFR phosphorylation, we investigated the impact of sialylation on the kinetics of EGF-binding and EGFR dimerization as well as autophosphorylation. The result indicated that sialylation of EGFR suppressed EGF/EGFR association, and this negative regulatory effect was confirmed by downregulation of tyrosine phosphosites in EGFR. Moreover, sialylation showed significant impact on EGFR serine/threonine phosphorylation in lung cancer cells and affected the interactive dynamics between EGFR and other kinases. Of particular interest is a site-specific suppression of pY1173 by sialylation was observed in an EGFR tyrosine kinase inhibitor (TKI)-resistant mutant (L858R/T790M) and the sensitivity to gefitinib was enhanced by sialylation in the lung cancer cell line with this EGFR mutant. Our studies showed a selective effect on the phosphorylation of a TKI-resistant mutant, and this observation may provide insights into a new therapeutic intervention.
Subjects
涎酸醣化
表皮生長因子接收器
二聚體化
磷酸化
突變
艾瑞莎
SDGs
Type
thesis
File(s)![Thumbnail Image]()
Loading...
Name
ntu-103-D97b46007-1.pdf
Size
23.32 KB
Format
Adobe PDF
Checksum
(MD5):b3cd97e2525cbe53f9c30dd5644d52ef