title: Effect of sialylation on EGFR phosphorylation and resistance to tyrosine kinase inhibition.
abstract: Epidermal growth factor receptor (EGFR) is a heavily glycosylated transmembrane receptor tyrosine kinase. Upon EGF-binding, EGFR undergoes conformational changes to dimerize, resulting in kinase activation and autophosphorylation and downstream signaling. Tyrosine kinase inhibitors (TKIs) have been used to treat lung cancer by inhibiting EGFR phosphorylation. Previously, we demonstrated that EGFR sialylation suppresses its dimerization and phosphorylation. In this report, we further investigated the effect of sialylation on the phosphorylation profile of EGFR in TKI-sensitive and TKI-resistant cells. Sialylation was induced in cancer progression to inhibit the association of EGFR with EGF and the subsequent autophosphorylation. In the absence of EGF the TKI-resistant EGFR mutant (L858R/T790M) had a higher degree of sialylation and phosphorylation at Y1068, Y1086, and Y1173 than the TKI-sensitive EGFR. In addition, although sialylation in the TKI-resistant mutants suppresses EGFR tyrosine phosphorylation, with the most significant effect on the Y1173 site, the sialylation effect is not strong enough to stop cancer progression by inhibiting the phosphorylation of these three sites. These findings were supported further by the observation that the L858R/T790M EGFR mutant, when treated with sialidase or sialyltransferase inhibitor, showed an increase in tyrosine phosphorylation, and the sensitivity of the corresponding resistant lung cancer cells to gefitinib was reduced by desialylation and was enhanced by sialylation.
authors.affiliation: Institute of Biochemical Sciences and Genomics Research Center.
authors.forename: Hsin-Yung
authors.initials: HY
authors.lastname: Yen
authors.affiliation: Genomics Research Center.
authors.forename: Ying-Chih
authors.initials: YC
authors.lastname: Liu
authors.affiliation: Genomics Research Center, Institute of Microbiology and Immunology, National Yang-Ming University, Taipei 112, Taiwan; and.
authors.forename: Nai-Yu
authors.initials: NY
authors.lastname: Chen
authors.affiliation: Institute of Chemistry and Department of Chemistry, National Taiwan University, Taipei 106, Taiwan;
authors.forename: Chia-Feng
authors.initials: CF
authors.lastname: Tsai
authors.affiliation: Institute of Biochemical Sciences and Institute of Chemistry and Chemical Biology and Molecular Biophysics Program, Taiwan International Graduate Program, Academia Sinica, Taipei 115, Taiwan;
authors.forename: Yi-Ting
authors.initials: YT
authors.lastname: Wang
authors.affiliation: Institute of Chemistry and.
authors.forename: Yu-Ju
authors.initials: YJ
authors.lastname: Chen
authors.affiliation: Genomics Research Center.
authors.forename: Tsui-Ling
authors.initials: TL
authors.lastname: Hsu
authors.affiliation: Department of Internal Medicine, College of Medicine, National Taiwan University, Taipei 100, Taiwan pcyang@ntu.edu.tw chwong@gate.sinica.edu.tw.
authors.forename: Pan-Chyr
authors.initials: PC
authors.lastname: Yang
authors.affiliation: Institute of Biochemical Sciences and Genomics Research Center, pcyang@ntu.edu.tw chwong@gate.sinica.edu.tw.
authors.forename: Chi-Huey
authors.initials: CH
authors.lastname: Wong
mesh_terms: D045744:Cell Line, Tumor; D019281:Dimerization; D004791:Enzyme Inhibitors; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D000077156:Gefitinib; D006801:Humans; D008958:Models, Molecular; D020125:Mutation, Missense / Q000235:genetics; D009439:Neuraminidase / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011799:Quinazolines
chemical_list: D004791:Enzyme Inhibitors; D011799:Quinazolines; C512478:EGFR protein, human; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D009439:Neuraminidase; D000077156:Gefitinib
keywords: dimerization; gefitinib; glycosylation; lung cancer; tyrosin kinase inhibitor