Yen H.-Y.Liu Y.-C.Chen N.-Y.Tsai C.-F.Wang Y.-T.Chen Y.-J.Hsu T.-L.PAN-CHYR YANGWong C.-H.2020-12-022020-12-0220150027-8424https://www.scopus.com/inward/record.uri?eid=2-s2.0-84930638381&doi=10.1073%2fpnas.1507329112&partnerID=40&md5=06af1dba470bb643894a4c3790dae50dhttps://scholars.lib.ntu.edu.tw/handle/123456789/523508Epidermal 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. ? 2015, National Academy of Sciences. All rights reserved.Dimerization; Gefitinib; Glycosylation; Lung cancer; Tyrosin kinase inhibitor[SDGs]SDG3epidermal growth factor; epidermal growth factor receptor; gefitinib; mutant protein; phosphoserine; phosphothreonine; protein tyrosine kinase; EGFR protein, human; enzyme inhibitor; epidermal growth factor receptor; protein binding; protein tyrosine kinase; quinazoline derivative; sialidase; Article; autophosphorylation; cancer resistance; chemosensitivity; controlled study; dimerization; enzyme inhibition; human; human cell; lung cancer cell line; priority journal; protein phosphorylation; sialylation; antagonists and inhibitors; chemical structure; dimerization; drug effects; genetics; metabolism; missense mutation; phosphorylation; tumor cell line; Cell Line, Tumor; Dimerization; Enzyme Inhibitors; Humans; Models, Molecular; Mutation, Missense; Neuraminidase; Phosphorylation; Protein Binding; Protein-Tyrosine Kinases; Quinazolines; Receptor, Epidermal Growth Factorjournal article10.1073/pnas.1507329112259717272-s2.0-84930638381