RRC ID 37078
著者 Yen HY, Liu YC, Chen NY, Tsai CF, Wang YT, Chen YJ, Hsu TL, Yang PC, Wong CH.
タイトル Effect of sialylation on EGFR phosphorylation and resistance to tyrosine kinase inhibition.
ジャーナル Proc Natl Acad Sci U S A
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.
巻・号 112(22)
ページ 6955-60
公開日 2015-6-2
DOI 10.1073/pnas.1507329112
PII 1507329112
PMID 25971727
PMC PMC4460513
MeSH Cell Line, Tumor Dimerization Enzyme Inhibitors ErbB Receptors / genetics ErbB Receptors / metabolism* Gefitinib Humans Models, Molecular* Mutation, Missense / genetics Neuraminidase / pharmacology* Phosphorylation / drug effects Protein Binding / drug effects Protein-Tyrosine Kinases / antagonists & inhibitors* Quinazolines
IF 9.412
引用数 50
WOS 分野 BIOCHEMISTRY & MOLECULAR BIOLOGY
リソース情報
ヒト・動物細胞 PC-9(RCB4455)