Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.4.99.7 (sialyltransferase)
 1,534 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glycosylation of the thyrotropin receptor (TSHR) has been shown to be essential for correct protein folding and for cell-surface targeting. In a recent study, we detected increased expression of beta-galactoside alpha(2,6)-sialyltransferase (SIAT1) in toxic thyroid adenomas where gain-of-function mutations of the TSHR have been invoked as one of the major causes. To investigate the physiological meaning of these findings, we designed experiments to evaluate the consequences of sialylation for the expression of the TSHR. Hence, we investigated the effect of coexpressing the TSHR and different sialyltransferases (SIAT1, SIAT4a, and SIAT8a) for cell-surface expression of the receptor. Coexpression of each of the three SIAT isoforms and the TSHR in COS-7 cells increased TSHR expression on the cell surface in the range of 50 to 100%. Moreover, Western blot analysis with lectins specific for alpha(2,3) and alpha(2,6)-linked sialic acids and lectin-binding enzyme-linked immunosorbent assay support a direct effect on TSHR cell-surface expression mediated by sialic acid transfer to the TSHR. Finally, we treated living COS-7 cells after cotransfection of TSHR and SIAT8a with neuraminidase for 30 min to remove covalently linked sialic acid. Subsequent loss of TSHR cell-surface expression suggests that sialylation prolongs the resting time of the TSHR on the cell surface. Our data demonstrate for the first time that the transfer of sialic acid can improve and prolong cell-surface expression of a transmembrane receptor.
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PMID:Sialylation of human thyrotropin receptor improves and prolongs its cell-surface expression. 1601 6

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.
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PMID:Effect of sialylation on EGFR phosphorylation and resistance to tyrosine kinase inhibition. 2597 27