期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 103, 期 50, 页码 18987-18991出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0609281103
关键词
carbohydrate-to-carbohydrate interaction; N-linked glycan; glycosphingolipid; ganglioside; oligosaccharide Fr.B
Epidermal growth factor receptor (EGFR) at membrane microdomains plays an essential role in the growth control of epidermal cells, including cancer cells derived therefrom. Ligand-dependent activation of EGFR tyrosine kinase is known to be inhibited by ganglioside GM3, but to a much lesser degree by other glycosphingolipids. However, the mechanism of the inhibitory effect of GM3 on EGFR tyrosine kinase has been ambiguous. The mechanism is now defined by binding of N-linked glycan having multiple GlcNAc termini to GM3 through carbohydrate-to-carbohydrate interaction, based on the following data: (i) EGFR (molecular mass, approximate to 170 kDa) has N-linked glycan with GlcNAc termini, as probed by mAb (J1) or lectin (GS-II); (h) GS-II-bound EGFR also bound to anti-EGFR Ab as well as to GM3-coated beads; (iii) GM3 inhibitory effect on EGFR tyrosine kinase was abrogated in vitro by coincubation with glycan having multiple GlcNAc termini and in cell culture in situ incubated with the same glycan; and (iv) cells treated with swainsonine, which increased expression of complex-type and hybrid-type glycans with GlcNAc termini, displayed higher inhibition of EGFR kinase by GM3 than swainsonine-untreated control cells. A similar effect was observed with 1-deoxymannojirimycin, which increased hybrid-type structure in addition to major accumulation of high mannose-type glycan. These findings indicate that Winked glycan with GlcNAc termini linked to EGFR is the target to interact with GM3, causing inhibition of EGF-induced EGFR tyrosine kinase.
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