Epidermal growth factor receptor tyrosine kinase is modulated by GM3 interaction with N-linked GlcNAc termini of the receptor
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- Seon-Joo Yoon
- *Pacific Northwest Research Institute and University of Washington, Seattle, WA 98122;
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- Ken-ichi Nakayama
- Institute of General Industrial Research, Takamatsu, Kagawa 761-0395, Japan; and
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- Toshiyuki Hikita
- *Pacific Northwest Research Institute and University of Washington, Seattle, WA 98122;
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- Kazuko Handa
- *Pacific Northwest Research Institute and University of Washington, Seattle, WA 98122;
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- Sen-itiroh Hakomori
- *Pacific Northwest Research Institute and University of Washington, Seattle, WA 98122;
書誌事項
- 公開日
- 2006-12-12
- DOI
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- 10.1073/pnas.0609281103
- 公開者
- Proceedings of the National Academy of Sciences
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説明
<jats:p> 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: ( <jats:italic>i</jats:italic> ) EGFR (molecular mass, ≈170 kDa) has N-linked glycan with GlcNAc termini, as probed by mAb (J1) or lectin (GS-II); ( <jats:italic>ii</jats:italic> ) GS-II-bound EGFR also bound to anti-EGFR Ab as well as to GM3-coated beads; ( <jats:italic>iii</jats:italic> ) GM3 inhibitory effect on EGFR tyrosine kinase was abrogated <jats:italic>in vitro</jats:italic> by coincubation with glycan having multiple GlcNAc termini and in cell culture <jats:italic>in situ</jats:italic> incubated with the same glycan; and ( <jats:italic>iv</jats:italic> ) 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 N-linked glycan with GlcNAc termini linked to EGFR is the target to interact with GM3, causing inhibition of EGF-induced EGFR tyrosine kinase. </jats:p>
収録刊行物
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- Proceedings of the National Academy of Sciences
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Proceedings of the National Academy of Sciences 103 (50), 18987-18991, 2006-12-12
Proceedings of the National Academy of Sciences
