title: Epidermal growth factor receptor tyrosine kinase is modulated by GM3 interaction with N-linked GlcNAc termini of the receptor.
abstract: 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, approximately 170 kDa) has N-linked glycan with GlcNAc termini, as probed by mAb (J1) or lectin (GS-II); (ii) 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 N-linked glycan with GlcNAc termini linked to EGFR is the target to interact with GM3, causing inhibition of EGF-induced EGFR tyrosine kinase.
authors.affiliation: Pacific Northwest Research Institute and University of Washington, Seattle, WA 98122, USA.
authors.forename: Seon-Joo
authors.initials: SJ
authors.lastname: Yoon
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Nakayama
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Hikita
authors.forename: Kazuko
authors.initials: K
authors.lastname: Handa
authors.forename: Sen-itiroh
authors.initials: SI
authors.lastname: Hakomori
mesh_terms: D000117:Acetylglucosamine / Q000378:metabolism*; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000378:metabolism*; D005679:G(M3) Ganglioside / Q000378:metabolism*; D006028:Glycosphingolipids / Q000378:metabolism; D006031:Glycosylation; D006801:Humans; D009844:Oligosaccharides / Q000378:metabolism; D019000:Phosphotyrosine / Q000378:metabolism; D011485:Protein Binding
chemical_list: D005679:G(M3) Ganglioside; D006028:Glycosphingolipids; D009844:Oligosaccharides; D019000:Phosphotyrosine; D066246:ErbB Receptors; D000117:Acetylglucosamine