Glycobiology Advance Access published online on October 23, 2003
Glycobiology, doi:10.1093/glycob/cwh016
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© 2003 Oxford University Press
ORIGINAL ARTICLES
1 Department of Biochemistry, Osaka University Graduate School of Medicine, B1, 2-2 Yamadaoka Suita, Osaka 565-0871, Japan A rat pheochromocytoma cell line (PC12), when transfected with
Revised on October 1, 2003
Accepted on October 3, 2003
1, 4-N-acetylglucosaminyltransferase III down-regulates neurite outgrowth induced by co-stimulation of epidermal growth factor and integrins through the Ras/ERK signaling pathway in PC12 cells
2 Department of Biochemistry, Osaka University Graduate School of Medicine, B1, 2-2 Yamadaoka Suita, Osaka 565-0871, Japan; Department of Molecular Genetics, Kochi Medical School, Kohasu, Oko-cho, Nankoku, Kochi 783-8505, Japan
1,4-N-acetylglucosaminyltransferase III (GnT-III), which catalyzes the formation of a bisecting GlcNAc structure in N-glycans, resulted in the suppression of neurite outgrowth induced by co-stimulation of epidermal growth factor (EGF) and integrins. The neurite outgrowth was restored by the overexpression of a constitutively activated mitogen- or extracellular signal-regulated kinase kinase-1 (MEK1). Consistent with this, the EGF receptor (EGFR)-mediated ERK activation was blocked in GnT-III transfectants. Conversely, the overexpression of dominant negative MEK1 or treatment with PD98059, a specific inhibitor of MEK1, inhibited neurite outgrowth in controls transfected with mock. Furthermore, GnT-III activity is required for these inhibitions, since the overexpression of a dominant negative GnT-III mutant (D321A) failed to reduce neurite outgrowth and EGFR-mediated ERK activation. Lectin blot analysis confirmed that EGFR from wild-type GnT-III transfectants had been modified by bisecting GlcNAc in its N-glycan structures. This modification led to a significant decrease in EGF binding and EGFR auto-phosphorylation. Collectively, the above constitutes a comprehensive body of evidence to clearly show that the overexpression of GnT-III prevents neurite outgrowth induced by co-stimulation of EGF and integrins through the Ras/MAP kinase activation pathway, and indicates that GnT-III may be an important regulator for cell differentiation in neural tissues.
EGF receptor, GnT-III, integrin, MAP kinase, neurite outgrowth
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