Glycobiology Advance Access originally published online on October 23, 2003
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Glycobiology vol 14 no 2 pp. 177-186, 2004
© Oxford University Press 2004; all rights reserved.
ß1,4-N-Acetylglucosaminyltransferase III down-regulates neurite outgrowth induced by costimulation 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; and 3 Department of Molecular Genetics, Kochi Medical School, Kohasu, Oko-cho, Nankoku, Kochi 783-8505, Japan
Received on August 13, 2003; revised on October 1, 2003; accepted on October 3, 2003
A rat pheochromocytoma cell line (PC12), when transfected with ß1,4-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 costimulation 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 (MEK-1). Consistent with this, the EGF receptor (EGFR)–mediated ERK activation was blocked in GnT-III transfectants. Conversely, the overexpression of dominant negative MEK-1 or treatment with PD98059, a specific inhibitor of MEK-1, inhibited neurite outgrowth in controls transfected with mock. Furthermore GnT-III activity is required for these inhibitions, because 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 autophosphorylation. Collectively, the results constitute a comprehensive body of evidence to show clearly that the overexpression of GnT-III prevents neurite outgrowth induced by costimulation of EGF and integrins through the Ras/MAPK activation pathway and indicates that GnT-III may be an important regulator for cell differentiation in neural tissues.
1 To whom correspondence should be addressed; e-mail: jgu{at}biochem.med.osaka-u.ac.jp
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