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J. Biol. Chem., Vol. 281, Issue 5, 2572-2577, February 3, 2006

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Core Fucosylation Regulates Epidermal Growth Factor Receptor-mediated Intracellular Signaling^*

Xiangchun Wang, Jianguo Gu¹, Hideyuki Ihara, Eiji Miyoshi, Koichi Honke, and Naoyuki Taniguchi

From the Department of Biochemistry, Osaka University Graduate School of Medicine, Japan and the Department of Molecular Genetics, Kochi University Graduate School of Medicine, Kohasu, Oko-cho, Nankoku, Kochi 783-8505, Japan

1,6-Fucosyltransferase (Fut8) catalyzes the transfer of a fucose residue to N-linked oligosaccharides on glycoproteins via an 1,6-linkage to form core fucosylation in mammals. We recently found that disruption of the Fut8 gene induces severe growth retardation and early postnatal death. To investigate the molecular mechanism involved, we have established embryonic fibroblasts of Fut8^+/+ and Fut8^–/–, derived from wild-type and Fut8-null mice, respectively. Interestingly, the epidermal growth factor (EGF)-induced phosphorylation levels of the EGF receptor (EGFR) were substantially blocked in Fut8^–/– cells, compared with Fut8^+/+ cells, while there are no significant changes in the total activities of tyrosine phosphatase for phosphorylated EGFR between two cells. The inhibition of EGFR phosphorylation was completely restored by re-introduction of the Fut8 gene to Fut8^–/– cells. Consistent with this, EGFR-mediated JNK or ERK activation was significantly suppressed in Fut8^–/– cells. Finally, we found that the core fucosylation of N-glycans is required for the binding of the EGF to its receptor, whereas no effect was observed for the expression levels of EGFR on the cell surface. Collectively, these results strongly suggest that core fucosylation is essential for EGF receptor-mediated biological functions.

Received for publication, October 5, 2005 , and in revised form, November 2, 2005.

^* This work was supported in part by the Special Coordination Funds for Promoting Science and Technology and the 21st Century Center of Excellence Program from the Ministry of Education, Culture, Sports, Science and Technology of Japan. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom all correspondence should be addressed. Tel.: 81-6-6879-3421; Fax: 81-6-6879-3429; E-mail: jgu{at}biochem.med.osaka-u.ac.jp.

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