N-glycan of ErbB family plays a crucial role in dimer formation and tumor promotion |
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Authors: | Motoko Takahashi Shunichi Yokoe Michio Asahi Seung Ho Lee Wei Li Daisuke Osumi Eiji Miyoshi Naoyuki Taniguchi |
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Affiliation: | 1. Department of Biochemistry, Sapporo Medical University School of Medicine, South-1 West-17, Chuo-ku, Sapporo 060-8556, Japan;2. Department of Biochemistry, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan;3. Department of Disease Glycomics, Research Institute for Microbial Diseases, 4th Floor, Center for Advanced Science and Innovation, Osaka University, 2-1 Yamadaoka, Suita, Osaka 565-0871, Japan |
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Abstract: | More and more evidence indicates that N-glycan regulates signal transduction by modulating receptor functions. Previous studies suggested that glycosylation of EGFR is involved in dimerization and endocytosis. We further determined the role of N-glycosylation of ErbB family. A series of human ErbB3 mutants that lack each of the 10 N-glycosylation sites were prepared and transfected to Flp-In-CHO cells for stable expression. A crosslinking study showed that Asn 418 to Gln mutant (N418Q) of ErbB3 underwent autodimerization without its ligand, heregulin, and the heterodimer formation with ErbB2 was also increased. The N418Q mutant of ErbB3 co-expressed with ErbB2 promoted downstream signaling, anchorage-independent cell growth and the tumor growth in athymic mice. These findings suggest that the specific N-glycan in domain III of ErbB family plays an essential role in regulating receptor dimerization and transforming activity. We assume that the N-glycans affect the conformation of ErbB family, which is crucial for their activity. Together with findings from other laboratories, it is suggested that N-glycosylation controls ErbB signaling by various mechanisms. |
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Keywords: | BS3, bis-(sulfosuccinimidyl)-suberate CHO, Chinese hamster ovary EGFR, epidermal growth factor receptor ERK, extracellular signal-regulated kinase GlcNAc, N-acetylglucosamine HRG, heregulin PI3K, phosphoinositide 3-kinase |
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