The Asn418-linked N-glycan of ErbB3 plays a crucial role in preventing spontaneous heterodimerization and tumor promotion.

Abstract

ErbB2 and ErbB3, two members of the ErbB family, form a high-affinity heregulin coreceptor that elicits potent mitogenic and transforming signals, and clinical studies indicate that these receptors play an important role in tumor incidence and progression. To determine whether N-glycosylation is involved in the function of ErbB3, a series of human ErbB3 molecules devoid of N-glycans were prepared and transfected to Flp-In-CHO cells for stable expression. A cross-linking study showed that the Asn(418) to Gln mutant (N418Q) of ErbB3 underwent autodimerization without its ligand, heregulin. The wild-type or N418Q mutant of ErbB3 was next coexpressed with ErbB2 in Flp-In-CHO cells, and the effect of N-glycan on heterodimerization was examined. The N418Q mutant of ErbB3 was autodimerized with ErbB2 without ligand stimulation, and receptor tyrosine phosphorylation and subsequent extracellular signal-regulated kinase (ERK) and Akt phosphorylation were promoted in the absence of heregulin. A cell proliferation assay and a soft agar colony formation assay showed that the N418Q mutant of ErbB3 coexpressed with ErbB2 promoted cell proliferation and colony formation in soft agar in an ERK- and Akt-dependent manner. The mutation also promoted the growth of tumors in athymic mice when injected s.c. These findings suggest that the Asn(418)-linked N-glycan in ErbB3 plays an essential role in regulating receptor heterodimerization with ErbB2 and might have an effect on transforming activity.

• Authors: Shunichi Yokoe, Motoko Takahashi, Michio Asahi, Seung Ho Lee, Wei Li, Daisuke Osumi, Eiji Miyoshi, Naoyuki Taniguchi
• Journal: Cancer research (Cancer Res) Vol. 67 Issue 5 Pg. 1935-42 (Mar 01 2007) ISSN: 0008-5472 [Print] United States
• PMID: 17332320 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Mutant Proteins
• Neuregulin-1
• Asparagine
• Receptor, ErbB-3
• Extracellular Signal-Regulated MAP Kinases

Topics

• Animals
• Asparagine
• Catalytic Domain (physiology)
• Cell Proliferation
• Cell Transformation, Neoplastic
• Cells, Cultured
• Dimerization
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Female
• Glycosylation
• Mice
• Mice, Nude
• Mutant Proteins (physiology)
• Neuregulin-1 (pharmacology)
• Protein Processing, Post-Translational (physiology)
• Receptor, ErbB-3 (chemistry, metabolism)
• Transfection