Premium
The Asn418‐linked N‐glycan of ErbB3 Inhibits Spontaneous Heterodimerization with ErbB2, and Suppresses Anchorage Dependent and Independent Cell Growth through MAPK and PI3K/Akt Pathways
Author(s) -
Yokoe Shunichi,
Takahashi Motoko,
Asahi Michio,
Gu Jianguo,
Miyoshi Eiji,
Taniguchi Naoyuki
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a56-a
Subject(s) - erbb3 , mapk/erk pathway , protein kinase b , phosphorylation , pi3k/akt/mtor pathway , cell growth , microbiology and biotechnology , erbb , chemistry , receptor tyrosine kinase , neuregulin , tyrosine phosphorylation , signal transduction , transfection , biology , cancer research , cell culture , biochemistry , genetics
ErbB2 and ErbB3, two members of the ErbB family, together form a high‐affinity heregulin co‐receptor that elicits a potent mitogenic and transforming signals, and clinical studies indicate that these receptors play an important role in tumor incidence and progression. To determine whether or not N ‐glycosylation is involved in the function of ErbB3, a series of human ErbB3 that were devoid of N ‐glycans were prepared and transfected to Flp‐In‐CHO cells for stable expression with or without co‐expression of wild type ErbB2. A crosslinking study using bis (sulfosuccinimidyl) suberate (BS 3 ) showed that only Asn418 to Gln (N418Q) mutant of ErbB3 was auto‐dimerized with wild type ErbB2 without its ligand, heregulin (HRG). In a Western blot analysis, the dimeric formation promoted tyrosine phosphorylation and subsequent ERK and Akt phosphorylation without HRG. Moreover, a cell proliferation assay and a soft agar colony formation assay demonstrated that the phosphorylation led to both cell proliferation and cell survival, which were inhibited by PI3K inhibitor or MEK inhibitor. These findings suggest that Asn418‐linked N ‐glycan in ErbB3 plays an essential role for regulating receptor heterodimerization with ErbB2, and might have an effect on cell proliferation and survival through both MAPK and PI3K/Akt pathways.