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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Yamaguchi, Yoshiki Ariki, Shigeru Tajiri, Michiko Hasegawa, Yoshihiro Ikeda, Yoshitaka Takamiya, Rina Wada, Yoshinao Kuroki, Yoshio Takahashi, Motoko Araki, Motoko Taniguchi, Naoyuki Nishitani, Chiaki |
| Description | Author Affiliation: Takahashi M ( From the Department of Biochemistry, Sapporo Medical University School of Medicine, Sapporo 060-8556, Japan.) |
| Abstract | Heregulin signaling is involved in various tumor proliferations and invasions; thus, receptors of heregulin are targets for the cancer therapy. In this study we examined the suppressing effects of extracellular domains of ErbB2, ErbB3, and ErbB4 (soluble ErbB (sErbB)) on heregulin ß signaling in human breast cancer cell line MCF7. It was found that sErbB3 suppresses ligand-induced activation of ErbB receptors, PI3K/Akt and Ras/Erk pathways most effectively; sErbB2 scarcely suppresses ligand-induced signaling, and sErbB4 suppresses receptor activation at â ¼10% efficiency of sErbB3. It was revealed that sErbB3 does not decrease the effective ligands but decreases the effective receptors. By using small interfering RNA (siRNA) for ErbB receptors, we determined that sErbB3 suppresses the heregulin ß signaling by interfering ErbB3-containing heterodimers including ErbB2/ErbB3. By introducing the mutation of N418Q to sErbB3, the signaling-inhibitory effects were increased by 2-3-fold. Moreover, the sErbB3 N418Q mutant enhanced anticancer effects of lapatinib more effectively than the wild type. We also determined the structures of N-glycan on Asn-418. Results suggested that the N-glycan-deleted mutant of sErbB3 suppresses heregulin signaling via ErbB3-containing heterodimers more effectively than the wild type. Thus, we demonstrated that the sErbB3 N418Q mutant is a potent inhibitor for heregulin ß signaling. |
| ISSN | 00219258 |
| e-ISSN | 1083351X |
| Journal | Journal of Biological Chemistry |
| Issue Number | 46 |
| Volume Number | 288 |
| Language | English |
| Publisher | American Society for Biochemistry and Molecular Biology (United States) |
| Publisher Date | 2013-11-15 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | MAP Kinase Signaling System Mutation, Missense Neuregulin-1 Metabolism Protein Multimerization Receptor, ErbB-3 Amino Acid Substitution Antineoplastic Agents Pharmacology Cell Line, Tumor Genetics Protein Structure, Tertiary Quinazolines Receptor, Epidermal Growth Factor Receptor, ErbB-2 Receptor, ErbB-4 Research Support, Non-U.S. Gov't Biochemistry Molecular Biology |
| Content Type | Text |
| Resource Type | Article |
| Subject | Cell Biology Biochemistry Molecular Biology |
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