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 β 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 ∼10% 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 β 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 β signaling.
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Authors | Motoko Takahashi, Yoshihiro Hasegawa, Yoshitaka Ikeda, Yoshinao Wada, Michiko Tajiri, Shigeru Ariki, Rina Takamiya, Chiaki Nishitani, Motoko Araki, Yoshiki Yamaguchi, Naoyuki Taniguchi, Yoshio Kuroki |
Journal | The Journal of biological chemistry
(J Biol Chem)
Vol. 288
Issue 46
Pg. 32910-21
(Nov 15 2013)
ISSN: 1083-351X [Electronic] United States |
PMID | 24097984
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Antineoplastic Agents
- NRG1 protein, human
- Neuregulin-1
- Quinazolines
- Lapatinib
- ERBB2 protein, human
- ERBB3 protein, human
- ERBB4 protein, human
- ErbB Receptors
- Receptor, ErbB-2
- Receptor, ErbB-3
- Receptor, ErbB-4
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Topics |
- Amino Acid Substitution
- Antineoplastic Agents
(pharmacology)
- Cell Line, Tumor
- ErbB Receptors
(genetics, metabolism)
- Humans
- Lapatinib
- MAP Kinase Signaling System
- Mutation, Missense
- Neuregulin-1
(genetics, metabolism)
- Protein Multimerization
- Protein Structure, Tertiary
- Quinazolines
(pharmacology)
- Receptor, ErbB-2
(genetics, metabolism)
- Receptor, ErbB-3
(genetics, metabolism)
- Receptor, ErbB-4
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