Suppression of heregulin β signaling by the single N-glycan deletion mutant of soluble ErbB3 protein.

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.

• 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)

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

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