Mechanism regulating cellular proliferation by HB-EGF-ErbB4 signaling and its application

2018 Fiscal Year Final Research Report

• Project/Area Number: 15K07046
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Cell biology
• Research Institution: Osaka University
• Principal Investigator: Iwamoto Ryo 大阪大学, 微生物病研究所, 准教授 (10213323)
• Project Period (FY): 2015-04-01 – 2019-03-31
• Keywords: 細胞増殖因子 / 心臓弁形成 / 増殖抑制 / 細胞・組織 / 形態形成 / シグナル伝達

Outline of Final Research Achievements

HB-EGF plays an indispensable role in suppression of cell proliferation during mouse valvulogenesis. HB-EGF binds to and activates ErbB1 and ErbB4. We investigated the role of ErbB receptors in valvulogenesis in vivo using ErbB1- and ErbB4-deficient mice, and an ex vivo model of endocardial cushion explants. HB-EGF suppresses valve mesenchymal cell proliferation through a heterodimer of ErbB1 and ErbB4, and certain ErbB1-ligand(s) promotes the proliferation through a homodimer of ErbB1. A rescue experiment with the cleavable (JM-a) or uncleavable (JM-b) isoform of ErbB4 in ERBB4 null cells suggests that intracellular domain of ErbB4 rather than the membrane-anchored tyrosine kinase achieves the suppression. Moreover, cytoplasmic region that is contained in both CYT-1 and CYT-2 subtypes of ErbB4 is essential for the suppression. These results predict that HB-EGF-ErbB4 signaling axis may be applicable for cancer therapy of the next generation.

Free Research Field

細胞生物学

Academic Significance and Societal Importance of the Research Achievements

本研究によって、心臓弁形成過程の細胞増殖制御におけるHB-EGF-ErbB4による増殖抑制シグナルの分子機構を明らかにすることで、従来仮想的に考えられていたErbBシグナル間の制御機構が実際の生体において存在している事の証明となり、細胞生物学上非常に意義が大きい。さらに、これまでの抗がん剤等における分子標的治療では、その標的分子の機能を封じる方向であったが、本研究によって、標的分子を封じるのではなく、活性転換という形で「標的を生かして使う」という新たなコンセプトが導き出され、医学的方法論的にも意義が大きい。