Regulatory mechanism that regulates ectodomain shedding of HB-EGF by ADAM17

2015 Fiscal Year Final Research Report

• Project/Area Number: 24570212
• 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): 2012-04-01 – 2016-03-31
• Keywords: 細胞増殖因子 / エクトドメイン・シェディング / 切断酵素 / 細胞・組織 / シグナル伝達

Outline of Final Research Achievements

ADAM17 is known to be a major sheddase for HB-EGF and ErbB4. Secreted HB-EGF, that binds to and activates EGF receptor (EGFR/ErbB1) and ErbB4, plays an indispensable role for normal valvulogenesis in mouse embryos by suppressing mesenchymal cell proliferation. In an ex vivo model of endocardial cushion explants, HB-EGF suppresses valve mesenchymal cell proliferation through a heterodimer of ErbB1 and ErbB4 with downstream p38MAPK/JNK-signals, and certain ErbB1-ligand(s) promotes the proliferation through a homodimer of ErbB1 with downstream MEK-ERK-signal. Moreover, a rescue experiment with the cleavable or uncleavable isoform of ErbB4 in ERBB4 null cells suggests that the cytoplasmic-released intracellular domain of ErbB4 rather than the membrane-anchored tyrosine kinase achieves the suppression. These results also suggest that ADAM17 is the physiologically important player that regulates proteolytic processing of ErbB4 as well as HB-EGF in valvulogenesis.

Free Research Field

細胞生物学