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

• 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
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000); Fiscal Year 2014: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2013: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000); Fiscal Year 2012: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• 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.

Research Products

• [Journal Article] Characterization of a novel anti-human HB-EGF monoclonal antibody applicable for paraffin-embedded tissues and diagnosis of HB-EGF-related cancers. (2016)
  • Author(s): Iwamoto,R., Takagi, M., Akatsuka, J., Ono, K., Kishi, Y., and Mekada, E.
  • Journal Title: Monoclonal Antibodies in Immunodiagnosis and Immunotherapy Volume: 35 Issue: 2 Pages: 1-10
  • DOI: 10.1089/mab.2015.0062
  • Peer Reviewed / Open Access
• [Journal Article] Identification of diphtheria toxin R domain mutants with enhanced inhibitory activity against HB-EGF (2015)
  • Author(s): Suzuki K, Mizushima H, Abe H, Iwamoto R, Nakamura H, Mekada E
  • Journal Title: J Biochem Volume: mvu079 Issue: 5 Pages: 331-343
  • DOI: 10.1093/jb/mvu079
  • NAID: 40020461422
  • Peer Reviewed / Open Access
• [Journal Article] Conditional loss of heparin-binding EGF-like growth factor results in enhanced liver fibrosis after bile duct ligation in mice. (2013)
  • Author(s): Takemura T, Yoshida Y, Kiso S, Kizu T, Furuta K, Ezaki H, Hamano M, Egawa M, Chatani N, Kamada Y, Imai Y, Higashiyama S, Iwamoto R, Mekada E, Takehara T.
  • Journal Title: Biochem Biophys Res Commun. Volume: 437 Issue: 2 Pages: 185-191
  • DOI: 10.1016/j.bbrc.2013.05.097
  • Peer Reviewed
• [Journal Article] Metastasis Suppressor Tetraspanin CD82/KAI1 Regulates Ubiquitylation of Epidermal Growth Factor Receptor. (2013)
  • Author(s): Odintsova E, van Niel G, Conjeaud H, Raposo G, Iwamoto R, Mekada E, Berditchevski F.
  • Journal Title: J Biol Chem. Volume: 288 Issue: 36 Pages: 26323-26334
  • DOI: 10.1074/jbc.m112.439380
  • Peer Reviewed / Open Access
• [Journal Article] Conditional knockout of heparin-binding epidermal growth factor-like growth factor in the liver accelerates carbon tetrachloride-induced liver injury in mice. (2012)
  • Author(s): Takemura, T., YoshidaY., Kiso, S., Saji, Y., Ezaki, H., Hamano, M., Kizu, T., Egawa, M., Chatani, N., Furuta, K., Kamada, Y., Iwamoto, R., Mekada, E., Higashiyama, S., Hayashi, N. and Takehara, T.
  • Journal Title: Hepatol Res Volume: 43 Issue: 4 Pages: 384-393
  • DOI: 10.1111/j.1872-034x.2012.01074.x
  • NAID: 10031194550
  • Peer Reviewed
• [Presentation] Physiological functions of diphtheria toxin receptor/HB-EGF. (2015)
  • Author(s): Ryo Iwamoto
  • Organizer: 17th Europian Workshop on Bacterial Protein Toxins
  • Place of Presentation: Braga, Portugal
  • Year and Date: 2015-06-20
  • Int'l Joint Research
• [Presentation] 心臓弁形成におけるHB-EGF-ErbBシグナルによる細胞増殖制御 (2014)
  • Author(s): 岩本亮、目加田英輔
  • Organizer: 第６６回日本細胞生物学会大会
  • Place of Presentation: 奈良
  • Year and Date: 2014-06-11 – 2014-06-13
• [Presentation] 心臓弁形成におけるHB-EGF-EGFRシグナルによる細胞増殖制御 (2013)
  • Author(s): 岩本亮、沼田雄基、目加田英輔
  • Organizer: 第６５回日本細胞生物学会大会
  • Place of Presentation: 名古屋
• [Presentation] C-terminal fragment of HB-EGF negatively regulates osteoclast differentiation (2012)
  • Author(s): 中村尚志、佐藤みずほ、北川教弘、岩本亮、目加田英輔
  • Organizer: 第４５回日本発生生物学会・第６４回日本細胞生物学会合同大会
  • Place of Presentation: 神戸国際会議場
• [Book] Encyclopedia of Signalling Molecules (HB-EGF (Heparin-binding EGF-Like Growth Factor)) (2012)
  • Author(s): Ryo Iwamoto, Eisuke Mekada
  • Publisher: Springer
• [Remarks] IWAMOTO'S PAGE
  • URL: http://cell-biology.biken.osaka-u.ac.jp/MekadaLabHP/Iwamoto/Iwamoto.html
• [Remarks] IWAMOTO'S PAGE
  • URL: http://cell-biology.biken.osaka-u.ac.jp/MekadaLabHP/Iwamoto/Iwamoto.html