Cell function regulation by membrane-anchored growth factors

2009 Fiscal Year Final Research Report

• Project/Area Number: 17014057
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Osaka University
• Principal Investigator: MEKADA Eisuke Osaka University, 微生物病研究所, 教授 (20135742)
• Co-Investigator(Kenkyū-buntansha): IWAMOTO Ryo 大阪大学, 微生物病研究所, 准教授 (10213323) ; ASANO Shiro 大阪大学, 微生物病研究所, 特任研究員 (00397613)
• Co-Investigator(Renkei-kenkyūsha): MIZUSHIMA Hiroto 大阪大学, 微生物病研究所, 助教 (30379094) ; NAKAMURA Kuniaki 大阪大学, 微生物病研究所, 特任研究員 (70311305)
• Project Period (FY): 2005 – 2009
• Keywords: 3次元増殖 / EGF / EGFR / HB-EGF / インテグリン / 細胞増殖因子 / 腫瘍形成 / 細胞外マトリックス

Research Abstract

Role of HB-EGF in cell growth and tumor growth and the clinical significance of HB-EGF in ovarian cancer were studied. Results indicated HB-EGF is a promising target for cancer therapy. Clinical development of HB-EGF inhibitor CRM197 is in progress.

Research Products

• [Journal Article] Proteolytic activation of heparin-binding EGF-like growth factor by membrane-type matrix metalloproteinase-1 in ovarian carcinoma cells. (2011)
  • Author(s): Koshikawa,N., Mizushima,H., Minegishi,T., Eguchi,F., Yotsumoto,F., Nabeshima,K. Miyamoto,S., Mekada,E., Seiki,M
  • Journal Title: Cancer Sci. 102 Pages: 111-116
  • Peer Reviewed
• [Journal Article] MT1-MMP cleaves off the NH2-terminal portion of HB-EGF and converts it into a heparin -independent growth factor. (2010)
  • Author(s): Koshikawa,N., Mizushima,H., Minegishi,T., Iwamoto,R., Mekada,E. Seiki,M
  • Journal Title: Cancer Res. 70 Pages: 6093-6103
  • Peer Reviewed
• [Journal Article] HB-EGF function in cardiac valve development requires interaction with heparan sulfate proteoglycans. (2010)
  • Author(s): Iwamoto,R., Mine,N., Kawaguchi,T., Minami,S., Saeki,K., Mekada,E.
  • Journal Title: Development 137 Pages: 2205-2214
  • Peer Reviewed
• [Journal Article] Anti-human HB-EGF monoclonal antibodies inhibiting ectodomain shedding of HB-EGF and diphtheria toxin binding. (2010)
  • Author(s): Hamaoka,M., Chinen,I., Murata,T., Takashima,S., Iwamoto,R., Mekada,E.
  • Journal Title: J. Biochem. 148 Pages: 55-69
  • Peer Reviewed
• [Journal Article] Humanized Gene Replacement in Mice Reveals the Contribution of Cancer Stroma-Derived HB-EGF to Tumor Growth. (2010)
  • Author(s): Ichise,T., Adachi,S., Ohishi,M., Ikawa,M., Okabe,M., Iwamoto,R., Mekada,E.
  • Journal Title: Cell Struct Funct. 35 Pages: 3-13
  • Peer Reviewed
• [Journal Article] Integrin signal masks growth-promotion activity of HB-EGF in monolayer cell cultures. (2009)
  • Author(s): Mizushima,H., Wang,X., Miyamoto,S., Mekada,E.
  • Journal Title: J. Cell Sci. 122 Pages: 4277-4286
  • Peer Reviewed
• [Journal Article] Synergistic antitumor effect of paclitaxel with CRM197, an inhibitor of HB-EGF, in ovarian cancer. (2009)
  • Author(s): Yagi,H., Yotsumoto,F., Sonoda,K., Kuroki,M., Mekada,E., Miyamoto,S
  • Journal Title: Int J Cancer 124 Pages: 1429-1439
  • Peer Reviewed
• [Journal Article] HB-EGF. UCSD-Nature Molecule Pages. (2008)
  • Author(s): Mekada,E., Iwamoto,R.
  • Journal Title: Published online 13 Pages: doi:10.1038/mp.a002932.01
  • Peer Reviewed
• [Journal Article] Heparin-binding epidermal growth factor-like growth factor as a new target molecule for cancer therapy. (2008)
  • Author(s): Miyamoto,S., Yagi,H., Yotsumoto,F., Kawarabayashi,T., Mekada,E.
  • Journal Title: Adv Exp Med Biol. 622 Pages: 281-295
  • Peer Reviewed
• [Journal Article] The fusing ability of sperm is bestowed by CD9-containing vesicles released from eggs in mice. (2008)
  • Author(s): Miyado,K., Yoshida,K., Yamagata,K., Sakakibara,K., Okabe,M., Wang,X., Miyamoto,K., Akutsu,H., Kondo,T., Takahashi,Y., Ban,T., Ito,C., Toshimori,K., Nakamura,A., Ito,M., Miyado,M., Mekada,E., Umezawa,A
  • Journal Title: Proc Natl Acad Sci USA 105 Pages: 12921-12926
  • Peer Reviewed
• [Journal Article] Double deficiency of tetraspanins CD9 and CD81 alters cell motility and protease production of macrophages and causes COPD-like phenotype in mice. (2008)
  • Author(s): Takeda,Y., He,P., Tachibana,I., Zhou,B., Miyado,K., Kaneko,H., Suzuki,M., Minami,S., Iwasaki,T., Goya,S., Kijima,T., Kumagai,T., Yoshida,M., Osaki,T., Komori,T., Mekada,E., Kawase,I
  • Journal Title: J Biol Chem. 283 Pages: 26089-26097
  • Peer Reviewed
• [Journal Article] Possible involvement of CD81 in acrosome reaction of sperm in mice. (2008)
  • Author(s): Tanigawa,M., Miyamoto,K., Kobayashi,S., Sato,M., Akutsu,H., Okabe,M., Mekada,E., Sakakibara,K., Miyado,M., Umezawa,A., Miyado,K.
  • Journal Title: Mol Reprod Dev 75 Pages: 150-155
  • Peer Reviewed
• [Journal Article] HB-EGF decelerates cell proliferation synergistically with TGF-a in perinatal distal lung development. (2008)
  • Author(s): Minami,S., Iwamoto,R., Mekada,E
  • Journal Title: Dev. Dyn. 237 Pages: 247-258
  • Peer Reviewed
• [Journal Article] Validation of HB-EGF and amphiregulin as targets for human cancer therapy. (2008)
  • Author(s): Yotsumoto,F., Yagi,H., Suzuki,S.O., Oki,E., Tsujioka,H., Hachisuga,T., Sonoda,K., Kawarabayashi,T., Mekada, E., Miyamoto,S.
  • Journal Title: Biochem Biophys Res Commun. 365 Pages: 555-561
  • Peer Reviewed
• [Journal Article] Maternal heparin-binding-EGF deficiency limits pregnancy success in mice. (2007)
  • Author(s): Xie,H., Wang,H., Tranguch,S., Iwamoto,R., Mekada,E., DeMayo F.J., Lydon,J.P., Das,S.K., Dey,S.K
  • Journal Title: Proc. Natl. Acad. Sci. USA 104 Pages: 18315-18320
  • Peer Reviewed
• [Journal Article] Sulfated glycosaminoglycans are necessary for Nodal signal transmission from the node to the left lateral plate in the mouse embryo. (2007)
  • Author(s): Oki,S., Hashimoto,R., Okui,Y., Shen,M.M., M ekada,E., Otani,H., Saijoh,Y., Hamada,H.
  • Journal Title: Development 134 Pages: 3893-3904
  • Peer Reviewed
• [Journal Article] Biologic significance of receptor-binding cancer antigen expressed on SiSo cells (RCAS1) as a pivotal regulator of tumor growth through angiogenesis in human uterine cancer. (2007)
  • Author(s): Sonoda,K., Miyamoto,S., Yamazaki,A., Kobayashi,H., Nakashima,M., Mekada, E., Wake,N
  • Journal Title: Cancer 110 Pages: 1979-1990
  • Peer Reviewed
• [Journal Article] Diphtheria toxin mutant CRM197 possesses weak EF2-ADP-ribosyl activity that potentiates its anti-tumorigenic activity. (2007)
  • Author(s): Kageyama,T., Ohishi,M., Miyamoto,S., Mizushima,H., Iwamoto,R. Mekada,E
  • Journal Title: J.Biochem. 142 Pages: 95-104
  • Peer Reviewed
• [Journal Article] Parasporin-1, a novel cytotoxic protein from Bacillus thuringiensis, induces Ca2+ influx and a sustained elevation of the cytoplasmic Ca2+ concentration in toxin-sensitive cells. (2007)
  • Author(s): Katayama,H., Kusaka,Y., Yokota,H., Akao,T., Kojima,M., Nakamura,O., Mekada,E. Mizuki,E.
  • Journal Title: J. Biol. Chem. 282 Pages: 7742-7752
  • Peer Reviewed
• [Journal Article] FRA1 is a determinant for the difference in RAS-induced transformation between human and rat fibroblasts. (2006)
  • Author(s): Kakumoto,K., Sasai,K., Sukezane,T., Oneyama,C., Ishimaru,S., Shibutani,K., Mizushima,H., Mekada E., Hanafusa,H. Akagi,T
  • Journal Title: Proc. Natl. Acad. Sci. USA 103 Pages: 5490-5495
  • Peer Reviewed
• [Journal Article] Loss of HB-EGF in smooth muscle or endothelial cell lineages causes heart malformation. (2006)
  • Author(s): Nanba,D., Kinugasa,Y., Morimoto,C., Koizumi,M., Yamamura,H., Takahashi,K., Takakura,N., Mekada,E., Hashimoto,K., Higashiyama,S.
  • Journal Title: Biochem Biophys Res Commun. 350 Pages: 315-321
  • Peer Reviewed
• [Journal Article] Heparin -binding EGF-like growth factor as a novel targeting molecule for cancer therapy. (2006)
  • Author(s): Miyamoto,s., Yagi,H., Yotsumoto,F., Kawarabayashi,T., Mekada,E.
  • Journal Title: Cancer Sci. 97 Pages: 341-347
  • Peer Reviewed
• [Journal Article] ErbB and HB-EGF signaling in heart development and function. (2006)
  • Author(s): Iwamoto,R. Mekada,E
  • Journal Title: Cell Struct. Funct. 31 Pages: 1-14
  • Peer Reviewed
• [Journal Article] Cytoplasmic Domain Phosphorylation of Heparin-Binding EGF-like Growth Factor. (2006)
  • Author(s): Wang,X., Mizushima,H., Adachi,S., Ohishi,M., Iwamoto,R., Mekada,E.
  • Journal Title: Cell Struct. Funct. 31 Pages: 15-27
  • Peer Reviewed
• [Journal Article] HB-EGF promotes epithelial cell migration in eyelid development. (2005)
  • Author(s): Mine,N., Iwamoto,R. Mekada,E.
  • Journal Title: Development 132 Pages: 4317-4326
  • Peer Reviewed
• [Presentation] HB-EGF is a novel therapeutic target for ovarian cancer : Development of an HB-EGF inhibitor as an anticancer drug. (2010)
  • Author(s): Eisuke Mekada
  • Organizer: at 8^th Joint Conference of the American Association for Cancer Research and the Japanese Cancer Association
  • Place of Presentation: Hawaii, USA.
  • Year and Date: 20100205-20100209
• [Presentation] HB-EGFの作用機構と癌分子標的としての解析 (2010)
  • Author(s): 目加田英輔
  • Organizer: 日本癌学会
  • Place of Presentation: 大阪
  • Year and Date: 2010-09-23
• [Presentation] インテグリンシグナルはEGFファミリー増殖因子の増殖因子活性を単層培養において不顕在化する (2009)
  • Author(s): 水島寛人、宮本新吾、目加田英輔
  • Organizer: 第61回日本細胞生物学会大会
  • Place of Presentation: 名古屋
  • Year and Date: 20090602-20090604
• [Presentation] HB-EGFの生理機能発揮におけるエクトドメイン・シェディングの役割 (2008)
  • Author(s): 岩本亮、目加田英輔
  • Organizer: 第60回日本細胞生物学会大会
  • Place of Presentation: 横浜
  • Year and Date: 2008-06-29
• [Presentation] 骨のリモデリング制御因子としてのHB-EGFの役割 (2007)
  • Author(s): 中村尚志、吉本晃正、戸井田英俊、小川拓哉、北川(石田)教弘、岩本亮、目加田英輔、竹家達夫
  • Organizer: 第30回日本分子生物学会・第80回日本生化学会合同大会
  • Place of Presentation: 横浜
  • Year and Date: 20071211-20071214
• [Presentation] HB-EGF:新しいがんの分子標的 (2007)
  • Author(s): 目加田英輔
  • Organizer: 日本癌学会
  • Place of Presentation: 横浜
  • Year and Date: 2007-10-04
• [Presentation] Regulation of HB-EGFfunction by HSPGs (2007)
  • Author(s): 岩本亮、目加田英輔
  • Organizer: 第40回日本発生生物学会・第59回日本細胞生物学会合同大会
  • Place of Presentation: 福岡
  • Year and Date: 2007-05-29
• [Presentation] Interaction of HB-EGF with heparan sulfate proteoglycans is required for normal cardiac valve development. (2007)
  • Author(s): Iwamoto, R.
  • Organizer: The 1^st Thailand-Japan Joint Forum on Infectious Diseases, Bangkok
  • Year and Date: 2007-01-30
• [Presentation] ヘパラン硫酸プロテオグリカンによる増殖因子HB-EGFの生理機能制御 (2006)
  • Author(s): 岩本亮、目加田英輔
  • Organizer: 日本分子生物学会2006フォーラム
  • Place of Presentation: 名古屋
  • Year and Date: 20061206-20061208
• [Presentation] ErbB signaling in cartilage and bone development. (2006)
  • Author(s): Dealy,C.N., Fisher,M., Omi,M., Seghatoleslami,M.R., Clinton,G.M., Maihle,N.J., Iwamoto,R., Mekada,E., Mine,N.
  • Organizer: 9^<th> International Conference on Limb Development and Regeneration, Awaji
  • Year and Date: 2006-07-26
• [Presentation] HB-EGF promotes epithelial cell migration in eyelid development. (2005)
  • Author(s): Mine,N., Iwamoto,R., Mekada,E.
  • Organizer: The 45^th Annual Meeting of The American Society for Cell Biology, San Francisco
  • Year and Date: 2005-12-13
• [Book] M.R. Academic Press (2006)
  • Author(s): Horiguchi,Y. Mekada,E
  • Publisher: Toxin receptors in The comprehensive Sourcebook of Bacterial Protein Toxins, ed by Alouf, J.E. and Popoff
• [Remarks] ホームページ
  • URL: http://cell-biology.biken.osaka-u.ac.jp/MekadaLabHP/Home.html
• [Patent(Industrial Property Rights)] 制癌剤 (2008)
  • Inventor(s): 目加田英輔、宮本新吾
  • Industrial Property Rights Holder: 阪大微生物病研究会
  • Industrial Property Number: 特許,特登-04203742
  • Acquisition Date: 2008-10-24
• [Patent(Industrial Property Rights)] 連続投与されたCRM197による抗腫瘍効果 (2007)
  • Inventor(s): 目加田英輔、宮本新吾、東雍
  • Industrial Property Rights Holder: 国立大学法人大阪大学、学校法人福岡大学、財団法人阪大微生物病研究会
  • Industrial Property Number: 特願2007-180081
  • Filing Date: 2007-07-09
• [Patent(Industrial Property Rights)] 肺がん治療薬 (2007)
  • Inventor(s): 目加田英輔、宮本新吾
  • Industrial Property Rights Holder: 大阪大学、福岡大学
  • Industrial Property Number: 特願2007-167529
  • Filing Date: 2007-06-26
• [Patent(Industrial Property Rights)] 抗癌剤の効果増強剤 (2007)
  • Inventor(s): 目加田英輔、宮本新吾
  • Industrial Property Rights Holder: 大阪大学、財団法人大阪産業振興機構、福岡大学
  • Industrial Property Number: 特願2007-011939
  • Filing Date: 2007-01-22
• [Patent(Industrial Property Rights)] アンフィレギュリン濃度に基づく絨毛膜羊膜炎の診断 (2006)
  • Inventor(s): 吉里俊幸、宮本新吾、瓦林達比古、目加田英輔
  • Industrial Property Rights Holder: 福岡大学、大阪大学
  • Industrial Property Number: 特願2006-238576
  • Filing Date: 2006-09-04
• [Patent(Industrial Property Rights)] ヘパリン結合上皮細胞増殖因子様増殖因子に結合するモノクローナル抗体 (2006)
  • Inventor(s): 目加田英輔、岩本亮、宮本新吾、設楽研也、古谷安希子、高橋久美子
  • Industrial Property Rights Holder: 大阪大学、福岡大学、協和発酵株式会社
  • Industrial Property Number: 特願2006-157279
  • Filing Date: 2006-06-06
• [Patent(Industrial Property Rights)] 分泌型ヘパリン結合上皮細胞増殖因子様増殖因子の測定方法 (2006)
  • Inventor(s): 目加田英輔、岩本亮、宮本新吾、設楽研也、古谷安希子
  • Industrial Property Rights Holder: 大阪大学、福岡大学、協和発酵株式会社
  • Industrial Property Number: 特願2006-157278
  • Filing Date: 2006-06-06
• [Patent(Industrial Property Rights)] 癌治療薬 (2006)
  • Inventor(s): 目加田英輔、宮本新吾
  • Industrial Property Rights Holder: 阪大微生物病研究会
  • Industrial Property Number: PCT/JP2006/312321,米国(11/917706、2009-0105135)7700546
  • Acquisition Date: 2006-06-20
  • Overseas
• [Patent(Industrial Property Rights)] 癌治療薬 (2005)
  • Inventor(s): 目加田英輔、宮本新吾
  • Industrial Property Rights Holder: 大阪大学、関西TLO
  • Industrial Property Number: 特願2005-181314
  • Filing Date: 2005-06-21
• [Patent(Industrial Property Rights)] CD9/CD81二重欠損非ヒト動物
  • Inventor(s): 目加田英輔, 他3名
  • Industrial Property Number: 特願2003-162916,PCT/JP2004/008261、EU11/293388(登録番号:04745835.1)米国(登録番号:11/293388)、EU、日本で特許成立
  • Overseas