膜型増殖因子アンフィレグリンとエピレグリンのカルボキシ末端断片シグナルの解明

2009 Fiscal Year Annual Research Report

• Project/Area Number: 20390082
• Research Institution: Ehime University
• Principal Investigator: 東山 繁樹 Ehime University, プロテオ医学研究センター, 教授 (60202272)
• Keywords: amphiregulin / epiregulin / CTF / 膜型増殖因子 / エンドサイトーシス / レトログレード小胞輸送 / 核膜移行 / shedding

Research Abstract

amphiregulinおよびepiregulinは細胞膜に発現するI型膜蛋白質であり、その細胞外領域は増殖因子活性を有する。細胞に様々な刺激が加わると、これらの膜型増殖因子はsheddingを受け増殖因子領域を放出すると同時にカルボキシ未端断片(CTF)を産生する。昨年までの研究でCTFと同時に、sheddingされずに細胞膜に残るunshed formが、共にエンドサイトーシスにより細胞内に取り込まれER/核膜に局在変化し、ヒストン蛋白質のメチル化が抑制することでグローバルな転写抑制を起こすことを明らかにしてきた。本年度は、さらにamphiregulin CTFとunshed formのエンドサイトーシスに細胞内ドメインの蛋白質修飾、特にモノユビキチン化が関与することことを明らかにし、その修飾部位を同定した。現在ユビキチン化酵素E3リガゼーゼの同定を試みている。一方、CTF産生の重要な反応であるsheddingを制御する因子の同定を試み、amphiregulin-regulating protein 35(ARP35)を同定した。ARP35はamphiregulinとそのshedding酵素であるADAM17に結合することを明らかにした。ARP35ノックダウンではamphiregulinのsheddingが抑制されることを見いだした。さらにARP35ファミリー分子は12種のメンバーからなることから、他のメンバーに付いても同様の検討をした結果、amphiregulinとADAM17の双方に結合すARP35ファミリー分子としてさらに3つのメンバーを同定した。現在、ノックダウン等により、機能的評価を進めている。

Research Products

• [Journal Article] Induction of striatal neurogenesis and generation of region-specific functional mature neurons after ischemia by growth factors (2010)
  • Author(s): Yoshikawa G, Momiyama T, Oya S, Takai K, Tanaka JI, Higashiyama S, Saito N, Kirino T, Kawahara N.
  • Journal Title: J Neurosung (In press)
  • Peer Reviewed
• [Journal Article] Novel monoclonal antibodies recognizing the active conformation of epidermal growth factor receptor (2010)
  • Author(s): Ise N, Omi K, Miwa Y, Honda H, Higashiyams S, Goishi K.
  • Journal Title: Biochem Biophys Res Commun (In press)
  • Peer Reviewed
• [Journal Article] Activation of epidermal growth factor receptor gene is involved in transforming growth factor-beta-mediated fibronectin expression in a chondrocyte progenitor cell line (2010)
  • Author(s): Takeda H, Inoue H, Kutsuna T, Matsushita N, Takahashi T, Watanabe S, Higashiyama S, Yamamoto H.
  • Journal Title: Int J Mol Med. (In press)
  • Peer Reviewed
• [Journal Article] Insulin-Induced Ectodomain Shedding of Heparin-Binding Epidermal Growth Factor-Like Growth Factor in Adipocytes In Vitro (2010)
  • Author(s): Yamamoto T, Suganami T, Kiso-Narita M, Scherle PA, Kamei Y, Isobe M, Higashiyama S, Ogawa Y.
  • Journal Title: Obesity (In press)
  • Peer Reviewed
• [Journal Article] Mitochondrial reactive oxygen Species mediate GPCR-induced TACE/ADAM17-dependent transforming growth-alpha shedding (2009)
  • Author(s): Myers TJ, Brennaman LH, Stevenson M, Higashiyama S, Russell WE, Lee DC, Sunnarborg SW
  • Journal Title: Mol Biol Cell. 24 Pages: 5236-5249
  • Peer Reviewed
• [Journal Article] Generation and characterization of conditional heparin-binding EGF-like growth factor knockout mice (2009)
  • Author(s): Oyagi A, Oida Y, Kakefuda K, Shimarawa M, Shioda N, Moriguchi S, Kitaichi K, Nanba D, Yamaguchi K, Furuta Y, Fukunaga K, Higashiyama S, Hara H
  • Journal Title: PLoS One 10 Pages: e7461
  • Peer Reviewed
• [Journal Article] Thromboxane A2 receptor-mediated epidermal growth factor receptor transactivation : involvement of PKC-delta and PKC-epsilon in the in the shedding of epidermal growth factor receptor ligands (2009)
  • Author(s): Uchiyama K, Saito M, Sasaki M, Obara Y, Higashiyama S, Nakahata N
  • Journal Title: Eur J Pharm Sci 38 Pages: 504-511
  • Peer Reviewed
• [Journal Article] Localisation of endothelin B receptor variants to plasma membrane microdomains and its effects on downstream signalling (2009)
  • Author(s): Grossmann S, Higashiyama S, Oksche A, Schaefer M, Tannert A
  • Journal Title: Mol Mernbr Biol. 5 Pages: 279-792
  • Peer Reviewed
• [Journal Article] Serine protease inhibitor Kazaltype 1 promotes proliferation of pancreatic cancer cells through the epidermal growth factor receptor (2009)
  • Author(s): Ozaki N, Ohmuraya M, Hirota M, Ida S, Wang J, Takamori H, Higashiyama S, Baba H, Yamamura K.
  • Journal Title: Mol Cancer Res 9 Pages: 1572-1581
  • Peer Reviewed
• [Journal Article] Carbon-ion beam irradiation effectively suppresses migration and invasion of human non-small-cell lung cancer cells (2009)
  • Author(s): Akino Y, Teshima T, Kihara A, Kodera-Suzumoto Y, Inaoka M, Higashiyama S, Furusawa Y, Matsuura N
  • Journal Title: Int J Radiat Oncol Biol Phys 75 Pages: 475-481
  • Peer Reviewed
• [Journal Article] Ectodomain shedding of E-cadherin and c-Met is induced by Helicobacter pylori infection (2009)
  • Author(s): Schimmeister W, Gnad T, Wex T, Higashiyama S, Wolke C, Naumann M, Lendeckel U.
  • Journal Title: Exp Cell Res 315 Pages: 3500-3508
  • Peer Reviewed
• [Journal Article] Promyelocytic leukemia zinc finger protein regulates interferon-mediated innate immunity (2009)
  • Author(s): Xu D, Holko M, Sadler AJ, Scott B, Higashiyama S, Berkofsky-fessler W, McConnell MJ, Pandolfi PP, Licht JD, Williams BR
  • Journal Title: Immunity 30 Pages: 802-816
  • Peer Reviewed
• [Journal Article] BCL6 degradation caused by the interaction with the C-terminus of pro-HB-EGF induces cyclin D2 expression in gastric cansers (2009)
  • Author(s): Hirata Y, Ogasawara N, Sasaki M, Mizushima T, Shimura T, Mizoshita T, Mori Y, Kubota E, Wada T, Tanida S, Kataoka H, Kamiya T, Higashiyama S, Joh T
  • Journal Title: BrJCancer 100 Pages: 1320-1329
  • Peer Reviewed
• [Journal Article] Insufficiency of pro-heparin-binding epidermal growth factor shedding enhances hypoxic cell death in H9c2 cardiomyoblasts via activation of caspase-3 and c-Jun N-terminal kinase (2009)
  • Author(s): Uetani T, Nakayama H, Okayama H, Okura T, Higaki J, Inoue H, Higashiyama S.
  • Journal Title: J Biol Chem. 284 Pages: 12399-12409
  • Peer Reviewed
• [Journal Article] Attenuation of Notch signaling promotes the differentiation of neural progenitors into neurons in the hippocampal CAl region after ischemic injury (2009)
  • Author(s): Oya S, Yoshikawa G, Takai K, Tanaka JI, Higashiyama S, Saito N, Kirino T, Kawahara N.
  • Journal Title: Neuroscience 58 Pages: 683-692
  • Peer Reviewed
• [Presentation] Inner nuclear membrane translocation and nuclear signaling of membrane-anchored growth factors (2009)
  • Author(s): 東山繁樹
  • Organizer: 第61回日本細胞生物学会大会 シンポジウム
  • Place of Presentation: 名古屋国際会議揚
  • Year and Date: 20090602-20090604
• [Presentation] 膜型増殖因子の Ectodomain Shedding-分子機構から生理機能まで (2009)
  • Author(s): 東山繁樹
  • Organizer: 第73回 日本生化学会中部支部例会 シンポジウム
  • Place of Presentation: 名古屋市立大学
  • Year and Date: 2009-05-23
• [Presentation] Innernuclear membrane targeting of membrane-anchored growth factors and transcriptional regulation (2009)
  • Author(s): 東山繁樹
  • Organizer: Gordon Research Conference "Signal Transduction within the Nucleus"
  • Place of Presentation: Ventura, Califomia, USA
  • Year and Date: 2009-04-01
• [Remarks]
  • URL: http://www.m.ehime-u.ac.jp/school/biochem2/index.html