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Molecular mechanism of auto-translocation of membrane anchored EGFR ligand into the nuclear membrane and its diagnostic application of cancer

Research Project

Project/Area Number 22650228
Research Category

Grant-in-Aid for Challenging Exploratory Research

Allocation TypeSingle-year Grants
Research Field Tumor biology
Research InstitutionEhime University

Principal Investigator

HIGASHIYAMA Shigeki  愛媛大学, プロテオ医学研究センター, 教授 (60202272)

Co-Investigator(Renkei-kenkyūsha) FUKUDA Shinji  愛媛大学, 医学系研究科, 助教 (70398238)
SAWASAKI Tatsuya  愛媛大学, 無細胞生命科学工学研究センター, 准教授 (50314969)
JOH Takashi  名古屋市立大学, 医学系研究科, 教授 (30231369)
Project Period (FY) 2010 – 2011
Project Status Completed (Fiscal Year 2011)
Budget Amount *help
¥3,330,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥330,000)
Fiscal Year 2011: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2010: ¥1,900,000 (Direct Cost: ¥1,900,000)
Keywordsがん細胞の特性 / 膜型増殖因子 / HB-EGF / amphiregulin / ER/核膜移行 / レトログレード小胞輸送 / 膜型プロテアーゼ / 抗がん剤抵抗性 / 胃がん / epiregulin / エンドサイトーシス / 核膜移行 / shedding
Research Abstract

HB-EGF and AREG are synthesized as a membrane-anchored growth factor and expressed at the plasma membrane as pro-forms in normal cells. In some malignant tumor cells in culture, however, proHB-EGF and proAREG trans-locate at the ER/nuclear membrane, which endows resistance for anti-cancer drugs. In this study, we established mouse models bearing tumor expressing proAREG auto-translocation mutant, and showed that the tumor acquired resistance for chemotherapy in vivo. We also tried to identify C-terminal processing proteases of proHB-EGF and proAREG.

Report

(3 results)
  • 2011 Annual Research Report   Final Research Report ( PDF )
  • 2010 Annual Research Report
  • Research Products

    (33 results)

All 2012 2011 2010 Other

All Journal Article (17 results) (of which Peer Reviewed: 17 results) Presentation (12 results) Remarks (4 results)

  • [Journal Article] Nuclear translocation of pro-amphiregulin induces chemoresistance in gastric cancer2012

    • Author(s)
      Yoshida M, Shimura T, Fukuda S, Mizoshita T, Tanida S, Kataoka H, Kamiya T, Nakazawa T, Higashiyama S, Joh T.
    • Journal Title

      Cancer Sci

      Volume: 103 Pages: 708-715

    • Related Report
      2011 Annual Research Report 2011 Final Research Report
    • Peer Reviewed
  • [Journal Article] A Disintegrin and Metalloenzyme(ADAM) 17 Activation Is Regulated byα5β1 Integrin in Kidney Mesangial Cells2012

    • Author(s)
      Gooz P, Dang Y, Higashiyama S, Twal WO, Haycraft CJ, Gooz M.
    • Journal Title

      PLoS One

      Volume: 7

    • Related Report
      2011 Final Research Report
    • Peer Reviewed
  • [Journal Article] Monoubiquitination of pro-amphiregulin regulates its endocytosis and ectodomain shedding2012

    • Author(s)
      Fukuda S, Nishida-Fukuda H, Nakayama H, Inoue H, Higashiyama S.
    • Journal Title

      Biochem Biophys Res Commun

      Volume: 420 Pages: 315-320

    • Related Report
      2011 Final Research Report
    • Peer Reviewed
  • [Journal Article] Cell surface-annexins regulate ADAM-mediated ectodomain shedding of proamphiregulin2012

    • Author(s)
      Nakayama H, Fukuda S, Inoue H, Nishida-Fukuda H, Shirakata Y, Hashimoto K, Higashiyama S.
    • Journal Title

      Mol. Biol. Cell

      Volume: (in press)

    • Related Report
      2011 Final Research Report
    • Peer Reviewed
  • [Journal Article] Nuclear envelope-localized EGF family protein amphiregulin activates breast cancer cell migration in an EGF growth factor domain independent manner2012

    • Author(s)
      Tanaka H, Nishioka Y, Yokoyama Y, Higashiyama S, Matsuura N, Matsuura S, Hieda M.
    • Journal Title

      Biochem. Biophys. Res. Commun

      Volume: (in press)

    • Related Report
      2011 Final Research Report
    • Peer Reviewed
  • [Journal Article] A disintegrin and metalloenzyme (ADAM) 17 activation is regulated by α5β1 integrin in kidney mesangial cells2012

    • Author(s)
      Gooz P, Dang Y, Higashiyama S, Twal WO, Haycraft CJ, Gooz M
    • Journal Title

      PLoS One

      Volume: 7

    • Related Report
      2011 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Monoubiquitination of pro-amphiregulin regulates its endocytosis and ectodomain shedding2012

    • Author(s)
      Fukuda S, Nishida-Fukuda H, Nakayama H, Inoue H, Higashiyama S
    • Journal Title

      Biochem.Biophys.Res.Commun.

      Volume: 420 Pages: 315-320

    • Related Report
      2011 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Cell surface-annexins regulate ADAM-mediated ectodomain shedding of proamphiregulin2012

    • Author(s)
      Nakayama H, Fukuda S, Inoue H, Nishida-Fukuda H, Shirakata Y, Hashimoto K, Higashiyama S
    • Journal Title

      Mol.Biol.Cell

      Volume: (未定)(In press)

    • Related Report
      2011 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Nuclear envelope-localized EGF family protein amphiregulin activates breast cancer cell migration in an EGF growth factor domain independent manner2012

    • Author(s)
      Tanaka H, Nishioka Y, Yokoyama Y, Higashiyama S, Matsuura N, Matsuura S, Hieda M
    • Journal Title

      Biochem.Biophys.Res.Commun.

      Volume: (未定)(In press)

    • Related Report
      2011 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Lysophosphatidic acid stimulates epidermal growth factor-family ectodomain shedding and paracrine signaling from human lung fibroblasts2011

    • Author(s)
      Shiomi T, Boudreault F, Padem N, Higashiyama S, Drazen JM, Tschumperlin DJ.
    • Journal Title

      Wound Repair Regen

      Volume: 19 Pages: 229-240

    • NAID

      10031181736

    • Related Report
      2011 Final Research Report
    • Peer Reviewed
  • [Journal Article] Corneal epithelial wound healing impaired in keratinocyte-specific HB-EGF-deficient mice in vivo and in vitro2011

    • Author(s)
      Yoshioka R, Shiraishi A, Kobayashi T, Morita S, Hayashi Y, Higashiyama S, Ohashi Y.
    • Journal Title

      Invest. Ophthalmol. Vis. Sci

      Volume: 51 Pages: 630-639

    • Related Report
      2011 Final Research Report
    • Peer Reviewed
  • [Journal Article] Ectodomain shedding and remnant peptide signalling of EGFRs and their ligands2011

    • Author(s)
      Higashiyama S, Nanba D, Nakayama H, Inoue H, Fukuda S.
    • Journal Title

      J. Biochem

      Volume: 150 Pages: 15-22

    • NAID

      10030586134

    • Related Report
      2011 Final Research Report
    • Peer Reviewed
  • [Journal Article] Lysophosphatidic acid stimulates epidermal growth factor-family ectodomain shedding and paracrine signaling from human lung fibroblasts.2011

    • Author(s)
      Shiomi T, Boudreault F, Padem N, Higashiyama S, Drazen JM, Tschumperlin DJ.
    • Journal Title

      Wound Repair Regen

      Volume: 19 Pages: 229-240

    • NAID

      10031181736

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Insulin-induced ectodomain shedding of heparin-binding epidermal growth factor-like growth factor in adipocytes in vitro2010

    • Author(s)
      Yamamoto T, Suganami T, Kiso-Narita M, Scherle PA, Kamei Y, Isobe M, Higashiyama S, Ogawa Y.
    • Journal Title

      Obesity

      Volume: 18 Pages: 1888-1894

    • Related Report
      2011 Final Research Report
    • Peer Reviewed
  • [Journal Article] TGFβinduces proHB-EGF shedding and EGFR transactivation through ADAM activation in gastric cancer cells2010

    • Author(s)
      Ebi M, Kataoka H, Shimura T, Kubota E, Hirata Y, Mizushima T, Mizoshita T, Tanaka M, Mabuchi M, Tsukamoto H, Tanida S, Kamiya T, Higashiyama S, Joh T.
    • Journal Title

      Biochem. Biophys. Res. Commun

      Volume: 1402 Pages: 449-454

    • Related Report
      2011 Final Research Report
    • Peer Reviewed
  • [Journal Article] TGFβ induces proHB-EGF shedding and EGFR transactivation through ADAM activation in gastric cancer cells.2010

    • Author(s)
      Ebi M, Kataoka H, Shimura T, Kubota E, Hirata Y, Mizushima T, Mizoshita T, Tanaka M, Mabuchi M, Tsukamoto H, Tanida S, Kamiya T, Higashiyama S, Joh T.
    • Journal Title

      Biochem Biophys Res Commun.

      Volume: 402 Pages: 449-454

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Corneal epithelial wound healing impaired in keratinocyte-specific HB-EGF-deficient mice in vivo and in vitro.2010

    • Author(s)
      Yoshioka R, Shiraishi A, Kobayashi T, Morita S, Hayashi Y, Higashiyama S, Ohashi Y.
    • Journal Title

      Invest Ophthalmol Vis Sci.

      Volume: 51 Pages: 630-639

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Presentation] The role of monoubiqutination in the regulation of endocytosis and ectodomain shedding of a ligand of epidermal growth factor(EGF) recetor, amphiregulin2011

    • Author(s)
      Fukuda S, Nishida-Fukuda H, Nakayama H, Inoue H, Higashiyama S.
    • Organizer
      第34回日本分子生物学会年会
    • Place of Presentation
      横浜
    • Year and Date
      2011-12-15
    • Related Report
      2011 Final Research Report
  • [Presentation] The role of monoubiqutination in the regulation of endocytosis and ectodomain shedding of a ligand of epidermal growth factor (EGF) recetor, amphiregulin2011

    • Author(s)
      Fukuda S, Nishida-Fukuda H, Nakayama H, Inoue H, Higashiyama S
    • Organizer
      第34回日本分子生物学会年会
    • Place of Presentation
      横浜
    • Year and Date
      2011-12-15
    • Related Report
      2011 Annual Research Report
  • [Presentation] HB-EGF-CTF nuclear translocation induce gastric cancer invasion2011

    • Author(s)
      Shimura T, Yoshida M, Fukuda S, Mizoshita T, Kataoka H, Higashiyama S, Joh T.
    • Organizer
      第70会日本癌学会学術総会
    • Place of Presentation
      名古屋
    • Year and Date
      2011-10-05
    • Related Report
      2011 Final Research Report
  • [Presentation] HB-EGF-CTF nuclear translocation induce gastric cancer invasion2011

    • Author(s)
      Shimura T, Yoshida M, Fukuda S, Mizoshita T, Kataoka H, Higashiyama S, Joh T
    • Organizer
      第70回日本癌学会学術総会
    • Place of Presentation
      名古屋
    • Year and Date
      2011-10-05
    • Related Report
      2011 Annual Research Report
  • [Presentation] Amphiregulin nuclear translocation might cause poor prognosis due to chemotherapeutic resistance in gastric cancer2011

    • Author(s)
      Yoshida M, Shimura T, Fukuda S, Higashiyama S, Mizoshita T, Kataoka H, Joh T.
    • Organizer
      第70会日本癌学会学術総会
    • Place of Presentation
      名古屋
    • Year and Date
      2011-10-04
    • Related Report
      2011 Annual Research Report 2011 Final Research Report
  • [Presentation] dentification of novel molecules that regulate ectodomain shedding of EGF ligands2010

    • Author(s)
      福田信治、中山寛尚、東山繁樹
    • Organizer
      第33回日本分子生物学会年会、第88回日本生化学会大会合同大会
    • Place of Presentation
      神戸
    • Year and Date
      2010-12-09
    • Related Report
      2011 Final Research Report
  • [Presentation] Identification of novel molecules that regulate ectodomain shedding of EGF ligands2010

    • Author(s)
      福田信治、中山寛尚、東山繁樹
    • Organizer
      第33回日本分子生物学会年会、第88回日本生化学会大会 合同大会
    • Place of Presentation
      神戸
    • Year and Date
      2010-12-09
    • Related Report
      2010 Annual Research Report
  • [Presentation] C-terminal fragment signaling of proHB-EGF for protection of cardiac cell death2010

    • Author(s)
      東山繁樹、井上博文
    • Organizer
      第18回日本血管生物医学会学術集会シンポジウム2 :心不全・冠動脈
    • Place of Presentation
      大阪
    • Year and Date
      2010-12-01
    • Related Report
      2011 Final Research Report
  • [Presentation] C-terminal fragment signaling of proHB-EGF for protection of cardiac cell death2010

    • Author(s)
      東山繁樹、井上博文
    • Organizer
      第18回 日本血管生物医学会学術集会 シンポジウム2:心不全・冠動脈
    • Place of Presentation
      大阪
    • Year and Date
      2010-12-01
    • Related Report
      2010 Annual Research Report
  • [Presentation] Ectodomain shedding of LYVE-1 : VEGF-A promotes the initial step of pathological lymphoangiogenesis2010

    • Author(s)
      Satoshi Hirakawa, Shigeki Higashiyama
    • Organizer
      第18回 日本血管生物医学会学術集会 シンポジウム5 : Angiogenesis/Lymphangiogenesis
    • Place of Presentation
      大阪
    • Year and Date
      2010-12-01
    • Related Report
      2010 Annual Research Report
  • [Presentation] 増殖因子による増殖の正と負のシグナル制御機構と癌微小環境制御2010

    • Author(s)
      東山繁樹
    • Organizer
      第48回日本癌治療学会学術集会JSCO-JCA joint symposium 1「がんの微小環境(血管浸潤、がんの転移・浸潤)からのがん治療」
    • Place of Presentation
      京都
    • Year and Date
      2010-09-29
    • Related Report
      2011 Final Research Report
  • [Presentation] 増殖因子による増殖の正と負のシグナル制御機構と癌微小環境制御2010

    • Author(s)
      東山繁樹
    • Organizer
      第48回日本癌治療学会 学術集会JSCO-JCA joint symposium 1「がんの微小環境(血管浸潤、がんの転移・浸潤)からのがん治療」
    • Place of Presentation
      京都
    • Year and Date
      2010-09-29
    • Related Report
      2010 Annual Research Report
  • [Remarks]

    • URL

      http://www.m.ehime-u.ac.jp/data/course/list_detail.php?id=201100000053

    • Related Report
      2011 Final Research Report
  • [Remarks]

    • URL

      http://www.m.ehime-u.ac.jp/data/course/list_detail.php?id=201100000053

    • Related Report
      2011 Annual Research Report
  • [Remarks]

    • URL

      http://www.m.ehime-u.ac.jp/school/biochem2/

    • Related Report
      2010 Annual Research Report
  • [Remarks]

    • URL

      http://www.proteo.ehime-u.ac.jp/

    • Related Report
      2010 Annual Research Report

URL: 

Published: 2010-08-23   Modified: 2016-04-21  

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