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

• Project/Area Number: 22650228
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Single-year Grants
• Research Field: Tumor biology
• Research Institution: Ehime 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: ¥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.

Research Products

• [Journal Article] Nuclear translocation of pro-amphiregulin induces chemoresistance in gastric cancer (2012)
  • 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
  • Peer Reviewed
• [Journal Article] A Disintegrin and Metalloenzyme(ADAM) 17 Activation Is Regulated byα5β1 Integrin in Kidney Mesangial Cells (2012)
  • Author(s): Gooz P, Dang Y, Higashiyama S, Twal WO, Haycraft CJ, Gooz M.
  • Journal Title: PLoS One Volume: 7
  • Peer Reviewed
• [Journal Article] Monoubiquitination of pro-amphiregulin regulates its endocytosis and ectodomain shedding (2012)
  • Author(s): Fukuda S, Nishida-Fukuda H, Nakayama H, Inoue H, Higashiyama S.
  • Journal Title: Biochem Biophys Res Commun Volume: 420 Pages: 315-320
  • Peer Reviewed
• [Journal Article] Cell surface-annexins regulate ADAM-mediated ectodomain shedding of proamphiregulin (2012)
  • 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)
  • Peer Reviewed
• [Journal Article] Nuclear envelope-localized EGF family protein amphiregulin activates breast cancer cell migration in an EGF growth factor domain independent manner (2012)
  • 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)
  • Peer Reviewed
• [Journal Article] A disintegrin and metalloenzyme (ADAM) 17 activation is regulated by α5β1 integrin in kidney mesangial cells (2012)
  • Author(s): Gooz P, Dang Y, Higashiyama S, Twal WO, Haycraft CJ, Gooz M
  • Journal Title: PLoS One Volume: 7
  • Peer Reviewed
• [Journal Article] Monoubiquitination of pro-amphiregulin regulates its endocytosis and ectodomain shedding (2012)
  • Author(s): Fukuda S, Nishida-Fukuda H, Nakayama H, Inoue H, Higashiyama S
  • Journal Title: Biochem.Biophys.Res.Commun. Volume: 420 Pages: 315-320
  • Peer Reviewed
• [Journal Article] Cell surface-annexins regulate ADAM-mediated ectodomain shedding of proamphiregulin (2012)
  • 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)
  • Peer Reviewed
• [Journal Article] Nuclear envelope-localized EGF family protein amphiregulin activates breast cancer cell migration in an EGF growth factor domain independent manner (2012)
  • 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)
  • 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
  • Peer Reviewed
• [Journal Article] Corneal epithelial wound healing impaired in keratinocyte-specific HB-EGF-deficient mice in vivo and in vitro (2011)
  • 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
  • Peer Reviewed
• [Journal Article] Ectodomain shedding and remnant peptide signalling of EGFRs and their ligands (2011)
  • Author(s): Higashiyama S, Nanba D, Nakayama H, Inoue H, Fukuda S.
  • Journal Title: J. Biochem Volume: 150 Pages: 15-22
  • NAID: 10030586134
  • 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
  • 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 Volume: 18 Pages: 1888-1894
  • Peer Reviewed
• [Journal Article] TGFβinduces 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: 1402 Pages: 449-454
  • 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
  • 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
  • Peer Reviewed
• [Presentation] The role of monoubiqutination in the regulation of endocytosis and ectodomain shedding of a ligand of epidermal growth factor(EGF) recetor, amphiregulin (2011)
  • 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
• [Presentation] The role of monoubiqutination in the regulation of endocytosis and ectodomain shedding of a ligand of epidermal growth factor (EGF) recetor, amphiregulin (2011)
  • 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
• [Presentation] HB-EGF-CTF nuclear translocation induce gastric cancer invasion (2011)
  • 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
• [Presentation] HB-EGF-CTF nuclear translocation induce gastric cancer invasion (2011)
  • 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
• [Presentation] Amphiregulin nuclear translocation might cause poor prognosis due to chemotherapeutic resistance in gastric cancer (2011)
  • 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
• [Presentation] dentification of novel molecules that regulate ectodomain shedding of EGF ligands (2010)
  • 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
• [Presentation] Identification of novel molecules that regulate ectodomain shedding of EGF ligands (2010)
  • 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
• [Presentation] C-terminal fragment signaling of proHB-EGF for protection of cardiac cell death (2010)
  • 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
• [Presentation] C-terminal fragment signaling of proHB-EGF for protection of cardiac cell death (2010)
  • 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
• [Presentation] Ectodomain shedding of LYVE-1 : VEGF-A promotes the initial step of pathological lymphoangiogenesis (2010)
  • 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
• [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
• [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
• [Remarks]
  • URL: http://www.m.ehime-u.ac.jp/data/course/list_detail.php?id=201100000053
• [Remarks]
  • URL: http://www.m.ehime-u.ac.jp/data/course/list_detail.php?id=201100000053
• [Remarks]
  • URL: http://www.m.ehime-u.ac.jp/school/biochem2/
• [Remarks]
  • URL: http://www.proteo.ehime-u.ac.jp/