Membrane trafficking mechanism of HB-EGF from the plasma membrane to the nuclear membrane

• Project/Area Number: 19570182
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Cell biology
• Research Institution: Osaka University (2008); Ehime University (2007)
• Principal Investigator: HIEDA Miki Osaka University, 大学院・医学系研究科, 特任助教 (00380254)
• Co-Investigator(Kenkyū-buntansha): MATSUURA Nariaki 大阪大学, 大学院・医学系研究科, 教授 (70190402) ; 東山 繁樹 愛媛大学, 大学院・医学系研究科, 教授 (60202272)
• Co-Investigator(Renkei-kenkyūsha): HIGASHIYAMA Shigeki 愛媛大学, 大学院・医学系研究科, 教授 (60202272)
• Project Period (FY): 2007 – 2008
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2008: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2007: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
• Keywords: メンブレントラフィック / HB-EGF / EGF 増殖因子 / 核膜 / EGFファミリー / 細胞増殖

Research Abstract

上皮増殖因子 (EGF) ファミリー分子 は膜貫通型タンパク質として細胞膜に発現し、細胞外領域の切断により増殖因子を細胞外へ遊離する。この時、細胞膜には膜貫通型ペプチド断片が残る。私達はEGF ファミリーメンバー、HB-EGF の膜貫通型ペプチド断片が細胞膜から核膜内膜へ局在変化し、転写因子に結合し、転写調節を行う事を明らかにした。 さらにHB-EGF だけでなく、他のEGF 分子、amphiregulin も細胞膜から核膜へ局在変化する事を示した。この時、カルボキシル末端が切断され、核膜裏打ちタンパク質ラミンと結合する事、核膜局在化によりヒストンH3 の修飾が変化し、グローバルな転写が一時的に抑制される事も明らかにした

Research Products

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  • Journal Title: Neuroscience 158 Pages: 683-692
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• [Journal Article] Insufficient shedding of proHB-EGF enhances hypoxic cell death in H9c2 cardiomyoblasts via activation of Caspase-3 and c-Jun N-terminal kinase (2009)
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  • Journal Title: J.Biol. Chem (in press)
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• [Journal Article] Combined autologous cellular cardiomyoplasty using skeletal myoblasts and bone marrow cells for human ischemic cardiomyopathy with left ventricular assist system implantation (2009)
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• [Journal Article] The plasma membrane-anchored growth factor, pro-amphiregulin, binds A-type lamin and regulates global transcription (2008)
  • Author(s): Isokane, M., Hieda, M., Hirakawa, S.,Shudou, M., Nakashiro, K., Hashimoto, K., Hamakawa, H., and Higashiyama, S.
  • Journal Title: J. Cell. Sci 121 Pages: 3608-3618
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• [Journal Article] Membrane-anchored growth factor,HB-EGF, on the cell surface targeted to the inner nuclear membrane (2008)
  • Author(s): Hieda, M., Isokane, M., Koizumi, M.,Higashi, C., Tachibana, T., Shudou, M.,Taguchi, T., Hieda, Y., and Higashiyama, S.
  • Journal Title: J. Cell Biol 180 Pages: 763-769
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• [Journal Article] Membrane-anchored Growth Factors, The EGF Family : Beyond receptor ligands (2008)
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• [Journal Article] Localized regulation of axonal RanGTPase controls retrograde injury signalingin peripheral nerve (2008)
  • Author(s): Yudin, D., Hanz S.,Yoo,S., Iavnilovitch,E., Willis,D., Gradus, T., Vuppalanchi,D.,Segal-Ruder,Y., Ben-Yaakov, K., Hieda,M., Yoneda, Y., Twiss, J.L., andFainzilber, M.
  • Journal Title: Neuron 59 Pages: 241-252
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• [Journal Article] Region-specific proliferative response of neural progenitors to exogenous stimulation by growth factors following ischemia (2008)
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  • Journal Title: Neuroreport 19 Pages: 805-809
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• [Journal Article] Oxaliplatin induces mitotic catastrophe and apoptosis in esophageal cancer cells (2008)
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  • Journal Title: Cancer Sci 99 Pages: 129-139
  • NAID: 10024001242
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• [Journal Article] Gene expression of colorectal cancer : Preoperative genetic diagnosis using endoscopic biopsies. Int. (2008)
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  • Journal Title: J. Oncol 32 Pages: 367-375
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• [Journal Article] Identification of L-plastin autoantibody in plasma of patients with non-Hodgkin's lymphoma using a proteomics-based analysis (2008)
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  • Journal Title: Ann Clin Biochem 45 Pages: 65-69
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• [Journal Article] Aberrant Expression of Connexin 26 Is Associated with Lung Metastasis of Colorectal Cancer (2008)
  • Author(s): Ezumi, K., Yamamoto, H., Murata, K.,Higashiyama, M., Damdinsuren, B.,Nakamura, Y., Kyo, N., Okami, J., Ngan,C.Y., Takemasa, I., Ikeda, M., Sekimoto,M., Matsuura, N., Nojima, H., Monden, M.
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• [Journal Article] Therapeutic effect of midkine on cardiac remodeling in infarcted rat hearts (2008)
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  • Journal Title: Ann. Thorac. Surg 85 Pages: 562-570
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• [Journal Article] Topoisomerase IIalpha-positive and BRCA1-negative phenotype : Association with favorable response to epirubicin-based regimens for human breast cancers (2008)
  • Author(s): Miyoshi, Y., Kurosumi, M., Kurebayashi, J.,Matsuura, N., Takahashi, M., Tokunaga,E., Egawa, C., Masuda, N., Kim, S.J.,Okishiro, M., Yanagisawa, T., Ueda, S.,Taguchi, T., Tamaki, Y., Noguchi, S.
  • Journal Title: Cancer Lett 264 Pages: 44-53
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• [Journal Article] Molecular mapping of human hepatocellular carcinoma provides deeper biological insight from genomic data (2008)
  • Author(s): 17. Kittaka, N., Takemasa, I., Takeda, Y.,Marubashi, S., Nagano, H., Umeshita, K.,Dono, K., Matsubara, K., Matsuura, N.,Monden, M.
  • Journal Title: Eur.J. Cancer 44 Pages: 885-897
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• [Journal Article] The Collaborative Study Group of Scientific Research of the Japanese Breast Cancer Society. Low nuclear grade but not cell proliferation predictive of pathological complete response to docetaxel in human breast cancers (2008)
  • Author(s): 18. Miyoshi, Y., Kurosumi, M., Kurebayashi, J.,Matsuura, N., Takahashi, M., Tokunaga,E., Egawa, C., Masuda, N., Kim, S.J.,Okishiro, M., Yanagisawa, T., Ueda, S.,Taguchi, T., Tamaki, Y., Noguchi, S.
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• [Journal Article] Morphological and biochemical signs of age-related neurodegenerative changes in klotho mutant mice. (2008)
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• [Journal Article] An application of the 2-nitrobenzenesulfenyl method to proteomic profiling of human colorectal carcinoma : A novel approach for biomarker discovery (2008)
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• [Journal Article] The implication of N-acetylglucosaminyltransferase V expression in gastric cancer (2008)
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• [Journal Article] In situ tissue regeneration using a novel tissue-engineered, small-caliber vascular graft without cell seeding (2008)
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• [Journal Article] Overexpression of MT1-MMP is insufficient to increase experimental liver metastasis of human colon cancer cells (2008)
  • Author(s): Yamamoto, H., Noura, S., Okami, J.,Uemura, M., Takemasa, I., Ikeda, M., Ishii, H., Sekimoto, M., Matsuura, N., Monden, M., Mori, M.
  • Journal Title: Int. J. Mol. Med. 22 Pages: 757-761
  • Peer Reviewed
• [Journal Article] Membrane anchored-growth factor, HB-EGF on the cell surface targeted to the inner nuclear membrane (2008)
  • Author(s): Hieda, et al.
  • Journal Title: Journal of Cell Biology 180 Pages: 763-769
  • Peer Reviewed
• [Journal Article] The plasma membrane-anchored growth factor, pro-amphiregulin, binds A-type lam in and regulates global transcription (2008)
  • Author(s): Isokane, et al.
  • Journal Title: Journal of Cell Science 121 Pages: 3608-3618
  • Peer Reviewed
• [Journal Article] Membrane-anchored growth factors, the EGF tamily. Beyond receptor ligands. (2008)
  • Author(s): Higashiyama, et al.
  • Journal Title: Cancer Science 211 Pages: 214-220
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• [Journal Article] Localized regulation of axonal RanGTPase controls retrogradeinjury signalingin peripheral nerve (2008)
  • Author(s): Yudin, et al.
  • Journal Title: Neuron 59 Pages: 241-252
  • Peer Reviewed
• [Journal Article] Membrane anchored-growth factor,HB-EGF on the cell surface targeted to the inner nuclear membrane (2008)
  • Author(s): Hieda, et. al.
  • Journal Title: Journal of Cell Biology 180 Pages: 763-769
  • Peer Reviewed
• [Journal Article] Membrane-anchored growth factors,the EGF family.Beyond receptor lig ands (2008)
  • Author(s): Higashiyama, et. al.
  • Journal Title: Cancer Science 99 Pages: 214-220
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• [Journal Article] The carboxyl-terminal fragment of proHB-EGF reverses Bcl6-mediated gene repression (2007)
  • Author(s): Kinugasa, Y., Hieda, M., Hori, M., and Higashiyama, S.
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• [Journal Article] Pbx1is a major target of PLZF-mediated melanoma cell growth suppression (2007)
  • Author(s): Shiraishi, K., Yamasaki, K., Nanba, D.,Inoue, H., Hanakawa, Y., Shirakata, Y.,Hashimoto, K., and Higashiyama, S.
  • Journal Title: Oncogene 26 Pages: 339-348
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• [Journal Article] and Higashiyama, S. Effects of promyelocytic leukemia zinc finger protein on the proliferation of cultured human corneal endothelial cells (2007)
  • Author(s): Joko, T., Nanba, D., Shiba, F., Miyata, K., Shiraishi, A., Ohashi, Y.
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• [Journal Article] An intermediary role of proHB-EGF shedding in growth factor-induced c-myc expression (2007)
  • Author(s): Nanba, D., Inoue, Y., Shigemi, Y., Shirakata, Y., Hashimoto, K., and Higashiyama, S.
  • Journal Title: J.Cell.Physiol 214 Pages: 465-473
  • Peer Reviewed
• [Journal Article] Osteoactivin fragments produced by ectodomain shedding induce MMP-3 expression via ERK pathway in mouse NIH-3T3 fibroblasts (2007)
  • Author(s): Furochi, H., Tamura, S., Mameoka, M.,Yamada, C., Ogawa, T., Hirasaka, K.,Okumura, Y., Imagawa, T., Oguri, S.,Ishidoh, K., Kishi, K., Higashiyama, S.Nikawa, T.
  • Journal Title: FEBS Lett 581 Pages: 5743-5750
  • Peer Reviewed
• [Journal Article] Human corneal epithelial cell proliferation by epiregulin and its cross-induction by other EGF family members (2007)
  • Author(s): Morita, S., Shirakata, Y., Shiraishi, A.Kadota, Y., Hashimoto , K., Higashiyama,S., Ohashi, Y.
  • Journal Title: Mol. Vision 13 Pages: 2119-2128
  • Peer Reviewed
• [Journal Article] Evidence against roles for phorbol binding protein Munc13-1, ADAM adaptor Eve-1, or vesicle trafficking phosphoproteins Munc18 or NSF as phospho-state-sensitive modulators of phorbol/PKC-activated Alzheimer APP ectodomain shedding (2007)
  • Author(s): Ikin, A.F., Causevic, M., Pedrini, S.,Lyndsey S. Bensonl, L.S., Buxbaum, J.D.,Suzuki, T., Simon Lovestone, S.,Higashiyama, S., Mustelin, T., Burgoyne, R.D., and Gandy, S.
  • Journal Title: Molecular Neurodegeneration 2, 23
  • Peer Reviewed
• [Presentation] Nuclear signaling of membrane-anchored growth factors and cell growth regulation (2009)
  • Author(s): Shigeki Higashiyama
  • Organizer: International Symposium "New Frontiers in Cancer Research"
  • Place of Presentation: Sapporo, Hokkaido
  • Year and Date: 2009-03-18
• [Presentation] Inner nuclear membrane targeting of membrane-anchored growth factors and transcriptional regulation (2009)
  • Author(s): Shigeki Higashiyama
  • Organizer: Gordon Research Conference "Signal Transduction within the Nucleus"
  • Place of Presentation: Ventura, California, USA
• [Presentation] Inner nuclear membrane targeting of pro-amphiregulin regulatesoral squamous cell carcinoma cell viability (2008)
  • Author(s): Miki Hieda
  • Organizer: 第67回日本癌学会学術総会
  • Place of Presentation: 愛知県・名古屋市 名古屋国際会議場
  • Year and Date: 2008-10-29
• [Presentation] Plasma membrane anchored growth factors HB-EGF and mamphiregulin targeted to the inner nuclear membrane and regulate gene expression (2008)
  • Author(s): Miki Hieda
  • Organizer: Cold Spring Harbar meeting, Nuclear structure and function Dynamic Organization of Nuclear Function
  • Place of Presentation: Cold Spring Harbar, NY, U.S.A.
  • Year and Date: 2008-09-18
• [Presentation] Intracellular transport of membrane-anchored EGF family growthfactor from the plasma membrane to the inner nuclear membrane (2008)
  • Author(s): Miki Hieda
  • Organizer: 60回日本細胞生物学会大会
  • Place of Presentation: 神奈川県・パシフィコ横浜
  • Year and Date: 2008-07-01
• [Presentation] The plasma membrane-anchored growth factor, amphiregulin, binds A-ype lamin and regulates global transcription (2008)
  • Author(s): Mayumi Isokane
  • Organizer: 第60回日本細胞生物学会大会
  • Place of Presentation: 神奈川県・パシフイコ横浜
  • Year and Date: 2008-06-29
• [Presentation] Mayumi Isokane, Miki Hieda, Satoshi Hirakawa, Koichi Nakashiro, Koji Hashimoto, Hiroyuki Hamakawa and Shigeki Higashiyama The plasma membrane-anchored growth factor, amphiregulin, binds A-type lamin and regulates global transcription (2008)
  • Author(s): Mayumi Isokane
  • Organizer: 12th International Congress on Oral Cancer conjunction with 24th Congress of ICMFS (former IAMFS)
  • Place of Presentation: Shanghai, China
  • Year and Date: 2008-05-22
• [Presentation] 膜型増殖因子の核膜内膜移行による転写調節 (2008)
  • Author(s): 東山繁樹
  • Organizer: 特定領域研究「核ダイナミクス」「遺伝情報デコード」合同シンポジウム「クロマチンシグナリングの分子機構」
  • Place of Presentation: 東京ステーションカンファレンス
  • Year and Date: 2008-01-08
• [Presentation] Inner nuclear membrane targeting of pro-amphiregulin regulates oral squamous cell carcinoma cell viability (2008)
  • Author(s): Mayumi Isokane, Miki Hieda, Eriko Koya, Koichi Nakashiro, Hiroyuki Hamakawa and Shigeki Higashiyama
  • Organizer: 第67回日本癌学会学術総会 (ミニシンポジウム・口頭発表)
  • Place of Presentation: 愛知県・名古屋市
• [Presentation] Induction of Metastatic Potential by Cleavage of Carcinoembryonic Antigen in Colorectal Carcinoma Cells (2008)
  • Author(s): Kaori Iwaki, Yasuko Yamamoto, Yukiko Ueno, Yuhki Yokoyama, Mohammed N.Shaker, Seiji Mori, Nariaki Matsuura
  • Organizer: 36th Congress of the International Society of Oncology & Biomarkers
  • Place of Presentation: Tokyo
• [Presentation] Novel Molecular Method for Rapid Diagnosis of Lymph Node Metastasis in Breast Cancer (2008)
  • Author(s): Mohammed N.Shaker, Seiji Mori, Yuhki Yokoyama, Kaori Iwaki, Yukiko Ueno,Nariaki Matsuura
  • Organizer: 36th Congress of the International Society of Oncology & Biomarkers
  • Place of Presentation: Tokyo
• [Presentation] Intermediate Surrogate Molecular Marker for the Prevention of Colorectal Cancer (2008)
  • Author(s): Yukiko Ueno, Hideki Ishikawa, Yuhki Yokoyama, Mohammed N. Shaker, KaoriIwaki, Seiji Mori, Nariaki Matsuura
  • Organizer: 36th Congress of the International Society of Oncology & Biomarkers
  • Place of Presentation: Tokyo
• [Presentation] Specific Binding of Fibroblast Growth Factor-1 (FGF1) to Integrins is Required for FGF1 Signaling (2008)
  • Author(s): Seiji Mori, Yoshikazu Takada, Nariaki Matsuura
  • Organizer: 36th Congress of the International Society of Oncology & Biomarkers
  • Place of Presentation: Tokyo
• [Presentation] Effect of Platelet Derived Growth Factor on Development and Progression of Breast Cancer (2008)
  • Author(s): Yuhki Yokoyama, Seiji Mori, Nariaki Matsuura
  • Organizer: 36th Congress of the International Society of Oncology & Biomarkers
  • Place of Presentation: Tokyo
• [Presentation] Plasma membrane anchored growth factors HB-EGF and mamphiregulin targeted to the inner nuclear membrane and regulate gene expression (2008)
  • Author(s): Mayumi Isokane, Miki Hieda, and Shigeki Higashiyama
  • Organizer: Cold Spring Harbar meeting, Nuclear structure and function Dynamic Organization of Nuclear Function (ポスタ ー発表)
  • Place of Presentation: Cold Spring Harbar, NY, U.S.A.
• [Presentation] Intracellular transport of membrane-anchored EGF family growth factor from the plasma membrane to the inner nuclear membrane 「膜型増殖因子EGF ファミリー分子は細胞膜から核膜へ局在変化する」 (2008)
  • Author(s): 檜枝美紀、礒兼真由美、東山繁樹
  • Organizer: 第60回日本細胞生物学会
  • Place of Presentation: 神奈川県・パシフィコ横浜
• [Presentation] The plasma membrane-anchored growth factor, amphiregulin, binds A-type lamin and regulates global transcription 「膜型増 殖因子amphiregulin の細胞内輸送経路およびその機能解析」 (2008)
  • Author(s): 礒兼真由美、檜枝美紀、東山繁樹
  • Organizer: 第60回日本細胞生物学会大会
  • Place of Presentation: パシフィコ横浜
• [Presentation] The plasma membrane-anchored growth factor, amphiregulin, binds A-type lamin and regulates global transcription (2008)
  • Author(s): Mayumi Isokane, Miki Hieda, Satoshi Hirakawa, Koichi Nakashiro, Koji Hashimoto, Hiroyuki Hamakawa and Shigeki Higashiyama
  • Organizer: 12th International Congress on Oral Cancer conjunction with 24th Congress of ICMFS (former IAMFS)
  • Place of Presentation: Shanghai, China
• [Presentation] The Role of ADAM9 in Metastasis of Non-Small Cell Lung Cancer (2008)
  • Author(s): Nariaki Matsuura, Yasushi Shintani, Yukiko Ueno, Kaori Iwaki, Yuhki Yokoyama, Mohammed N.
  • Organizer: Shaker, Seiji Mori. 36th Congress of the International Society of Oncology & Biomarkers, Symposium "New Molecular Markers in Lung Cancer"
  • Place of Presentation: Tokyo
• [Presentation] Development of a new molecular method for rapid diagnosis of lymph node metastasis in breast cancer (2008)
  • Author(s): N. Matsuura, F. Akiyama, S. Noguchi, M. Tsujimoto, H. Inaji, S. Nakamura, M. Mano, Y.
  • Organizer: Otomo, International Oncoplastic Breast Surgery Symposium,
  • Place of Presentation: Daegu, Korea
• [Presentation] 膜型増殖因子の核膜内膜移行とがん細胞特性の変化 (2008)
  • Author(s): 東山繁樹
  • Organizer: 文部科学省, 厚生労働省がん研究合同シンポジウム
  • Place of Presentation: 学術総合センター一橋記念講堂(東京)、招待講演
• [Presentation] 膜型増殖因子による遺伝子転写制御機構(招待講演) (2007)
  • Author(s): 東山繁樹
  • Organizer: 第44回日本口腔組織培養学会
  • Place of Presentation: 松山
  • Year and Date: 2007-12-01
• [Presentation] 癌微小環境における細胞特性の変化-膜型増殖因子の役割(招待講演) (2007)
  • Author(s): 東山繁樹
  • Organizer: 第59回日本泌尿器科学会西日本総会
  • Place of Presentation: 松山
  • Year and Date: 2007-11-10
• [Presentation] Membrane-anchored growth factor HB-EGF on cell surface targets to the nuclear membrane and regulates gene expression (2007)
  • Author(s): Miki Hieda and Shigeki Higashiyama
  • Organizer: 国際シンポジウム「メンブレントラフィック」
  • Place of Presentation: 淡路島
• [Presentation] 「膜型増殖因子HB-EGFは核膜内膜に移行し転写を調節する (2007)
  • Author(s): 檜枝美紀、衣笠由美、東山繁樹
  • Organizer: 核ダイナミクス研究会
  • Place of Presentation: 札幌
• [Presentation] Membrane-anchored growth factor HB-EGF on cell surface targets to the nuclear membrane and regulates gene expression (2007)
  • Author(s): Miki Hieda and Shigeki Higashiyama
  • Organizer: EMBO Conference Series on Nuclear Structure and Dynamics Montpellier
• [Presentation] Membrane-anchored growth factor, HB-EGF targets to the nuclear membrane and regulates gene expression (2007)
  • Author(s): Miki Hieda, Yumi Kinugasa, Chizuru Higashi, Taro Tachibana, Tomohiko Taguchi, and Shigeki Higashiyama
  • Organizer: 第40回発生生物学会第49回日本細胞生物学会合同大会
  • Place of Presentation: 福岡県福岡市国際会議場
• [Presentation] Membrane-anchored growth factor, HB-EGF targets tothe nuclear membrane and regulates gene expression (2007)
  • Author(s): Hieda M, Kinugasa Y, Higashi C., Tachibana T, Taguchi T., and Higashiyama S.
  • Organizer: 第40回発生生物学会第49回日本細胞生物学会合同大会
  • Place of Presentation: 福岡県福岡市
• [Presentation] Membrane-anchored growth factor HB-EGF on cell surface targets to the nuclear membra ne and regulates gene expression (2007)
  • Author(s): Hieda M, and Higashiyama S.
  • Organizer: EMBO Conference Series on Nuclear Structure and Dynamics
  • Place of Presentation: フランス モンペリエ
• [Presentation] Membrance-anchored growth factor HB-EGF on cell surface targets to the nuclear membrane and regulates gene expression (2007)
  • Author(s): Hieda M, and Higashiyama S.
  • Organizer: 国際シンポジウム「メンブレントラフィック」
  • Place of Presentation: 兵庫県洲本町