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膜型増殖因子の持つ細胞増殖のアクセル機能とブレーキ解除機能の分子機構の解明

研究報告コード R070000189
整理番号 R070000189
掲載日 2008年4月11日
研究者
  • 東山 繁樹
研究者所属機関
報告名称 膜型増殖因子の持つ細胞増殖のアクセル機能とブレーキ解除機能の分子機構の解明
報告概要 細胞が外界から様々なリガンド刺激を受けると膜型増殖因子Heparin-binding EGF-like Growth Factor(proHB-EGF)が細胞膜表面上でsheddingを受ける。sheddingによって生じる遊離型細胞外ドメインは、EGFレセプターを活性化して増殖シグナルを惹起する。我々はshedding後に細胞膜に残るC末端断片ペプチド(CTF)が速やかに核内に移行し、転写抑制因子と結合しこれを核外に汲み出す反応を誘導することを見い出した。これにより、HB-EGF-CTFが遺伝子転写抑制解除機能を持つことを明らかにし、新たなシグナル分子として機能すると共に、新たな細胞増殖シグナル経路が存在することを示した(J Cell Biol. 163,489-502,2003)。本研究では膜型増殖因子が持つ増殖アクセル機能と増殖ブレーキ解除の巧妙な分子機構を明らかにし、細胞増殖分子機構の新たな概念を創出することを研究のねらいとした。
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研究分野
  • 細胞生理一般
関連発表論文 (1) Sahin, U., Weskam, G., Zhou, H., Higashiyama, S., Peschon, J., Hartmann, D., Safting, P., Blobel, C.P. Distinct roles for ADAM10 and 17 in ectodomain shedding of six EGFR-ligands J. Cell Biol. 164, 769-779, 2004.
(2) Nakano, N., Higashiyama, S., Ohmoto, H., Ishiguro, H., Taniguchi, N., and Wada, Y. The N-terminal region of NTAK/neuregulin-2 isoforms has an inhibitory activity of angiogenesis. J. Biol. Chem. 279, 11465-11470, 2004.
(3) Shintani, Y., Higashiyama, S., Ohta, M., Hirabayashi, H., Yamamoto, S., Yoshimasu, T., Matsuda, H. and Matsuura, N. Overexpression of ADAM9 in non-small cell lung cancer correlates with brain metastasis Cancer Res. 64, 4190-4196, 2004.
(4) Murayama, Y., Miyagawa, J., Oritani, K., Yoshida, H., Yamamoto, K., Kishida, O., Miyazaki, T., Tsutsui, S., Kiyohara, T., Miyazaki, Y., Higashiyama, S., and Matsuzawa, Y., Shinomura, Y. CD9-mediated activation of the p46 Shc isoform leads to apoptosis in cancer cells. J. Cell. Sci. 117, 3379-3388, 2004.
(5) Tanida, S., Joh, T., Watanabe, K., Itoh, Y., Seno. K., Ohara, H., Nomura, T., Yokoyama, Y., Ishiguro, H., Yoshino, K., Higaashiyama, S. and Itoh, M. The mechanism of cleavage of EGFR ligands induced by inflammatory cytokines in gastric epithelial cells; ADAM10 mediates IL-8-induced EGFR transactivation. Gastroenterology. 127, 559-569, 2004.
(6) Nanba, D., Toki,. F., and Higashiyama, S. Charged amino acid residues in the cytoplamic domain of proHB-EGF regulate its distribution and interaction with PLZF. Biochem. Biophys. Res. Commun. 320, 376-382, 2004.
(7) Kinugasa, Y., Ohomoto, H., Ishiguro, H., Tokita, Y., Oohira, A, and Higashiyama, S. Neuroglycan C, a novel member of the neuregulin family. Biochem. Biophys. Res. Commun. 321, 1045-1049, 2004.
(8) Ongusaha, P.P., Kwak, J.C., Zwible, A.J., Macip, S., Higashiyama, S., Taniguchi, N., Fang, L. and Lee, S.W. HB-EGF Is a Potent Inducer of Tumor Growth and Angiogenesis. Cancer Res. 64, 5283-5290, 2004.
(9) Tanaka, M., Nanba, D., Mori, S., Shiba F., Ishiguro, H., Yoshino, K., Matsuura, N. and Higashiyama. S. ADAM-binding protein Eve-1 is required for ectodomain shedding of EGF receptor ligands J. Biol. Chem. 279, 41950-41959, 2004.
(10) Oh, M., Im l., Lee, Y.J., Kim, Y.H., Yoon, J.H., Park, H.G., Higashiyama, S., Kima, Y.-C. and Park, W.J. Structure-based virtual screening and biological evaluation of potent and selective ADAM12 inhibitors Bioorg. Med Chem Lett. 14: 6071-6074, 2004.
(11) Toki, F., Nanba, D., Matsuura, N. and Higashiyama, S. Ectodomain shedding of membrane-anchored heparin-binding EGF like growth factor and subcellular localization of the C-terminal fragment in a cell cycle. J.Cell Physlol. 202, 839-848, 2005.
(12) Itoh, Y., Joh, T., Tanida, S., Sasaki, M., Kataoka, H., Itoh, K., Oshima, T., Ogasawara, N., Togawa, S., Wada, T., Kubota, H., Mori, Y., Ohara, H., Nomura, T., Higashiyama, S. and Itoh, M. IL-8 promotes cell proliferation and migration through metalloproteinase-cleavage proHB-EGF in Human Colon Carcinoma Cells. Cytokine 29, 275-282, 2005.
(13) Shirakata, Y., Kimura, R., Nanba, D., Morimoto, C., Yokota, K., Nakamura, M., Mekada, E., Higashiyama, S., and Hashimoto, K. Heparin-binding EGF-like growth factor is essential for keratinocyte migration in skin wound heaking. J. Cell Science 118, 2363-2370, 2005.
(14) Mifune, M., Ohtsu, H., Suzuki, H., Nakashima, H., Brailoiu, E., Dun, N.J., Frank, G.D., Inagami, T., Higashiyama, S., Thomas, W.G., Eckhart, A.D., Dempsey, P.J., Eguchi, S. G protein coupling and second messenger generation are indispensable for metalloprotease-dependent, heparin-binding epidermal growth factor shedding through angiotensin II type-1 receptor. J. Biol. Chem. 280, 26592-26599, 2005.
(15) Kozawa, J., Tokui, Y., Moriwaki, M., Li, M., Ohmoto, H., Yuan, M., Zhang, J., Iwahashi, H., Imagawa, A., Yamagata, K., Tochino, Y., Shimomura, I., Higashiyama, S., Miyagawa, J. Regenerative and therapeutic effects of heparin-binding epidermal growth factor-like growth factor on diabetes by gene transduction through retrograde pancreatic duct injection of adenovirus vector. Pancreas 31, 32-42, 2005.
(16) Tokumaru, S., Sayama, K., Shirakata, Y., Komatsuzawa, H., Ouhara, K., Hanakawa, Y., Yahata. Y., Dai, X., Tohyama, M., Nagai, H., Yang, L., Higashiyama, S., Yoshimura, A., Sugai, M., Hashimoto, K. Induction of Keratinocyte Migration via Transactivation of the Epidermal Growth Faetor Receptor by the Antimicrobial Peptide LL-37. J. Immunol. 175, 4662-4668, 2005.
(17) Joh, T., Kataoka, H., Tanida, S., Watanabe, K., Ohshima, T., Sasaki, M., Nakao, H., Ohhara, H., Higashiyama, S., and Itoh, M. Helicobacter pylori-Stimulated Interleukin-8 (IL-8) Promotes Cell Proliferation Through Transaotivation of Epidermal Growth Factor Receptor (EGFR) by Disintegrin and Metalloproteinase (ADAM) Activation. Dig Dis Sci. 50, 2081-2089, 2005.
(18) Fukui, K., Yang. Q., Cao, Y., Takahashi, N., Hatakeyama, H., Wang, H., Wada, J., Zhang, Y., Marselli, L., Namno, T., Yoneda, K., Onishi, M., Higashiyama, S., Matsuzawa, Y., Gonzalez, F.J., Weir. G.C., Kasai, H., Shimomura, I., Miyagawa, J., Wollheim, C.B., and Yamagata, K. The HNF-1 target collectrin controls insulin exocytosis by SNARE complex formation. Cell Metabolism 2, 373-384, 2005.
(19) Hirao, F., Nanba, D., Tanaka. M., Ishiguro, H., Kinugasa, Y., Doki, Y., Yanao, M., Matuura, N., Monden, M., and Higashiyama, S. Alternative recycling of E-cadeherin depends on metalloprotease activity of ADAM9. Exp. Cell Res. 312, 331-339, 2006.
(20) Kikugawa, T., Kinugasa, Y., Shiraishi, K., Nanba, D., Nakashiro K., Tanji, N., Yokoyama, M., and Higashiyama, S. PLZF regulates Pbx1 transcription and Pbxl-HoxC8 complex leads to androgen-independent prostate cancer proliferation. The Prostate 66, 1092-2099, 2006.
(21) Shishido, Y., Tanaka, T., Piao, Y.S., Araki, K., Takei, N., Higashiyama, S., Nawa H. Activity-dependent shedding of heparin-binding EGF-like growth factor in brain neurons. Biochem Blophys Res Commun. 348, 963-970, 2006.
(22) Nanba, D., Kinugasa, Y., Morimoto, C., Koizumi, M., Yamamutra, H., Takahashi, K., Takakura, N., Mekada. E., Hashimoto, K., Higashiyama, S. Loss of HB-EGF in smooth muscle or endothelial cell lineages causes heart valve malformation and cardiac hypertrophy. Biochem Biophys Res Commun. 350, 315-321, 2006.
(23) Shiraishi, K., Yamasaki, K., Nanba, D., Inoue, H., Hanakawa, Y., Shirakata, Y., Hashimoto, K., and Higashiyama, S. Pbxlis a major target of PLZF-mediated melanoma cell growth suppression. Oncogene in press, 2006.
(24) Higashiyama, S. Metalloproteinase-mediated shedding of Heparin-binding EGF-like growth factor and its pathophysiological roles. Protein and Peptide Letters 11, 443-450, 2004.
(25) Nanba, D. and Higashiyama, S. Dual intracellular signaling by proteolytic cleavage of membrane-anchored heparin-binding EGF-like growth factor, Cytokine and Growth Factor Reviews 15, 13-19, 2004.
(26) Higashiyama, S. and Nanba, D. ADAM mediated ectodomain shedding of the EGFR ligands in receptor cross talk Biochemica Biophysica Acta 751 , 110-117, 2005
(27) 難波大輔、東山繁樹:膜結合型細胞増殖因子 proHB-EGF.細胞工学 Vol 24,p210-215,2004 秀潤社、東京
(28) 東山繁樹:細胞増殖因子HB-EGF 腎臓ナビゲータ p94-95,2004 メディカルレビュー社 東京
(29) 東山繁樹:細胞増殖因子HB-EGF 心臓ナビゲーター p62-63,2004メディカルレビュー社 東京
(30) 東山繁:EGF,TGFα,HB-EGF,アンフィレグリン、SDGF,ベーターセルリン、エピレグリン、エピジェン、ニューレグリン1、2、3、4、5、6 サイトカイン・増殖因子 用語ライブラリー:p181-195.2005 羊土社、東京
(31) 東山繁樹、難波大輔、田中基成:アンジオテンシン受容体と増殖因子のクロストークの新知見:血管医学 vol 5,p345-350,2004メディカルレビュー社 東京
(32) 東山繁樹、木曽真一:HB-EGFと肝再生 細胞増殖因子と再生医療 p50-57,2006.メディカルレビュー社 東京
(33) Daisuke Nanba, Fujio Toki, Chie Morimoto, Shigeki Higashiyama. Analysis of the carboxy-terminal fragment of membrane-anchored heparin-binding EGF-like growth factor. Gordon research conference -Growth Factor Signaling-, Oxford, July 25-30, 2004.
(34) Fujio Toki, Daisuke Nanba, Nariaki Matsuura, Shigeki Higashiyama. Ectodomain shedding of membrane-anchored heparin-binding EGF-like growth factor and subcellular localization of the C-terminal fragment in the cell cyole. Gordon research conference -Growth Factor Signaling-, Oxford, July 25-30, 2004.
(35) Y. Kinugasa, S. Higashiyama and M. Hieda. The carboxy-terminal domain of HB-EGF regulates Bcl6, a transcriptional repressor, via direct interaction (Poster). EMBO/FEBS Conference on Nuclear Structure and Dynamics, France, Sep. 25, 2005.
(36) S. Morita, Y. Shirakata, Y. Ohashi and S. Higashiyama. Epiregulin, a novel member of the EGF family, plays an important role in the growth of normal human corneal epithelial cells (Oral). 15th SOE Congress (European Society of Ophthalmology), Berlin, Germany, Sep. 25-29, 2005.
(37) T. Joko , A. Shiraishi , Y. Ohashi and S. Higashiyama. Transcriptional repressor PLZF(promyelocytic leukemia zinc finger) may play a role in the growth suppression of human corneal endothelial cells (Oral). 15th SOE Congress (European Society of Ophthalmology), Berlin, Germany Sep. 25-29, 2005.
(38) Shigeki Higashiyama, Ectodomain shedding of membrane-anchored growth factor HB-EGF - new insight in signal transduction, International Symposium on Proteolysis, Nagoya, Japan. Nov. 12, 2003
(39) Shigeki Higashiyama, Eotodomain shedding of HB-EGF and novel cell signaling. International Symposium on Tumor Biology in Kanazawa, Kanazawa, Japan. Jan. 20, 2005.
(40) Daisuke Nanba, Chie Morimoto, Shigeki Higashiyama, Deregulation of PLZF, a transcriptional repressor, by C-terminal fragment signaling of the EGFR-ligand precursors. JBS International Symposium in 2005, New Frontier of Transcription Research, Kusatsu, Japan, Jan 11-13. 2005.
(41) Yumi Kinugasa, Miki Hieda, Shigeki Higashiyama. Bcl6, a transcriptional repressor, is regulated by the carboxy-terminal domain of HB-EGF via direct interaction. JBS International Symposium in 2005, New Frontier of Transcription Research, Kusatsu, Japan, Jan. 11-13, 2005.
(42) Shigeki Higahsiyama, Ectodomain shedding of membrane-anchored growth factor HB-EGF by ADAM and HB-EGF-C terminal fragment signaling. The Kennedy institute of Rheumatology Symposium, Metalloproteinases: Biology and Pathology, London, UK, Nov. 21-22, 2005.
(43) Kinugasa, M. Hieda, S. Higashiyama, The Carboxyl-terminal Domain of HB-EGF Regulates a Transcriptional Repressor, Bcl6 via Direct Interaction. (Poster). 国際シンポジウム“細胞核機能の分子スイッチRanと細胞周期”.淡路、兵庫. Oct. 2-4, 2005.
(44) Y. Kinugasa, M. Hieda, S. Higashiyama. The Carboxyl-terminal Domain of HB-EGF Regulates Bcl6, a transcriptional Repressor, via Direct Interaction. (Poster) 45th Annual Meeting for the American Society for Cell Biology San Francisco, CA, USA, Dec.10-14, 2005.
(45) Miki Hieda, Chizuru Higashi, Taro Tachibana, Shigeki Higashiyama, Nuclear translocation of cell-surface transmembrane growth factor, HB-EGF. 20th IUBMB International Congress of Biochemistry and Molecular Biology and 11th FAOBMB Congress. Kyoto, Japan, June 20, 2006.
(46) Chie Morimoto, Mamoru Matsubara, Daisuke Nanba, Hidehiko Iwabuki, Hiroshi Ishiguro, Koichiro Yoshino, Shigeki Higashiyama. The carboxy-terminal fragment of epidermal growth factor receptor ligands directly interact with the transcriptional repressor PLZF. 20th IUBMB International Congress of Biochemistry and Molecular Biology and 11th FAOBMB Congress. Kyoto, Japan. June 21, 2006.
(47) Hirofumi Inoue, Daisuke Nanba, Shigeki Higashiyama. Full activation of c-myc gene expression by growth factors need shedding of proHB-EGF. 20th IUBMB International Congress of Biochemistry and Molecular Biology and 11th FAOBMB Congress. Kyoto, Japan. June 21, 2006.
(48) Y. Kinugasa, M. Hieda, S. Higashiyama. The carboxyl-terminal fragment of HB-EGF regulates the function of a transcription factor, Bcl6. 20th IUBMB International Congress of Biochemistry and Molecular Biology and 11th FACBMB Congress. Kyoto, Japan. June 21 , 2006.
(49) Miki Hieda, Chizuru Higashi, Taro Tachibana, Shigeki Higashiyama. Nuclear envelope targeting of cell-surface transmembrane growth factor, HB-EGF. Cold Spring Harbor Laboratory meeting: Dynamic Organization of Nuclear Function. Cold Spring Harbor Laboratory, NY, USA. Sep. 18-23, 2006.
研究制度
  • 戦略的創造研究推進事業 さきがけタイプ(旧若手個人研究推進事業を含む)/情報と細胞機能
研究報告資料
  • 東山 繁樹. 膜型増殖因子の持つ細胞増殖のアクセル機能とブレーキ解除機能の分子機構の解明. 個人型研究さきがけタイプ 「情報と細胞機能」領域 研究報告会 講演要旨集 第3期研究者(研究期間2003-2006), 2007. p.15 - 20.

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