Carboxy-ternminal fragment signaling of membrane-anchored growth factors the EGF family

• Project/Area Number: 17390081
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: General medical chemistry
• Research Institution: Ehime University
• Principal Investigator: HIGASHIYAMA Shigeki Ehime University, Graduate School of Medicine, Professor, 大学院医学系研究科, 教授 (60202272)
• Co-Investigator(Kenkyū-buntansha): HIEDA Miki Ehime University, Graduate School of Medicine, Lecturer, 大学院医学系研究科, 講師 (00380254) ; INOUE Hirofumi Ehime University, Graduate School of Medicine, Lecturer, 大学院医学系研究科, 講師 (70321635) ; 難波 大輔 愛媛大学, 医学部, 特任助手 (10380255)
• Project Period (FY): 2005 – 2006
• Project Status: Completed (Fiscal Year 2006)
• Budget Amount: ¥14,700,000 (Direct Cost: ¥14,700,000); Fiscal Year 2006: ¥4,900,000 (Direct Cost: ¥4,900,000); Fiscal Year 2005: ¥9,800,000 (Direct Cost: ¥9,800,000)
• Keywords: HB-EGF / CTF / PLZF / c-myc / EGF / bFGF / PDGF / cell cycle progression / EGF-ファミリー / Shedding / TGF-α / ampbiregulin / epiregulin / メタロプロテアーゼ / γ-セクレターゼ

Research Abstract

A key step for signaling through the epidermal growth factor receptor (EGFR) is the release of mature ligands such as heparin-binding EGF-like growth factor (HB-EGF) from their membrane-anchored precursor forms, a process termed "ectodomain shedding". The HB-EGF precursor (proHB-EGF) is cleaved by members of the "a disintegrin and metalloprotease" (ADAM) protease family, yielding the carboxyl terminal fragment of proHB-EGF (HB-EGF-CTF) in parallel with the production of HB-EGF. We have previously characterized HB-EGF-CTF as a novel intracellular signaling molecule acquired posttranslationally which is translocated into the nucleus, binding and inactivating the promyelocytic leukemia zinc finger protein (PLZF). PLZF is a transcriptional repressor that suppresses the transcription of genes such as c-MYC, Cyclin A2, and HoxD11. Activation of growth factor receptors by ligand binding leads to increased expression of c-Myc, a transcriptional regulator for cell proliferation. The activation of transcriptional factors through the activated receptors has been thought to be a main role in the c-Myc gene expression. We demonstrate here that EGFR-,FGFR-, and PDGFR-mediated c-Myc induction and cell cycle progression in the primary cultured mouse embryonic fibroblasts (MEFs) are abrogated by knockout of the heparin-binding EGF-like growth factor (Hb-egf) gene, or by a metalloproteinase inhibitor, although the downstream of the receptors is activated. The induction of c-Myc expression by EGF or bFGF recovers in the Hb-egf-knockouted MEFs by overexpression of wildtype proHB-EGF, though no recovery with an uncleavable mutant of proHB-EGF. It is also observed that the uncleavable mutant inhibits the EGF-induced acetylation of histone H3 at the mouse c-Myc first intron region which negatively affects the transcriptional activation. We conclude that the signal transduction initiated by generation of the carboxyl terminal fragment of proHB-EGF (HB-EGF-CTF) in the shedding event can play an essential intermediary role between growth factor receptor activation and c-Myc gene induction.

Research Products

• [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., Higashiyama, S.
  • Journal Title: Oncogene 26 Pages: 339-348
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Pbxl is 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., Higashiyama, S.
  • Journal Title: Oncogene 26 Pages: 339-348
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Alternative recycling of E-cadeherin depends on metalloprotease activity of ADAM9 (2006)
  • Author(s): Hirao, F., Nanba, D., Tanaka, M., Ishiguro, H., Kinugasa, Y., Doki, Y., Yanao, M., Matuura, N., Monden, M., Higashiyama, S.
  • Journal Title: Exp. Cell Res. 312 Pages: 331-339
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] PLZF regulates Pbx1 transcription and Pbx1-HoxC8 complex leads to androgen-independent prostate cancer proliferation. (2006)
  • Author(s): Kikugawa, T., Kinugasa, Y., Shiraishi, K., Nanba, D., Nakashiro K., Tanji, N., Yokoyama, M., Higashiyama, S.
  • Journal Title: The Prostate 66 Pages: 1092-2099
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Activity-dependent shedding of heparin-binding EGF-like growth factor in brain neurons. (2006)
  • Author(s): Shishido, Y., Tanaka, T., Piao, Y.S., Araki, K., Takei, N., Higashiyama, S., Nawa H.
  • Journal Title: Biochem Biophys Res Commun. 348 Pages: 963-970
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Loss of HB-EGF in smooth muscle or endothelial cell lineages causes heart valve malformation and cardiac hypertrophy. (2006)
  • Author(s): Nanba, D., Kinugasa, Y., Morimoto, C., Koizumi, M., Yamamutra, H., Takahashi K., Takakura, N., Mekada, E., Hashimoto, K., Higashiyama, S.
  • Journal Title: Biochem Biophys Res Commun. 350 Pages: 315-321
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Alternative recycling of E-cadeherin depends on metalloprotease activity of ADAM9 (2006)
  • Author(s): Hirao, F., Nanba, D., Tanaka, M., Ishiguro, H., Kinugasa, Y., Doki, Y., Yanao, M., Matuura, N., Monden, M., Higashiyama, S.
  • Journal Title: Exp.Cell Res. 312 Pages: 331-339
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] PLZF regulates Pbxl transcription and Pbxl-HoxC8 complex leads to androgen-independent prostate cancer proliferation. (2006)
  • Author(s): Kikugawa, T., Kinugasa, Y., Shiraishi, K., Nanba, D., Nakashiro K., Tanji, N., Yokoyama.M., Higashiyama.S.
  • Journal Title: The Prostate 66 Pages: 1092-2099
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Loss of HB-EGF in smooth muscle or endothelial cell lineages causes heart valve malformation and cardiac hypertrophy. (2006)
  • Author(s): Nanba, D., Kinugasa, Y., Morimoto, C., Koizumi, M., Yamamutra, H., Takahashi, K., Takakura, N., Mekada, E., Hashimoto, K., Higashiyama, S.
  • Journal Title: Biochem Biophys Res Commun. 350 Pages: 315-321
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] HB-EGF ad liver regeneration. (2006)
  • Author(s): Higashiyama, S., Kiso, S.
  • Journal Title: Growth Factor ＆ Regenerative Medicine Pages: 50-57
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] PLZF regulates Pbx1 transcription and Pbx1-HoxC8 complex leads to androgen-independent prostate cancer proliferation. (2006)
  • Author(s): Kikugawa T., Kinugasa Y., Shiraishi K., Nanba D., Nakashiro K., Tanji N., Yokoyama M., Higashiyama S.
  • Journal Title: The Prostate 66 Pages: 1092-2099
• [Journal Article] Activity-dependent shedding of heparin-binding EGF-like growth factor in brain neurons. (2006)
  • Author(s): Shishido, Y., Tanaka, T., Piao, Y.S., Araki, K., Takei, N., Higashiyama, S., Nawa H.
  • Journal Title: Biochem Biophys Res Commun. 348, Pages: 963-970
• [Journal Article] Loss of HB-EGF in smooth muscle or endothelial cell lineages causes heart valve malformation and cardiac hypertrophy. (2006)
  • Author(s): Nanba, D., Kinugasa, Y., Morimoto, C., Koizumi, M., Yamamutra, H., Takahashi, K., Mekada, E., Hashimoto, K., Higashiyama, S.
  • Journal Title: Biochem Biophys Res Commun. 350 Pages: 315-321
• [Journal Article] Ectodomain shedding of membrane-anchored heparin-binding EGF-like growth factor and subcellular localization of the C-terminal fragment in a cell cycle. (2005)
  • Author(s): Toki, F., Nanba, D., Matsuura, N., Higashiyama, S.
  • Journal Title: J. Cell. Physiol. 202 Pages: 839-848
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] IL-8 promotes cell proliferation and migration through metalloproteinase-cleavage proHB-EGF in Human Colon Carcinoma Cells. (2005)
  • Author(s): 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., Itoh, M.
  • Journal Title: Cytokine 29 Pages: 275-282
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Heparin-binding EGF-like growth factor is essential for keratinocyte migration in skin wound heaking. (2005)
  • Author(s): Shirakata, Y., Kimura, R., Nanba, D., Morimoto, C., Yokota, K., Nakamura, M., Mekada, E., Higashiyama, S., Hashimoto, K.
  • Journal Title: J. Cell Science 118 Pages: 2363-2370
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] G protein coupling and second messenger generation are indispensable for metalloprotease-dependent, heparin-binding epidermal growth factor shedding through angiotensin II type-1 receptor. (2005)
  • Author(s): 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.
  • Journal Title: J. Biol Chem. 280 Pages: 26592-26599
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] 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. (2005)
  • Author(s): 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.
  • Journal Title: Pancreas 31 Pages: 32-42
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Induction of Keratinocyte Migration via Transactivation of the Epidermal Growth Factor Receptor by the Antimicrobial Peptide LL-37. (2005)
  • Author(s): 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.
  • Journal Title: J. Immunol. 175 Pages: 4662-4668
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Helicobacter pylori-Stimulated Interleukin-8 (IL-8) Promotes Cell Proliferation Through Transactivation of Epidermal Growth Factor Receptor (EGFR) by Disintegrin and Metalloproteinase (ADAM) Activation. (2005)
  • Author(s): Joh, T., Kataoka, H., Tanida, S., Watanabe, K., Ohshima, T., Sasaki, M., Nakao, H., Ohhara, H., Higashiyama, S., Itoh, M.
  • Journal Title: Dig Dis Sci. 50 Pages: 2081-2089
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] The HNF-1 target collectrin controls insulin exocytosis by SNARE complex formation. (2005)
  • Author(s): 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., Yamagata, K.
  • Journal Title: Cell Metabolism 2 Pages: 373-384
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Ectodomain shedding of membrane-anchored heparin-binding EGF like growth factor and subcellular localization of the C-terminal fragment in a cell cycle. (2005)
  • Author(s): Toki, F., Nanba, D., Matsuura, N., Higashiyama, S.
  • Journal Title: J.Cell.Physiol. 202 Pages: 839-848
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] IL-8 promotes cell proliferation and migration through metalloproteinase-cleavage proHB-EGF in Human Colon Carcinoma Cells. (2005)
  • Author(s): 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., Itoh, M.
  • Journal Title: Cytokine 29 Pages: 275-282
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Heparin-binding EGF-like growth factor is essential for keratinocyte migration in skin wound heaking. (2005)
  • Author(s): Shirakata, Y., Kimura, R, Nanba, D., Morimoto, C., Yokota, K., Nakamura, M, Mekada, E., Higashiyama, S., Hashimoto, K.
  • Journal Title: J.Cell Science 118 Pages: 2363-2370
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] G protein coupling and second messenger generation are indispensable for metalloprotease-dependent, heparin-binding epidermal growth factor shedding through angiotensin II type-1 receptor. (2005)
  • Author(s): Mifune, M., Ohtsu, H., Suzuki, H., Nakashima, H., Brailoiu, E., Dun, N.J., Frank, GD., Inagami, T., Higashiyama, S., Thomas, W.G, Eckhart, A.D., Dempsey, P.J., Eguchi, S.
  • Journal Title: J.Biol.Chem. 280 Pages: 26592-26599
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] 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. (2005)
  • Author(s): 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.
  • Journal Title: Pancreas 31 Pages: 32-42
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Induction of Keratinocyte Migration via Transactivation of the Epidermal Growth Factor Receptor by the Antimicrobial Peptide LL-37. (2005)
  • Author(s): 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.
  • Journal Title: J.Immunol. 175 Pages: 4662-4668
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Helicobacter pylori-Stimulated Interleukin-8 (IL-8) Promotes Cell Proliferation Through Transactivation of Epidermal Growth Factor Receptor (EGFR) by Disintegrin and Metalloproteinase (ADAM) Activation. (2005)
  • Author(s): Joh, T., Kataoka, H., Tanida, S., Watanabe, K., Ohshima, T., Sasaki M., Nakao, H., Ohhara, H., Higashiyama, S., Itoh, M.
  • Journal Title: Dig Dis Sci. 50 Pages: 2081-2089
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] The HNF-1 target collectrin controls insulin exocytosis by SNARE complex formation. (2005)
  • Author(s): 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, GC., Kasai, H., Shimomura, I., Miyagawa, J., Wollheim, C.B., Yamagata, K.
  • Journal Title: Cell Metabolism 2 Pages: 373-384
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Ectodomain shedding of membrane-anchored heparin-binding EGF like growth factor and subcellular localization of the C-terminal fragment in a cell cycle (2005)
  • Author(s): Toki, F.et al.
  • Journal Title: J.Cell.Physiol. 202 Pages: 839-848
• [Journal Article] Heparin-binding EGF-like growth factor is essential for keratinocyte migration in skin wound heaking (2005)
  • Author(s): Shirakata, Y.et al.
  • Journal Title: J.Cell.Science 118 Pages: 2363-2370
• [Journal Article] G protein coupling and second messenger generation are indispensable for metalloprotease dependent, heparin-binding epidermal growth factor shedding through angiotensin II type-1 receptor. (2005)
  • Author(s): Mifune, M.et al.
  • Journal Title: J.Biol.Chem. 280 Pages: 26592-26599
• [Journal Article] Induction of Keratinocyte Migration via Transactivation of the Epidermal Growth Factor Receptor by the Antimicrobial Peptide LL-37. (2005)
  • Author(s): Tokumaru, S.et al.
  • Journal Title: J.Immunol. 175 Pages: 4662-4668
• [Journal Article] Alternative recycling of E-cadeherin depends on metalloprotease activity of ADAM9 (2005)
  • Author(s): Hirao, F.et al.
  • Journal Title: Exp.Cell Res. 12 Pages: 331-339
• [Journal Article] The HNF-1 target collectrin controls insulin exocytosis by SNARE complex formation. (2005)
  • Author(s): Fukui, K., et al.
  • Journal Title: Cell Metabolism 2 Pages: 373-384
• [Book] 細胞増殖因子と再生医療 (2006)
  • Author(s): 松本邦夫, 田畑泰彦, 東山繁樹 他
  • Total Pages: 401
  • Publisher: メディカルレビュー社
  • Description: 「研究成果報告書概要(和文)」より
• [Book] 細胞増殖因子と再生医療 (2006)
  • Author(s): 松本邦夫, 田畑恭彦, 東山繁樹 他
  • Total Pages: 401
  • Publisher: メディカルレビュー社