Study of H. pylori CagA-mediated gastric pathogenesis

• Project/Area Number: 17390087
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Pathological medical chemistry
• Research Institution: HOKKAIDO UNIVERSITY
• Principal Investigator: HIGASHI Hideaki HOKKAIDO Univ., Inst. for Genetic Med., Asso. Prof., 遺伝子病制御研究所, 助教授 (20311227)
• Project Period (FY): 2005 – 2006
• Project Status: Completed (Fiscal Year 2006)
• Budget Amount: ¥14,500,000 (Direct Cost: ¥14,500,000); Fiscal Year 2006: ¥7,000,000 (Direct Cost: ¥7,000,000); Fiscal Year 2005: ¥7,500,000 (Direct Cost: ¥7,500,000)
• Keywords: gastric cancer / infection disease / Helicobacler pylori / tyrosine phosphorylation / transcriptional factor / ヘリコバクターピロリ

Research Abstract

1.Membrane association of CagA is important for the pathogenic action of CagA in gastric epithelial cells and requires the EPIYA motif but is independent of EPIYA tyrosine phosphorylation.
2.The activated SHP-2 with CagA directly dephosphorylates phospho-tyrosine residues of FAK, which are the activating phosphorylation sites. Accordingly, FAK activation is abolished in cells, and the inhibition of FAK by SHP-2 plays a crucial role in the morphogenetic activity of CagA.
3.By screening of CagA-responsive genes using DNA microarray, we identified NFAT. CagA induced nuclear translocation and transcriptional activity of NFAT depending on calcineurin/PLC_γ pathway. Furthermore, H. pylori VacA toxin counteracted the ability of CagA to activate NFAT.
4.Using a series of EPIYA-repeat variants of CagA that represent reported variations in clinical isolates of H. pylori, we show that EPIYA-repeat polymorphism, 'which is due to differences of both number and order of EPIYA segment, influences the phosphorylation-dependent CagA biological activity.
5.We identified CagA multimerization motif that is composed of 16 amino acid residues and mediates an intermolecular interaction between CagA molecules. The CagA multimerization is necessary to express CagA biological activity 'that relates with cell morphogenetic activity and stimulation of cell motility.

Research Products

• [Journal Article] Helicobacter pylori CagA interacts with E-cadherin and deregulates the β-catenin signal that promotes intestinal transdifferentiation in gastric epithelial cells. (2007)
  • Author(s): Murata-Kamiya, N.
  • Journal Title: Oncogene (in press)
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Helicobacter pylori CagA associates with E-cadherin and deregulates β -catenin signal that promotes intestinal transdifferentiation in gastric epithelial cells. (2007)
  • Author(s): Murata-Kamiya, N., Kurashima, Y., Teishikata, Y., Yamahashi, Y., Saito, Y., Higashi, H., Aburatani, H., Peek, R.M., Jr., Azuma, T., Hatakeyama, M.
  • Journal Title: Oncogene (in press)
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Structural basis and functional consequence of Helicobacter pylori CagA multimerization in cells. (2006)
  • Author(s): Ren, S.
  • Journal Title: J. Biol. Chem. 281 Pages: 32344-32352
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Influence of EPIYA-repeat polymorphism on the phosphorylation-dependent biological activity of Helicobacter pylori CagA. (2006)
  • Author(s): Naito, M.
  • Journal Title: Gastroenterolory 130 Pages: 1181-1190
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Focal adhesion kinasc is a substrate and downstream effector of SHP-2 complexed with Helicobacter pylori CagA. (2006)
  • Author(s): Tsutsumi, R.
  • Journal Title: Mol. Cell. Biol. 26 Pages: 261-276
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Structural basis and functional consequence of Helicobacter pylori CagA multimcrization in Cells. (2006)
  • Author(s): Ren, S., Higashi.H., Lu, H., Azuma, T., Hatakeyama, M.
  • Journal Title: J. Biol. Chem. 281 Pages: 32344-32352
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Influence of EPI YA-repeat polymorphism on the phosphorylation-dependent biological activity of Helicobacter pylori CagA. (2006)
  • Author(s): Naito, M., Yamazaki, T., Tsutsumi, R., Higashi, H., Onoe, K., Yamazaki, S., Azuma, T., Hatakeyama, M.
  • Journal Title: Gastroenterolory 130 Pages: 1181-1190
  • NAID: 120000953487
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Focal adhesion kinase is a substrate and downstream effector of SHP-2 complexed with Helicobacter pylori CagA. (2006)
  • Author(s): Tsutsumi, R., Takahashi, A., Azuma, A., Higashi, H., Hatakeyama, M.
  • Journal Title: Mol. Cell. Biol. 26 Pages: 261-276
  • NAID: 120000957433
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Helicobacter pylori CagA Deregulates the Cell Signaling. (2006)
  • Author(s): Higashi H., Hatakeyama M.
  • Journal Title: Recent Advances in Gastrointestinal Carcinogenesis, (Editors : Hiromi Banba and Shinichi Ota) (TRANSWORLD RESEARCH NETWORK) 14
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Helicobacter pylori CagA interacts with E-cadherin and deregulates the β-catenin signal that promotes intestinal transdifferentiation in gastric epithclial cells. (2006)
  • Author(s): Murata-Kamiya, N.
  • Journal Title: Oncogene (in press)
• [Journal Article] Focal adhesion kinase is a substrate and downstream effector of SHP-2 complexed with Helicobacter pylori CagA. (2006)
  • Author(s): Tsutsumi, R.
  • Journal Title: Mol. Cell. Biol. 26 Pages: 261-276
• [Journal Article] FAK is a substrate and downstream effector of SHP-2 complexed with Helicobacter pylori CagA. (2006)
  • Author(s): Tsutsumi R.
  • Journal Title: Mol.Cell.Biol. 26 Pages: 261-276
• [Journal Article] Helicobacter pylori CagA - a new paradigm for bacterial carcinogenesis. (2005)
  • Author(s): Hatakeyama, M.
  • Journal Title: Cancer Sci. 96 Pages: 835-843
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Downregulation of cyclin-dependent kinase inhibitor ; p57(kip2), is involved in the cell cycle progression of vascular smooth muscle cells. (2005)
  • Author(s): Nakano, N.
  • Journal Title: Biochem. Biophys. Res. Commun. 338 Pages: 1661-1667
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Functional antagonism between Helicobacter pylori CagA and vacuolating toxin VacA in control of the NFAT signaling pathway in gastric epithelial cells. (2005)
  • Author(s): Yokoyama, K.
  • Journal Title: Proc. Natl. Acad. Sci. USA 102 Pages: 9661-9666
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] EPIYA motif is a membrane-targeting singnal of Helicobacter pylori virulence factor CagA in mammalian cells. (2005)
  • Author(s): Higashi, H.
  • Journal Title: J. Biol. Chem. 280 Pages: 23130-23137
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Distinct diversity of vacA, cagA, and cagE genes of Helicobacter pylori associated with peptic ulcer in Japan. (2005)
  • Author(s): Yamazaki, S.
  • Journal Title: J. Clin. Microbiol. 43 Pages: 3906-3916
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Identification of Helicobacter pylori and the cagA genotype in gastric biopsies using higly sensitive real-time PCR as a new diagnostic tool. (2005)
  • Author(s): Yamazaki, S.
  • Journal Title: FEMS Immunol. Med. Microbiol. 44 Pages: 261-268
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Helicobacter pylori CagA -a new paradigm for bacterial carcinogenesis. (2005)
  • Author(s): Hatakeyama, M., Higashi, H.
  • Journal Title: Cancer Sci. 96 Pages: 835-843
  • NAID: 10017103932
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Downregulation of cyclin-dependent kinase inhibitor ; p57(kip2), is involved in the cell cycle progression of vascular smooth muscle cells. (2005)
  • Author(s): Nakano, N., Urasawa, K., Takagi, Y., Saito, T., Kaneta, S., shikawa, S., Higashi, H., Tsutsui, H., Hatakeyama, M., Kitabatake, A.
  • Journal Title: Biochem. Biophys. Res. Commun. 338 Pages: 1661-1667
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Functional antagonism between Helicobacter pylori CagA and vacuolating toxin VacA in control of the NFAT signaling pathway in gastric epithelial cells. (2005)
  • Author(s): Yokoyama, K., Higashi.H., Ishikawa, S., Fujii, Y., Kondo, S., Kato, H., Azuma, T., Wada, A., Hirayama, T., Aburatani, H., Hatakeyama, M.
  • Journal Title: Proc. Natl. Acad. Sci. USA 102 Pages: 9661-9666
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] EPIYA motif is a membrane-targeting signal of Helicobacter pylori virulence factor CagA in mammalian cells. (2005)
  • Author(s): Higashi, H., Yokoyama, K., Fujii, Y., Ren, S., Yuasa, H., Isaadat, I., Murata-Kamiya, N., Azuma, T., Hatakeyama, M.
  • Journal Title: J. Biol. Chem. 280 Pages: 23130-23137
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Distinct diversity of vacA cagA, and cagE genes of Helicobacter pylori associated with peptic ulcer in Japan. (2005)
  • Author(s): Yamazaki, S., Yamakawa, A., Okuda, T., Ohtani, M., Suto H., Ito, Y., Yamazaki, Y., Keida, Y., Higashi, H.Hatakeyama, M., Azuma, T.
  • Journal Title: J. Clin. Microbiol. 43 Pages: 3906-3916
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Identification of Helicobacter pylori and the cagA genotype in gastric biopsies using highly sensitive real-time PCR as a new diagnostic tool. FEMS Immunol. (2005)
  • Author(s): Yamazaki, S., Kato, S., Matsukura, N., Ohtani, M., Ito, Y., Suto, H., Yamazaki, Y., Yamakawa, A., Tokudome, S., Higashi, H., Hatakeyama, M., Azuma, T.
  • Journal Title: FEMS Immunol. Med. Microbiol. 44 Pages: 261-268
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] EPIYA motif is a membrane targeting signal of Helicobacter pylori virulence factor CagA in mammalian cells. (2005)
  • Author(s): Higashi H.
  • Journal Title: J.Biol.Chem. 280 Pages: 23130-23137
• [Journal Article] Functional antagonism between Helicobacter pylori CagA and vacuolating toxin VacA in control of the NFAT signaling pathway in gastric epithelial cells. (2005)
  • Author(s): Yokoyama K.
  • Journal Title: Proc.Natl.Acad.Sci.USA. 102 Pages: 9661-9666
• [Journal Article] Helicobacter pylori CagA - a new paradigm for bacterial carcinogenesis (2005)
  • Author(s): Hatakeyama M.
  • Journal Title: Cancer Sci. 96 Pages: 835-843
• [Journal Article] Distinct diversity of vacA, cagA, and cagE genes of Helicobacter pylori associated with peptic ulcer in Japan. (2005)
  • Author(s): Yamazaki S.
  • Journal Title: J.Clin.Microbiol. 43 Pages: 3906-3916
• [Journal Article] Identification of Helicobacterpylori and the cagA genotype in gastric biopsies using highly sensitive real-time PCR as a new diagnostic tool. (2005)
  • Author(s): Yamazaki S.
  • Journal Title: FEMS Immunol.Med.Microbiol. 44 Pages: 261-268
• [Journal Article] Influence of EPIYA-repeat polymorphism on thephosphorylation-dependent biological activity of Helicobacter pylori CagA.
  • Author(s): Naito M.
  • Journal Title: Gastroenterology (In press)
• [Book] Recent Advances in Gastrointestinal Carcinogenesis(分担執筆)Helicobacter pylori CagA Deregulates the Cell Signaling (2006)
  • Author(s): Higashi, H.
  • Total Pages: 14
  • Publisher: TRANSWORLD RESEARCH NETWORK
  • Description: 「研究成果報告書概要(和文)」より
• [Book] Recent Advances in Gastrointestinal Carcinogenesis (2006)
  • Author(s): Higashi, H.
  • Total Pages: 13
  • Publisher: TRANSWORLD RESEARCH NETWORK