Proteomic study on the mechanism underlying mucosal distruction by Helicobacter pylori CagA

• Project/Area Number: 19390122
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Bacteriology (including Mycology)
• Research Institution: Hokkaido University
• Principal Investigator: HATAKEYAMA Masanori Hokkaido University, 遺伝子病制御研究所, 教授 (40189551)
• Project Period (FY): 2007 – 2008
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥18,850,000 (Direct Cost: ¥14,500,000、Indirect Cost: ¥4,350,000); Fiscal Year 2008: ¥8,970,000 (Direct Cost: ¥6,900,000、Indirect Cost: ¥2,070,000); Fiscal Year 2007: ¥9,880,000 (Direct Cost: ¥7,600,000、Indirect Cost: ¥2,280,000)
• Keywords: 感染症 / 細菌 / シナルグ伝達 / プロテオーム / 上皮細胞極性 / タイトジャンクション / 質量分析 / PAR1b / MARK2 / ヘリコバクター・ピロリ / CagA / 二量体化

Research Abstract

ヘリコバクター・ピロリ菌は、自らが保有するIV型分泌機構を介して病原タンパク質CagAを宿主胃上皮細胞内に注入する。本研究を通して、胃上皮細胞内に侵入したピロリ菌CagAの細胞内標的分子分子として、上皮細胞極性制御のマスターレギュレーターであるPAR1ファミリーキナーゼが同定された。CagAはPAR1と結合しそのキナーゼ活性を抑制する結果、胃粘膜を構成する極性化上皮細胞層の崩壊を引き起こし、胃粘膜を傷害することが明らかとなった。

Research Products

• [Journal Article] Linking epithelial polarity and carcinogenesis by multitasking Helicobacter pylori virulence factor CagA. (2008)
  • Author(s): Hatakeyama, M.
  • Journal Title: Oncogene 27 Pages: 7047-7054
  • Peer Reviewed
• [Journal Article] Structural and functional diversity in the PAR1b/MARK2-binding region of Helicobacter pylori CagA. (2008)
  • Author(s): Lu, H., Saito, Y., Umeda, M., Murata-Kamiya, N., Zhang, H., Higashi, H. and Hatakeyama, M.
  • Journal Title: Cancer Science 99 Pages: 2004-2011
  • NAID: 10024012093
  • Peer Reviewed
• [Journal Article] Anti-tumor activity of ESX1 on cancer cells harboring oncogenic K-ras mutation. (2008)
  • Author(s): Nakajima, J., Ishikawa, S., Hamada, J., Yanagihara, M., Koike, T. and Hatakeyama, M., Yanagihara, M., Koike, T. and Hatakeyama, M.
  • Journal Title: Biochem. Biophys. Res. Commun. 370 Pages: 189-194
  • Peer Reviewed
• [Journal Article] Transgenic expression of Helicobacter pylori CagA induces gastrointestinal and hematopoietic neoplasms in mouse. (2008)
  • Author(s): Ohnishi, N., Yuasa, H., Tanaka, S., Sawa, H., Miura, M., Matsui, A., Higashi, H., Musashi, M., Iwabuchi, K., Suzuki, M., Yamada, G., Azuma, T. and Hatakeyama, M.
  • Journal Title: Proc. Natl. Acad. Sci. USA 105 Pages: 1003-1008
  • Peer Reviewed
• [Journal Article] SagA of CagA in Helicobacter pylori pathogenesis. (2008)
  • Author(s): Hatakeyama, M.
  • Journal Title: Cur. Opin. Microbiol. 11 Pages: 30-37
  • Peer Reviewed
• [Journal Article] Isolation of a distinct class of gain-of-function SHP-2 muntants with oncogenic RAS-like transforming activity from solid tumors. (2008)
  • Author(s): Miyamoto, D., Miyamoto, M., Takahashi, A., Yomogita, Y., Higashi, H., Kondo, S. and Hatakeyama, M.
  • Journal Title: Oncogene 27 Pages: 3508-3515
  • Peer Reviewed
• [Journal Article] Deregulation of ss-catenin signal by Helicobacter pylori CagA requires the CagA-multimerization sequence. (2008)
  • Author(s): Kurashima, Y., Murata-Kamiya, N., Kikuchi,K., Higashi, H., Azuma, T., Kondo, S. and Hatakeyama, M.
  • Journal Title: International Journal of Cancer 122 Pages: 823-831
  • Peer Reviewed
• [Journal Article] H. pylori除菌と3剤併用療法。 (2008)
  • Author(s): 菊地健司、畠山昌則
  • Journal Title: 医薬ジャーナル 44, S-1 Pages: 263-268
• [Journal Article] ヘリコバクター・ピロリCagAによる細胞がん化メカニズム。 (2008)
  • Author(s): 齊藤康弘、紙谷尚子、畠山昌則
  • Journal Title: 実験医学 26 Pages: 2445-2452
• [Journal Article] 胃がん発症におけるHelicobacter pylori CagAの意義。 (2008)
  • Author(s): 齊藤康弘、紙谷尚子、畠山昌則
  • Journal Title: 血液・腫瘍科 56 Pages: 219-225
  • NAID: 40019063616
• [Journal Article] H. pylori CagAによる細胞癌化のメカニズム。 (2008)
  • Author(s): 畠山昌則
  • Journal Title: 医学のあゆみ 224 Pages: 704-710
• [Journal Article] ピロリ菌がつくるタンパク質の発がん活性を証明。 (2008)
  • Author(s): 畠山昌則
  • Journal Title: Medical Bio(March) Pages: 14-15
• [Journal Article] Linking epithelial polarity and carcinogenesis by multitasking Helicobacter pylori virulence factor CagA (2008)
  • Author(s): Hatakeyama, M.
  • Journal Title: Oncogene 27 Pages: 7047-7054
  • Peer Reviewed
• [Journal Article] Structural and functional diversity in the PARIb / MARK2-binding region of Helicobacter pylori CagA (2008)
  • Author(s): Lu, H.
  • Journal Title: Cancer Science 99 Pages: 2004-2011
  • Peer Reviewed
• [Journal Article] Anti-tumor activity of ESX1 on cancer cells harboring oncogenic K-ras mutation (2008)
  • Author(s): Nakajima, J.
  • Journal Title: Biochem. Biophys. Res. Commun. 370 Pages: 189-194
  • Peer Reviewed
• [Journal Article] Transgenic expression of Helicobacter pylori CagA induces gastrointestinal and hematopoietic neoplasms in mouse (2008)
  • Author(s): Ohnishi, N.
  • Journal Title: Proc. Natl. Acad. Sci. USA 105 Pages: 1003-1008
  • Peer Reviewed
• [Journal Article] SagA of CagA in Helicobacter pylori pathogenesis (2008)
  • Author(s): Hatakeyama, M.
  • Journal Title: Cur. Opin. Microbiol. 11 Pages: 30-37
  • Peer Reviewed
• [Journal Article] Isolation of a distinct class of gain-of-function SHP-2 muntants with oncogenic RAS-like transforming activity from solid tumors (2008)
  • Author(s): Miyamoto, D.
  • Journal Title: Oncogene 27 Pages: 3508-3515
  • Peer Reviewed
• [Journal Article] Deregulation of β-cateninsignal by Helicobacter pylori CagA requires the CagA-multimerization sequence (2008)
  • Author(s): Kurashima, Y.
  • Journal Title: International Journal of Cancer 122 Pages: 823-831
  • Peer Reviewed
• [Journal Article] ピロリ菌がつくるタンパク質の発がん活性を証明 (2008)
  • Author(s): 畠山昌則
  • Journal Title: 医学のあゆみ 224 Pages: 704-710
• [Journal Article] 胃がん発症におけるHelicobacter pylori CagAの意義 (2008)
  • Author(s): 齊藤康弘
  • Journal Title: 血液・腫瘍科 56 Pages: 219-225
• [Journal Article] H. pyori除菌と3剤併用療法 (2008)
  • Author(s): 菊地健司
  • Journal Title: 医薬ジャーナル 44, S-1 Pages: 263-268
• [Journal Article] Anti-tumor activity of ESXI on cancer cells harboring oncogenic K-ras mutation (2008)
  • Author(s): Nakajima, J.
  • Journal Title: Biochem. Biophys. Res. Commun. (in press)
  • Peer Reviewed
• [Journal Article] Isolation of a distinct class of gain-of-function SHP-2 muntants with oncogenic RAS-like transforming activity from solid tumors. (2008)
  • Author(s): Miyamoto, D.
  • Journal Title: Oncogene (in press)
  • Peer Reviewed
• [Journal Article] Transgenic expression of Helicobacter pylori CagA induces gastrointestinal and hematopoietic neoplasms in mouse. (2008)
  • Author(s): Ohnishi, N.
  • Journal Title: Proc. Natl. Acad. Sci. USA 105 Pages: 1003-1008
  • Peer Reviewed
• [Journal Article] H.pylori除菌と3剤併用療法。 (2008)
  • Author(s): 菊地 健司
  • Journal Title: 医薬ジャーナル 44 Pages: 263-268
• [Journal Article] 胃がん発症におけるHelicobacter pyloriCagAの意義。 (2008)
  • Author(s): 齊藤 康弘
  • Journal Title: 血液・腫瘍科 56 Pages: 219-225
• [Journal Article] H. pylori CagAによる細胞癌化のメカニズム。 (2008)
  • Author(s): 畠山 昌則
  • Journal Title: 医学のあゆみ 224 Pages: 704-710
• [Journal Article] ピロリ菌がつくるタンパク質の発がん活性を証明。 (2008)
  • Author(s): 畠山 昌則
  • Journal Title: Medical Bio(March) Pages: 14-15
• [Journal Article] Helicobacter pylori CagA targets PAR1/MARK kinase to disrupt epithelial cell polarity. (2007)
  • Author(s): Saadat, I., Higashi, H., Obuse, C., Umeda, M., Murata-Kamiya, N., Saito, Y., Lu, H., Ohnishi, N., Azuma, T., Suzuki, A., Ohno, S. and Hatakeyama, M.
  • Journal Title: Nature 447 Pages: 330-333
  • Peer Reviewed
• [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., Kurashima, Y., Teishikata, Y., Yamahashi, Y., Saito, Y., Higashi, H., Aburatani, H., Akiyama, T., Peek, R.M., Jr., Azuma, T. and Hatakeyama, M.
  • Journal Title: Oncogene 26 Pages: 4617-4626
  • Peer Reviewed
• [Journal Article] Helicobacter pylori CagAはPAR1b/MARK2キナーゼを標的として上皮細胞の極性を破壊する。 (2007)
  • Author(s): 紙谷尚子、畠山昌則
  • Journal Title: 分子消化器病学 4 Pages: 114-118
• [Journal Article] ヘリコバクター・ピロリCagAによる上皮細胞極性破壊と細胞癌化のカップリング (2007)
  • Author(s): 畠山昌則
  • Journal Title: 細胞工学 27 Pages: 172-177
  • NAID: 40015848589
• [Journal Article] ヘリコバクター・ピロリと胃癌 (2007)
  • Author(s): 畠山昌則
  • Journal Title: 日本消化器病学会雑誌総説 104 Pages: 635-643
  • NAID: 10019545240
• [Journal Article] Deregulation of Sβ-catenin signal by Helicobacter pylori CagA requires the CagA-multimerization sequence. (2007)
  • Author(s): Kurashima, Y.
  • Journal Title: International Journal of Cancer 122 Pages: 823-831
  • Peer Reviewed
• [Journal Article] Helicobacter pylori CagA targets PAR1/MARK kinase to disrupt epithelial cell polarity. (2007)
  • Author(s): Saadat, I.
  • Journal Title: Nature 447 Pages: 330-333
  • Peer Reviewed
• [Journal Article] Helicobacter pylori CagA interacts with E-cadherin and deregulates the β-ceteninsignal that promotes intestinal transdifferentiation in gastric epitbelial cells. (2007)
  • Author(s): Murata-Kamiya, N.
  • Journal Title: Oncogene 26 Pages: 4617-4626
  • Peer Reviewed
• [Journal Article] Helicobacter pylori CagAはPAR1b/MARK2キナーゼを標的として上皮細胞の極性を破壊する。 (2007)
  • Author(s): 紙谷 尚子
  • Journal Title: 分子消化器病学 4 Pages: 114-118
• [Journal Article] ヘリコバクター・ピロリCagAによる上皮細胞極性破壊と細胞癌化のカップリング。 (2007)
  • Author(s): 畠山 昌則
  • Journal Title: 細胞工学 27 Pages: 172-177
  • NAID: 40015848589
• [Journal Article] ヘリコバクター・ピロリと胃癌。 (2007)
  • Author(s): 畠山 昌則
  • Journal Title: 日本消化器病学会雑誌-総説 104 Pages: 635-643
  • NAID: 10019545240
• [Journal Article] Helicobacter pylori and gastric carcinogenesis
  • Author(s): Hatakeyama, M.
  • Journal Title: J Gastroenterol. (in press)
  • NAID: 10025173914
  • Peer Reviewed
• [Journal Article] Helicobacter pylori VacA-induced inhibition of GSK3 through the PI3K / Akt signaling pathway
  • Author(s): Nakayama, M.
  • Journal Title: J. Biol.Chem. (in press)
  • Peer Reviewed
• [Presentation] Oncogenic mechanisms of Helicobacter pylori CagA (2009)
  • Author(s): Hatakeyama, M.
  • Organizer: The G-COE First International Symposium
  • Place of Presentation: 神戸-神戸大学医学部
  • Year and Date: 2009-03-23
• [Presentation] Oncogenic mechanisms of Helicobacter pylori CagA (2009)
  • Author(s): Hatakeyama, M.
  • Organizer: The G-COE First International Symposium
  • Place of Presentation: 神戸市、神戸大学医学部
  • Year and Date: 2009-03-23
• [Presentation] ピロリ菌感染症としての胃がん (2008)
  • Author(s): 畠山昌則
  • Organizer: 第3回学習院大学生命科学シンポジウム
  • Place of Presentation: 東京-学習院大学
  • Year and Date: 2008-05-24
• [Presentation] ピロリ菌感染症としての胃がん (2008)
  • Author(s): 畠由昌則
  • Organizer: 第3回学習院大学生命科学シンポジウム
  • Place of Presentation: 東京, 学習院大学
  • Year and Date: 2008-05-24
• [Presentation] Gastric Cancer as a Bacterial Disease (2008)
  • Author(s): Hatakeyama, M.
  • Organizer: 未来創薬・医療イノベーション拠点形成シンポジウム
  • Place of Presentation: 北大・学術交流会館.
  • Year and Date: 2008-03-14
• [Presentation] Gastric Cancer as a Bacterial Disease (2008)
  • Author(s): Hatakeyama, M.
  • Organizer: 未来創薬・医療イノベーション拠点形成シンポジウム
  • Place of Presentation: 北大・学術交流会館
  • Year and Date: 2008-03-14
• [Presentation] Cellular targets of Helicobacter pylori CagA in gastric carcinogenesis (2008)
  • Author(s): 畠山昌則
  • Organizer: 金沢がん生物学国際シンポシウム2008
  • Place of Presentation: 金沢大学医学部
  • Year and Date: 2008-01-24
• [Presentation] The role of SHP-2 tyrosine phosphatase in human cancers (2008)
  • Author(s): 畠山昌則
  • Organizer: 第31回日本分子生物学会年会・第81回日本生化学会大会合同大会
  • Place of Presentation: 神戸-神戸国際会議場
• [Presentation] SHP-2 phosphatase and human cancer (2008)
  • Author(s): Hatakeyama, M.
  • Organizer: The 8^<th> International Conference on Protein Phosphatase
  • Place of Presentation: 前橋-前橋テレサ
• [Presentation] H. pyloriと胃発がん (2008)
  • Author(s): 畠山昌則
  • Organizer: 第67回日本癌学会学術総会
  • Place of Presentation: 名古屋-名古屋国際会議場
• [Presentation] Does cag cause cancer and if so how? (2008)
  • Author(s): Hatakeyama, M.
  • Organizer: UEGW Vienna 2008/16th United European gastroenterology Week
  • Place of Presentation: Vienna, Austria, Austria Center Vienna
• [Presentation] The role of SHP2 phosphatase in H. pylori-mediated gastric carcinogenesis (2008)
  • Author(s): Hatakeyama, M.
  • Organizer: 2008 FASEB Summer Research Conferences
  • Place of Presentation: Colorado, USA, Snowmass Village.
• [Presentation] 細菌性癌タンパク質としてのピロリ菌CagA (2008)
  • Author(s): 畠山昌則
  • Organizer: Joint Conference in Sapporo 2008
  • Place of Presentation: 札幌-北大学術交流会館
• [Presentation] The role of SHP2 phosphatase in H. pylori-mediated gastric carcinogenesis (2008)
  • Author(s): Hatakeyama, M.
  • Organizer: IMBA主催生物学セミナーシリーズ
  • Place of Presentation: Vienna, Austria, Vienna Biocenter
• [Presentation] Helicobacter pylori and molecular pathogenesis (2008)
  • Author(s): Hatakeyama, M.
  • Organizer: AACR Annual meeting 2008
  • Place of Presentation: USA, San Diego convention center.
• [Presentation] H. pylori and gastric carcinogenesis (2008)
  • Author(s): Hatakeyama, M.
  • Organizer: JSPS Asia Africa Science Platform Program and The Fourth LiverCare Center Symposium
  • Place of Presentation: Charoen Thani Princess Hotel, Khon Kaen, Thailand.
• [Presentation] The role of SHP-2 tyrosine phosphatase in human cancers (2008)
  • Author(s): 畠山昌則
  • Organizer: 第31回日本分子生物学会年会・第81回日本生学会大会合同大会
  • Place of Presentation: 神戸市、神戸国際会議場
• [Presentation] SHP-2 phosphatase and human cancer (2008)
  • Author(s): Hatakeyama, M.
  • Organizer: The 8^<th> International Conference on Protein Phosphatase
  • Place of Presentation: 前橋市、前橋テレサ
• [Presentation] H. pyloriと胃発がん (2008)
  • Author(s): 畠山昌則
  • Organizer: 第67回日本癌学会学術総会
  • Place of Presentation: 名古屋市、名古屋国際会議場
• [Presentation] Does cag cause cancer and if so how (2008)
  • Author(s): Hatakeyama, M.
  • Organizer: UEGW Vienna 2008 / 16th United European gastroenterology Week
  • Place of Presentation: Vienna, Austria, Austria Center Vienna
• [Presentation] The role of SHP2 phosphatase in H. pylori-mediated gastric carcinogenesis (2008)
  • Author(s): Hatakeyama, M.
  • Organizer: 2008 FASEB Summer Research Conferences
  • Place of Presentation: Colorado, USA, Snowmass Village
• [Presentation] 細菌性癌タンパク質としてのピロリ菌CagA (2008)
  • Author(s): 畠山昌則
  • Organizer: Joint Confbrence in Sapporo 2008
  • Place of Presentation: 札幌市、北大学術交流会館
• [Presentation] Helicobacter pylori and molecular pathogenesis (2008)
  • Author(s): Hatakeyama, M.
  • Organizer: AACR Annual meeting 2008
  • Place of Presentation: USA, San Diego convention center
• [Presentation] H. pylori and gastric carcinogenesis (2008)
  • Author(s): Hatakeyama, M.
  • Organizer: JSPS Asia Africa Science Platform Program and The Fourth LiverCare Center Symposium
  • Place of Presentation: Charoen Thani Princess Hotel, Khon Kaen, Thailand
• [Presentation] Disruption of epithelial cell polarity by Helicobacter pylori virulence factor CagA (2007)
  • Author(s): Hatakeyama, M.
  • Organizer: International Symposium on Cell Polarity System and Future Medicine
  • Place of Presentation: 湘南国際村・Shonan Village Center
  • Year and Date: 2007-12-03
• [Presentation] The role of Helicobacter pylori CagA in gastric carcinogenesis (2007)
  • Author(s): Hatakeyama, M.
  • Organizer: Seoul International Digestive Disease Symposium 2007
  • Place of Presentation: Seoul National University, Korea.
  • Year and Date: 2007-11-22
• [Presentation] The role of Helicobacter pylori CagA in gastric carcinogenesis (2007)
  • Author(s): Hatakeyama, M.
  • Organizer: Seoul International Digestive Disease Symposium 2007
  • Place of Presentation: Seoul National University, Korea
  • Year and Date: 2007-11-22
• [Presentation] Oncogenic protenital of the Helicobacter pylori CagA (2007)
  • Author(s): Hatakeyama, M.
  • Organizer: Seoul International Digestive Disease Symposium 2007
  • Place of Presentation: Seoul National University, Korea.
  • Year and Date: 2007-11-21
• [Presentation] Oncogenic protenital of the Helicobacter pylori CagA (2007)
  • Author(s): Hatakeyama, M.
  • Organizer: Seoul International Digestive Disease Symposium 2007
  • Place of Presentation: Seoul National University, Kore
  • Year and Date: 2007-11-21
• [Presentation] Oncogenic mechnism of Helicobacter pylori CagA (2007)
  • Author(s): Hatakeyama, M.
  • Organizer: The 14^<th> Seoul International Cancer Symposium
  • Place of Presentation: Seoul National University, Korea.
  • Year and Date: 2007-11-19
• [Presentation] Oncogenic mechnism of Helicobacter pylori CagA (2007)
  • Author(s): Hatakeyama, M.
  • Organizer: The 14th Seoul International Cancer Symposium
  • Place of Presentation: Seoul National University, Korea
  • Year and Date: 2007-11-19
• [Presentation] H. pyloriによる胃粘膜破壊の分子機構 (2007)
  • Author(s): 畠山昌則
  • Organizer: 第19回広島ヘリコバクター研究会
  • Place of Presentation: 広島大学医学部
  • Year and Date: 2007-10-02
• [Presentation] H.pyloriによる胃粘膜破壊の分子機構 (2007)
  • Author(s): 畠山昌則
  • Organizer: 第19回広島ヘリコバクター研究会
  • Place of Presentation: 広島大学医学部
  • Year and Date: 2007-10-02
• [Presentation] The role of Helicobacter pylori CagA in gastric carcinogenesis (2007)
  • Author(s): Hatakeyama, M.
  • Organizer: The 19^<th> FAOBMB Seoul Conference
  • Place of Presentation: COEX Center, Seoul, Korea.
  • Year and Date: 2007-05-29
• [Presentation] The role of Helicobacter pylori CagA in gastric carcinogenesis (2007)
  • Author(s): Hatakeyama, M.
  • Organizer: The 19th FAOBMB Seoul Conference
  • Place of Presentation: COEX Center, Seoul, Korea
  • Year and Date: 2007-05-29
• [Presentation] Disruption of epithelial cell polarity by Helicobacter pylori virulence factor CagA (2007)
  • Author(s): Hatakeyama, M.
  • Organizer: BMB 2007 Symposium
  • Place of Presentation: パシフィコ横浜
• [Presentation] Microbial-host interactions in infectious cancer (2007)
  • Author(s): Hatakeyama, M.
  • Organizer: International Symposium of the DFG graduate program 1167
  • Place of Presentation: Otto von Guericke University, Magdeburg, Germany.
• [Presentation] Microbial-host interactions in infectious cancer (2007)
  • Author(s): Hatakeyama, M.
  • Organizer: International Symposium of the DFG graduate program 1167
  • Place of Presentation: Otto von Guericke University, Magdeburg, Germany
• [Book] バイオとナノの融合II新生命科学の応用 (2007)
  • Author(s): 畠山昌則
  • Total Pages: 26
  • Publisher: 北海道大学発行
• [Book] バイオとナノの融合II新生命科学の応用 (2007)
  • Author(s): 畠山昌則
  • Total Pages: 26
  • Publisher: 北海道大学
• [Remarks]
  • URL: http://www.igm.hokudai.ac.jp/oncology/index.html