Journal of Life Science (생명과학회지)

Korean Society of Life Science (한국생명과학회)
권호 표지
DOI QR코드

DOI QR Code

Analysis of the SHP-2 Binding Site of Helicobacter pylori CagA Protein in Korean

한국인에서 획득한 Helicobacter pylori의 CagA에 존재하는 SHP-2 binding site의 분석

  • Jo Ji-Yun (Department of Internal Medicine, Asan Medical Center) ;
  • Jeong Jin-Yong (Asan Institute for Life Scienres, University of Ulsan College of Medicine) ;
  • Kang Ho Young (Department of Microbiology, Pusan National University, Pusan) ;
  • Kim Gun-Do (Department of Microbiology, Pukyong National University) ;
  • Byeon Jeong-Sik (Department of Internal Medicine, Asan Medical Center) ;
  • Myung Seung-Jae (Department of Internal Medicine, Asan Medical Center) ;
  • Jung Hwoon-Yong (Department of Internal Medicine, Asan Medical Center) ;
  • Yang Suk-Kyun (Department of Internal Medicine, Asan Medical Center) ;
  • Hong Weon-Seon (Department of Internal Medicine, Asan Medical Center) ;
  • Kim Jin-Ho (Department of Internal Medicine, Asan Medical Center) ;
  • Lee Gin Hyug (Department of Internal Medicine, Asan Medical Center)
  • 조지윤 (울산대학교 의과대학 서울아산병원 소화기내과) ;
  • 정진용 (울산대학교 의과대학 아산생명과학연구소) ;
  • 강호영 (부산대학교 자연과학대학 미생물학과) ;
  • 김군도 (부경대학교 자연과학대학 미생물학과) ;
  • 변정식 (울산대학교 의과대학 서울아산병원 소화기내과) ;
  • 명승재 (울산대학교 의과대학 서울아산병원 소화기내과) ;
  • 정훈용 (울산대학교 의과대학 서울아산병원 소화기내과) ;
  • 양석균 (울산대학교 의과대학 서울아산병원 소화기내과) ;
  • 홍원선 (울산대학교 의과대학 서울아산병원 소화기내과) ;
  • 김진호 (울산대학교 의과대학 서울아산병원 소화기내과) ;
  • 이진혁 (울산대학교 의과대학 서울아산병원 소화기내과)
  • Published : 2005.12.01
Download PDF
⟨ Previous Next ⟩

Abstract

Recently the pathological actions of CagA of Helicobacter pylori (H. pylori) on gastric epithelial cells have been reported. CagA is directly injected into the host cytoplasm and undergoes tyrosine phosphorylation in the cells. In addition, translocated CagA forms a physical complex with SHP-2. There are two major CagA subtypes according to the amino acid sequence in the 3'region of CagA; i) the East Asian type (A-B-D of EPIYA motifs) and ii) the Western type (A-B-C of EPIYA motifs). Repeated EPIYA motifs in the 3'region of CagA are involved in the interaction with SHP-2. The East Asian type conferred stronger SHP-2 binding activity than the Westrrn type of CagA. Here we analyzed the amino acid sequences of the SHP-2 binding site of cagA gene in H. pyzori, and investigated whether there is my relationship between the diversities of cagA and the disease out-come in Korea. Most of Korean H. pylori strains showed A-B-D motifs(the East Asian type), and only one strain showed A-B-B-D motifs. In Korea, the incidence of atrophic gastritis and gastric cancer is significantly high compared with Western countries. The high frequency of the East Asian type CagA among Korean H. pylori strains would be involved in increasing the risk of gastric cancer in Korean populations.

최근에 발표된 연구 결과에 의하면 pylori CagA내에 존재하는 SHP-2 binding site의 아미노산 서열을 분석한 후, 특정 서열이 위선암의 발병과 연관되어 있다고 보고하였다. 그러나 한국인을 대상으로 CagA 내 에 존재하는 SHP-2 binding site아미노산 서열의 특성을 밝힌 연구는 없다. 따라서 본 연구는 한국인에서 획득한 H. pylori의 CagA SHP-2 binding site에 대해 아미노산 서열을 분석하여 그 특성을 알아보고자 하였다. 총 62 균주의 H. pylori 를 분석한 결과 환자의 질환과 관계없이 모든 H. pylori 균주에서 East Asian (A-B상 혹은 A-B-B-D)을 보여주었다. 일본과 더불어 한국은 위선암 유병률이 높은 나라이므로, 연구 대상의 모든 한국인에서 East Asian type CagA를 가진 H. pylori가 발견된 것이 위선암 유병률과 연관될 가능이 높아 보인다. 그러나 H. pylori의 발병 기전을 보다 더 명확히 이해하기 위해서는 보다 많은 국가와 지역을 대상으로 이러한 유전형 조사가 필요할 것 같다.

Keywords

References

  1. Argent, R. H., M. Kidd, R. J. Owen, R. J. Thomas, M. C. Limb and J. C. Atherton. 2004. Determinants and consequences of different levels of CagA phosphorylation for clinical isolates of Helicobacter pylori. Gastroenterology 127, 514-523 https://doi.org/10.1053/j.gastro.2004.06.006
  2. Atherton, J. C., P. Cao, R. M. Peek Jr, Tummuru R, M. J. Blaser and T. L. Cover. 1995. Mosaicism in vacuolating cytotoxin alleles of Helicobacter pylori. Association of specific vacA types with cytotoxin production and peptic ulceration. J. BioI. Chem. 270, 17771-17777 https://doi.org/10.1074/jbc.270.30.17771
  3. Azuma, T. 2004. Helicobacter pylori CagA protein variation associated with gastric cancer in Asia. J. Gastroenterol. 39, 97-103 https://doi.org/10.1007/s00535-003-1279-4
  4. Azurna, T., A. Yarnakawa, S. Yamazaki, K. Fukuta, M, Ohtani, Y. Ito, M. Doju, Y. Yamazaki and M. Kuriyama. 2002. Correalation between variation of the 3'region of the cagA gene in Helicobacetr pylori and disease outcome in Japan. Journal Infect. Dis. 186, 1621-1630 https://doi.org/10.1086/345374
  5. Azuma, T., S. Yamazaki, A. Yamakawa, M. Ohtani, A. Muramatsu, H. Suto, Y. Ito, M. Doju, Y. Yamazaki, M. Kuriyama, Y. Keida, H. Higashi and M. Hatakeyama. 2004. Association between diversity in the Src homology 2 domain-containing tyrosine phosphatase binding site of Helicobacter pylori CagA protein and gastric atrophy and cancer. J. Infect. Dis. 189, 820-827 https://doi.org/10.1086/381782
  6. Backert, S, E. Ziska, V. Brinkmann, U. Zimny-Arndt, A. Fauconnier, P. R. Jungblut, M. Naumann and T. F. Meyer. 2000. Translocation of the Helicobacter pylori CagA protein in gastric epithelial cells by a type IV secretion apparatus. Cell Microbiol. 2, 155-164 https://doi.org/10.1046/j.1462-5822.2000.00043.x
  7. Clemens, J., M. J. Albert, M. Rao, F. Qadri, S. Huda, B. Kay, F. P. van Loon, D. Sack, B. A. Pradhan and R. B. Sack. 1995. Impact of infection by Helicobacter pylori on the risk and severity of endemic cholera. J. Infect. Dis. 171, 1653-1656 https://doi.org/10.1093/infdis/171.6.1653
  8. Dale, A, J. E. Thomas, M. K. Darboe, W. A Coward, M. Harding and L. T. Weaver. 1998. Helicobacter pylori infection, gastric acid secretion, and infant growth. J. Pediatr. Gastroenterol. Nutr. 26, 393-397 https://doi.org/10.1097/00005176-199804000-00006
  9. Gerhard, M., R. Rad, C. Prinz and M. Naumann. 2002. Pathogenesis of Helicobacter pylori infection. Helicobacter 7, 17-23 https://doi.org/10.1046/j.1523-5378.7.s1.3.x
  10. Hatakeyama, M. 2003. Helicobacter pylori CagA-a potential bacterial oncoprotein that functionally mimics the mammalian Gab family of adaptor proteins. Microbes Infect. 5, 143-150 https://doi.org/10.1016/S1286-4579(02)00085-0
  11. Hsu P. I., I. R. Hwang, D. Cittelly, K. H. Lai, H. M. EL-Zimaity, O. Gutierrez, J. G. Kim, M. S. Osato, D. Y. Graham and Y. Yamaoka. 2002. Clinical presentation in relation to diversity within 'the Helicabacter pylorimg pathogenicity island. Am. J. Gastroenterol. 97, 2231-2238 https://doi.org/10.1111/j.1572-0241.2002.05977.x
  12. Lai, Y. P., J. C. Yang, T. Z. Lin, J. T. Wang and J. T. Lin. 2003. CagA tyrosine phosphorylation in gastric epithelial cells caused by Helicobacter pylori in patients with gastric adenocarcinoma. Helicobacter 8, 235-243 https://doi.org/10.1046/j.1523-5378.2003.00148.x
  13. Lipkin, M. 1988. Biomarkers of increased susceptibility to gastrointestinal cancer: new application to studies of cancer prevention in human subjects. Cancer Res. 48, 235-245
  14. Odenbreit, S., J. PuIs, B. Sedlmaier, E. Gerland, W. Fischer and R. Haas. 2000. Translocation of Helicobacter pylori CagA into gastric epithelial cells by type IV secretion. Science 287, 1497-1500 https://doi.org/10.1126/science.287.5457.1497
  15. Parsonnet, J. 1999. Helicobacter andgastric adenocarcinoma. p. 372-408. In J. Parsonnet (ed.), Microbes and Malignancy:Infection as a cause of human cancers. Oxford Univ Press., NY
  16. Peek, R. M. Jr, G. G. Miller, K. T. Tham, G. L. Perez, T. L. Cover, J. C. Atherton, G. D. Dunn and M. J. Blaser. 1995. Detection of Helicobacter pylori gene expression in human gastric mucosa. J. Clin. Microbiol. 33, 28-32
  17. Shahinian, M. L., D. J. Passaro, D. L. Swerdlow, E. D. Mintz, M. Rodriguez, and J. Parsonnel. 2000. Helicobacter pylori and epidemic Vibrio cholerae O1 infection in Peru. Lancet 355, 377-378 https://doi.org/10.1016/S0140-6736(99)05143-0
  18. Yamaoka, Y., M. Kita, T. Kodama, N. Sawai, K. Kashima and J. Imanishi. 1997. Induction of various cytokines and development of severe mucosal inflammation by cagA gene positive Heicobacter pylori strains. Gut 41, 442-451 https://doi.org/10.1136/gut.41.4.442
  19. Yamazaki, S., A Yamakawa, Y. lto, M. Ohtani, H. Higasi, M. Hatakeyama and T. Azuma. 2003. The CagA protein of Helicobacter pylori is translocated into epithelial cells and binds to SHP-2 in human gastric mucosa. J. Infect. Dis. 187, 334-337 https://doi.org/10.1086/367807
  20. Zhou, W., S. Yamazaki, A Yamakawa, M. Ohtani, Y. lto, Y. Keida, H. Higashi, M. Hatakeyama, J. Si and T. Azuma. 2004. The diversity of vacA and cagA genes of Helicobacter pylori in East Asia. FEMS Immunol. Med. Microbiol. 40, 81-87 https://doi.org/10.1016/S0928-8244(03)00299-2
  21. Westblom, T. U, S. J. Czinn, and J. G. Nedrud. 1999. (eds) Gastroduodenal disease and Helicobacter pylori: pathophysiology, diagnosis and treatment. Curro Top. Microbiol. lmmunol. vol. 241. Springer Press (Berlin)