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  • Review Article
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Oncogenic mechanisms of the Helicobacter pylori CagA protein

Key Points

  • Gastric carcinoma is the second most common cause of cancer-related death worldwide. Chronic infection with Helicobacter pylori that carries the cytotoxin-associated antigen A (cagA) gene is associated with gastric carcinoma.

  • The cagA gene product, CagA, is delivered into gastric epithelial cells by the bacterial type IV secretion system and undergoes tyrosine phosphorylation by SRC family kinases. Tyrosine phosphorylation occurs at EPIYA motifs on CagA.

  • Phosphorylated CagA specifically binds and activates SHP2, the first phosphatase found to act as a human oncoprotein.

  • As SHP2 transmits positive signals for cell growth and motility, deregulation of SHP2 by CagA is an important mechanism by which cagA-positive H. pylori promotes gastric carcinogenesis.

  • CagA is noted for its variation at the SHP2 binding site and, based on the sequence variation, is subclassified into two main types — East-Asian CagA and Western CagA. East-Asian CagA shows stronger SHP2 binding and greater biological activity than Western CagA.

  • In East-Asian countries, endemic circulation of H. pylori strains that carry biologically active forms of CagA might underlie the high incidence of gastric carcinoma.

Abstract

Infection with strains of Helicobacter pylori that carry the cytotoxin-associated antigen A (cagA) gene is associated with gastric carcinoma. Recent studies have shed light on the mechanism through which the cagA gene product, CagA, elicits pathophysiological actions. CagA is delivered into gastric epithelial cells by the bacterial type IV secretion system, where it deregulates the SHP2 oncoprotein. Intriguingly, CagA is noted for its variation, particularly at the SHP2-binding site, which could affect the potential of different strains of H. pylori to promote gastric carcinogenesis.

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Figure 1: The interaction between cagA-positive Helicobacter pylori and gastric epithelial cells.
Figure 2: Diversity in the tyrosine phosphorylation sites of CagA.
Figure 3: Deregulation of SHP2 by CagA.
Figure 4: A model for the feedback regulation of CagA–SHP2 signalling by CSK.
Figure 5: Differential properties of Western and East-Asian CagA proteins.

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References

  1. Uemura, N. et al. Helicobacter pylori infection and the development of gastric cancer. N. Engl. J. Med. 345, 784–789 (2001). Provides compelling epidemiological evidence for the role of H. pylori in the development of gastric carcinoma.

    Article  CAS  PubMed  Google Scholar 

  2. Wong, B. C. et al. Helicobacter pylori eradication to prevent gastric cancer in a high-risk region of China: a randomized controlled trial. JAMA 291, 187–194 (2004).

    Article  CAS  PubMed  Google Scholar 

  3. Cover, T. L. et al. Characterization of and human serologic response to proteins in Helicobacter pylori broth culture supernatants with vacuolizing cytotoxin activity. Infect. Immun. 58, 603–610 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Crabtree, J. E. et al. Mucosal IgA recognition of Helicobacter pylori 120 kDa protein, peptic ulceration, and gastric pathology. Lancet 338, 332–335 (1991).

    Article  CAS  PubMed  Google Scholar 

  5. Covacci, A. et al. Molecular characterization of the 128-kDa immunodominant antigen of Helicobacter pylori associated with cytotoxicity and duodenal ulcer. Proc. Natl Acad. Sci. USA 90, 5791–5795 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Tummuru, M. K., Cover, T. L. & Blaser, M. J. Cloning and expression of a high-molecular-mass major antigen of Helicobacter pylori: evidence of linkage to cytotoxin production. Infect. Immun. 61, 1799–1809 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Censini, S. et al. cag, a pathogenicity island of Helicobacter pylori, encodes type I-specific and disease-associated virulence factors. Proc. Natl Acad. Sci. USA 93, 14648–14653 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Kuipers, E. J., Perez-Perez, G. I., Meuwissen, S. G. & Blaser, M. J. Helicobacter pylori and atrophic gastritis: importance of the cagA status. J. Natl Cancer Inst. 87, 1777–1780 (1995).

    Article  CAS  PubMed  Google Scholar 

  9. Blaser, M. J. et al. Infection with Helicobacter pylori strains possessing cagA is associated with an increased risk of developing adenocarcinoma of the stomach. Cancer Res. 55, 2111–2115 (1995).

    CAS  PubMed  Google Scholar 

  10. Parsonnet, J., Friedman, G. D., Orentreich, N. & Vogelman, H. Risk for gastric cancer in people with CagA positive or CagA negative Helicobacter pylori infection. Gut 40, 297–301 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Segal, E. D., Cha, J., Lo, J., Falkow, S. & Tompkins, L. S. Altered states: involvement of phosphorylated CagA in the induction of host cellular growth changes by Helicobacter pylori. Proc. Natl Acad. Sci. USA 96, 14559–14564 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Asahi, M. et al. Helicobacter pylori CagA protein can be tyrosine phosphorylated in gastric epithelial cells. J. Exp. Med. 191, 593–602 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Stein, M., Rappuoli, R. & Covacci, A. Tyrosine phosphorylation of the Helicobacter pylori CagA antigen after cag-driven host cell translocation. Proc. Natl Acad. Sci. USA 97, 1263–1268 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Odenbreit, S. et al. Translocation of Helicobacter pylori CagA into gastric epithelial cells by type IV secretion. Science 287, 1497–1500 (2000).

    Article  CAS  PubMed  Google Scholar 

  15. Fischer, W. et al. Systematic mutagenesis of the Helicobacter pylori cag pathogenicity island: essential genes for CagA translocation in host cells and induction of interleukin-8. Mol. Microbiol. 42, 1337–1348 (2001).

    Article  CAS  PubMed  Google Scholar 

  16. Stein, M. et al. c-Src/Lyn kinases activate Helicobacter pylori CagA through tyrosine phosphorylation of the EPIYA motifs. Mol. Microbiol. 43, 971–980 (2002).

    Article  CAS  PubMed  Google Scholar 

  17. Selbach, M., Moese, S., Hauck, C. R., Meyer, T. F. & Backert, S. Src is the kinase of the Helicobacter pylori CagA protein in vitro and in vivo. J. Biol. Chem. 277, 6775–6778 (2002).

    Article  CAS  PubMed  Google Scholar 

  18. Higashi, H. et al. SHP-2 tyrosine phosphatase as an intracellular target of Helicobacter pylori CagA protein. Science 295, 683–686 (2002). The first demonstration that tyrosine-phosphorylated CagA specifically binds and activates SHP2 phosphatase in gastric epithelial cells.

    Article  CAS  PubMed  Google Scholar 

  19. Higashi, H. et al. Biological activity of the Helicobacter pylori virulence factor CagA is determined by variation in the tyrosine phosphorylation sites. Proc. Natl Acad. Sci. USA 99, 14428–14433 (2002). Provides evidence that East-Asian CagA is biologically more active than Western CagA.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Backert, S., Moese, S., Selbach, M., Brinkmann, V. & Meyer, T. F. Phosphorylation of tyrosine 972 of the Helicobacter pylori CagA protein is essential for induction of a scattering phenotype in gastric epithelial cells. Mol. Microbiol. 42, 631–644 (2001).

    Article  CAS  PubMed  Google Scholar 

  21. Feng, G. S. & Pawson, T. Phosphotyrosine phosphatases with SH2 domains: regulators of signal transduction. Trends Genet. 10, 54–58 (1994).

    Article  CAS  PubMed  Google Scholar 

  22. Hof, P., Pluskey, S., Dhe-Paganon, S., Eok, M. J. & Shoelson, S. E. Crystal structure of the tyrosine phosphatase SHP-2. Cell 92, 441–450 (1998).

    Article  CAS  PubMed  Google Scholar 

  23. Van Vactor, D., O'Reilly, A. M. & Neel, B. G. Genetic analysis of protein tyrosine phosphatases. Curr. Opin. Genet. Dev. 8, 112–126 (1998).

    Article  CAS  PubMed  Google Scholar 

  24. Yu, I. H., Qu, C. K., Henegariu, O., Lu, X. & Feng, G. S. Protein-tyrosine phosphatase Shp-2 regulates cell spreading, migration, and focal adhesion. J. Biol. Chem. 273, 21125–21131 (1998).

    Article  CAS  PubMed  Google Scholar 

  25. Manes, S. et al. Concerted activity of tyrosine phosphatase SHP-2 and focal adhesion kinase in regulation of cell motility. Mol. Cell. Biol. 19, 3125–3135 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Maroun, C. R., Naujokas, M. A., Holgado-Madruga, M., Wong, A. J. & Park, M. The tyrosine phosphatase SHP-2 is required for sustained activation of extracellular signal-regulated kinase and epithelial morphogenesis downstream from the met receptor tyrosine kinase. Mol. Cell. Biol. 20, 8513–8525 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Tartaglia, M. et al. Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. Nature Genet. 29, 465–468 (2001).

    Article  CAS  PubMed  Google Scholar 

  28. Tartaglia, M. et al. Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia. Nature Genet. 34, 148–150 (2003).

    Article  CAS  PubMed  Google Scholar 

  29. Loh, M. L. et al. Mutations in PTPN11 implicate the SHP-2 phosphatase in leukemogenesis. Blood 103, 2325–2331 (2004). References 28 and 29 demonstrate gain-of-function mutations in SHP2 in human leukaemias.

    Article  CAS  PubMed  Google Scholar 

  30. Higashi, H. et al. Helicobacter pylori CagA induces Ras-independent morphogenetic response through SHP-2 recruitment and activation. J. Biol. Chem. 279, 17205–17216 (2004).

    Article  CAS  PubMed  Google Scholar 

  31. Higuchi, M., Tsutsumi, R., Higashi, H. & Hatakeyama, M. Conditional gene silencing utilizing the lac repressor reveals a role of SHP-2 in cagA-positive Helicobacter pylori pathogenicity. Cancer Sci. 95, 442–447 (2004).

    Article  CAS  PubMed  Google Scholar 

  32. Tsutsumi, R., Higashi, H., Higuchi, M., Okada, M. & Hatakeyama, M. Attenuation of Helicobacter pylori CagA-SHP-2 signaling by interaction between CagA and C-terminal Src kinase. J. Biol. Chem. 278, 3664–3670 (2003).

    Article  CAS  PubMed  Google Scholar 

  33. Selbach, M. et al. The Helicobacter pylori CagA protein induces cortactin dephosphorylation and actin rearrangement by c-Src inactivation. EMBO J. 22, 515–528 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Joneson, T. & Bar-Sagi, D. Suppression of Ras-induced apoptosis by the Rac GTPase. Mol. Cell. Biol. 19, 5892–5901 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Correa, P., Haenszel, W., Cuello, C., Tannenbaum, S. & Archer, M. A model for gastric cancer epidemiology. Lancet 2, 58–60 (1975).

    Article  CAS  PubMed  Google Scholar 

  36. Yamazaki, S. et al. 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 (2003).

    Article  CAS  PubMed  Google Scholar 

  37. Hansson, L. E. et al. The risk of stomach cancer in patients with gastric or duodenal ulcer disease. N. Engl. J. Med. 335, 242–249 (1996).

    Article  CAS  PubMed  Google Scholar 

  38. Nomura, A. M., Perez-Perez, G. I., Lee, J., Stemmermann, G. & Blaser, M. J. Relation between Helicobacter pylori cagA status and risk of peptic ulcer disease. Am. J. Epidemiol. 155, 1054–1059 (2002).

    Article  PubMed  Google Scholar 

  39. El-Omar, E. M. et al. Increased risk of noncardia gastric cancer associated with proinflammatory cytokine gene polymorphisms. Gastroenterology 124, 1193–1201 (2003).

    Article  CAS  PubMed  Google Scholar 

  40. De Souza, D. et al. SH2 domains from suppressor of cytokine signaling-3 and protein tyrosine phosphatase SHP-2 have similar binding specificities. Biochemistry 41, 9229–9236 (2002).

    Article  CAS  PubMed  Google Scholar 

  41. Azuma, T. et al. 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 (2004).

    Article  CAS  PubMed  Google Scholar 

  42. Yamaoka, Y. et al. Relationship between the cagA 3′ repeat region of Helicobacter pylori, gastric histology, and susceptibility to low pH. Gastroenterology 117, 342–349 (1999).

    Article  CAS  PubMed  Google Scholar 

  43. Judd, L. M. et al. Gastric cancer development in mice lacking the SHP2 binding site on the IL-6 family co-receptor gp130. Gastroenterology 126, 196–207 (2004). Reports the development of a mouse model of gastric carcinoma by expressing the interleukin-6 receptor gp130 that lacks the SHP2 binding site.

    Article  CAS  PubMed  Google Scholar 

  44. Mimuro, H. et al. Grb2 is a key mediator of Helicobacter pylori CagA protein activities. Mol. Cell 10, 745–55 (2002).

    Article  CAS  PubMed  Google Scholar 

  45. Churin, Y. et al. Helicobacter pylori CagA protein targets the c-Met receptor and enhances the motogenic response. J. Cell Biol. 161, 249–255 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Amieva, M. R. et al. Disruption of the epithelial apical-junctional complex by Helicobacter pylori CagA. Science 300, 1430–1434 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Gruenheid, S. et al. Enteropathogenic E. Coli Tir binds Nck to initiate actin pedestal formation in host cells. Nature Cell Biol. 3, 856–859 (2001).

    Article  CAS  PubMed  Google Scholar 

  48. Ye, W. et al. Helicobacter pylori infection and gastric atrophy: risk of adenocarcinoma and squamous-cell carcinoma of the esophagus and adenocarcinoma of the gastric cardia. J. Natl Cancer Inst. 96, 388–396 (2004).

    Article  PubMed  Google Scholar 

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Acknowledgements

The author thanks T. Azuma and H. Higashi for valuable discussions. He also thanks members of the Division of Molecular Oncology, Institute for Genetic Medicine, Hokkaido University, for help. This work was supported by grants for science research from the Ministry of Education, Culture, Sports, Science and Technology of Japan, and by grants from the Uehara Memorial Foundation and Princess Takamatsu Cancer Research Foundation.

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DATABASES

Cancer.gov

acute lymphocytic leukaemia

acute myelocytic leukaemia

gastric cancer

oesophageal cancer

Entrez Gene

CagA

CSK

gp130

GRB2

SHP1

SHP2

OMIM

Noonan syndrome

FURTHER INFORMATION

European Helicobacter Study Group

Glossary

CAG PATHOGENICITY ISLAND

A roughly 40-kb segment of the Helicobacter pylori genome that is considered to have been acquired by a process of horizontal transfer from an unknown organism. Genes located in this region mediate the pathogenicity of this bacterium.

TYPE IV SECRETION SYSTEM

In Gram-negative bacteria, secretion of macromolecules across bacterial membranes is mediated by diverse macromolecular transport assemblies. The type IV secretion system is one of main secretion systems that exports virulence factors from inside to outside of the bacteria. The components of the type IV secretion system are homologous in sequence and in structure to those of conjugative transfer systems of plasmids.

SH2 DOMAIN

A small protein module that mediates protein–protein interactions by interacting with phosphotyrosine-containing sequences. Its functions include targeting of proteins to different cellular compartments and assembly of signalling molecules in response to extracellular signals.

TIGHT JUNCTION

An intercellular junction adjacent to the apical end of the lateral membrane. It regulates the passage of water, ions and macromolecules through paracellular spaces while maintaining cell polarity.

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Hatakeyama, M. Oncogenic mechanisms of the Helicobacter pylori CagA protein. Nat Rev Cancer 4, 688–694 (2004). https://doi.org/10.1038/nrc1433

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