Key Points
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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.
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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.
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Phosphorylated CagA specifically binds and activates SHP2, the first phosphatase found to act as a human oncoprotein.
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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.
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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.
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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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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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Glossary
- CAG PATHOGENICITY ISLAND
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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
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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
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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
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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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DOI: https://doi.org/10.1038/nrc1433
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