Helicobacter pylori CagA: a new paradigm for bacterial carcinogenesis

@article{Hatakeyama2005HelicobacterPC,
  title={Helicobacter pylori CagA: a new paradigm for bacterial carcinogenesis},
  author={Masanori Hatakeyama and Hideaki Higashi},
  journal={Cancer Science},
  year={2005},
  volume={96}
}
Infection with cagA‐positive Helicobacter pylori is associated with the development of gastric adenocarcinoma. The cagA gene product CagA is injected directly from the bacterium into the bacterium‐attached gastric epithelial cells via the type‐IV secretion system. Upon membrane localization and subsequent tyrosine phosphorylation by Src family kinases, CagA functions as a scaffolding adaptor and interacts with a number of host proteins that regulate cell growth, cell motility and cell polarity… 

Molecular anatomy and pathogenic actions of Helicobacter pylori CagA that underpin gastric carcinogenesis

Acquisition of genetic and epigenetic alterations that compensate for CagA-directed cancer hallmarks may be required for completion of the “hit-and-run” process of gastric carcinogenesis.

Anthropological and clinical implications for the structural diversity of the Helicobacter pylori CagA oncoprotein

The pylogeographic distribution of differential CagA isoforms is discussed in the context of human migration history, which may underlie large geographical variations in the incidence of gastric cancer in different parts of the world.

Structural and functional diversity in the PAR1b/MARK2‐binding region of Helicobacter pylori CagA

It is shown that the level of PAR1b‐binding activity of CagA correlates with the magnitude of junctional defects and the degree of hummingbird phenotype induction, and structural diversity in the CM sequence is an important determinant for thedegree of virulence of CAGA, a bacterial oncoprotein associated with gastric carcinogenesis.

Novel effects of Helicobacter pylori CagA on key genes of gastric cancer signal transduction: a comparative transfection study.

The result proposed that the ABCCC type can induce the intestinal metaplasia, IL-8, perturbation of Crk adaptor proteins, anti-apoptotic effect and carcinogenic effect more significantly than ABC type is supported.

Integrin but not CEACAM receptors are dispensable for Helicobacter pylori CagA translocation

Genetic evidence is provided that the cag-T4SS-mediated interaction of Hp with cell surface integrins on human gastric epithelial cells is not essential for CagA translocation, but interaction ofHp with CEACAM receptors is facilitating Cag a translocation by the cAG-T 4SS of this important microbe.

Structural characterization of Cag proteins from the Pathogenicity Island of Helicobacter pylori

The three-dimensional structure of some of the proteins encoded by the cag-PAI are determined, a task that will allow to elucidate the function and the organization of the entire T4SS of such a relevant pathogenic bacterium.

Systematic site-directed mutagenesis of the Helicobacter pylori CagL protein of the Cag type IV secretion system identifies novel functional domains

Characterizing the CagL mutants, it is determined that their function to activate cells and transport the effector CagA was reduced to different extents and their structure-function correlation can be instructive for the functional characterization of other potential VirB5 orthologs whose structure is not yet known.

Variations in the multimerization region of the Helicobacter pylori cytotoxin CagA affect virulence.

It is demonstrated that, following 18 h, the CagA-THE AUTHORS-transfected cells were less adherent compared with the CAgA-WW transfecting cells, which suggest that different CM motif types may affect CAGA virulence.

CagA protein of Helicobacter pylori: a hijacker of gastric epithelial cell signaling.

Helicobacter Pylori Cytotoxin-Associated Gene A (CagA) and Gastric Carcinoma

  • N. Soliman
  • Biology, Medicine
    Suez Canal University Medical Journal
  • 2019
This review highlights how the upregulation of cagA gene could be a risk factor for developing gastric carcinoma and its potential relationship on the selection of patients who would benefit from H. Pylori treatment.
...

References

SHOWING 1-10 OF 65 REFERENCES

Attenuation of Helicobacter pylori CagA·SHP-2 Signaling by Interaction between CagA and C-terminal Src Kinase*

The results thus indicate that CagA-Csk interaction prevents excess cell damage caused by deregulated activation of SHP-2, and down-regulates CAGA·SHP- 2 signaling by both competitively inhibiting Cag a·SHp-2 complex formation and reducing levels of Cag A phosphorylation.

c‐Src/Lyn kinases activate Helicobacter pylori CagA through tyrosine phosphorylation of the EPIYA motifs

CagA translocation followed by tyrosine phosphorylation at the EPIYA motifs promotes a growth factor‐like response with intense cytoskeletal rearrangements, cell elongation effects and increased cellular motility.

Helicobacter pylori CagA Induces Ras-independent Morphogenetic Response through SHP-2 Recruitment and Activation*

Results indicate that SHP-2 is involved in the Ras-independent modification of Erk signals that is necessary for the morphogenetic activity of CagA, and suggests a key role of SHp-2 in the pathological activity of H. pylori virulence factor Cag a.

Functional antagonism between Helicobacter pylori CagA and vacuolating toxin VacA in control of the NFAT signaling pathway in gastric epithelial cells.

These findings indicate that the two major H. pylori virulence factors inversely control NFAT activity, and deregulation of NFAT, either positively or negatively, depending on the relative exposure of cells to CagA and VacA, may contribute to the various disease outcomes caused by H.pylori infection.

Tyrosine phosphorylation of the Helicobacter pylori CagA antigen after cag-driven host cell translocation.

It is demonstrated that CagA, a virulence factor commonly expressed in peptic ulcer disease and thought to be an orphan of a specific biological function, is delivered into the epithelial cells by the cag type IV secretion system where it is phosphorylated on tyrosine residues by an as yet unidentified host cell kinase and wired to eukaryotic signal transduction pathways and cytoskeletal plasticity.

EPIYA Motif Is a Membrane-targeting Signal of Helicobacter pylori Virulence Factor CagA in Mammalian Cells*

The results indicate that the EPIYA motif has a dual function in membrane association and tyrosine phosphorylation, both of which are critically involved in the activity of CagA to deregulate intracellular signaling, and suggest that the H. pylori strains carrying the cagA gene are more virulent than cagC-negative strains and are associated with the development of gastric adenocarcinoma.

Translocation of the Helicobacter pylori CagA protein in gastric epithelial cells by a type IV secretion apparatus

Evidence that the H. pylori protein encoded by the cytotoxin‐associated gene A (cagA) is translocated and phosphorylated in infected epithelial cells supports the view that H.pylori actively translocates virulence determinants, including CagA, which could be involved in the development of a variety of gastric disease.

Helicobacter pylori CagA protein activates serum response element-driven transcription independently of tyrosine phosphorylation.

The C-terminal portion of CagA enhances SRE-driven transcription by activating an upstream signaling cascade without requiring CAGA Tyr phosphorylation, suggesting that translocated Cag a regulates 2 distinct cellular responses: phosphorylated-dependent cytoskeletal rearrangement and phosphorylations-independent transcriptional activation.

SHP-2 Tyrosine Phosphatase as an Intracellular Target of Helicobacter pylori CagA Protein

Wild-type but not phosphorylation-resistant CagA induced a growth factor–like response in gastric epithelial cells and formed a physical complex with the SRC homology 2 domain (SH2)–containing tyrosine phosphatase SHP-2 in a phosphorylations-dependent manner and stimulated the phosphat enzyme activity.

Biological activity of the Helicobacter pylori virulence factor CagA is determined by variation in the tyrosine phosphorylation sites

The results indicate that the potential of individual CagA to perturb host-cell functions is determined by the degree of SHP-2 binding activity, which depends in turn on the number and sequences of tyrosine phosphorylation sites.
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