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H. pylori's CagA deregulates gastric cell protein to induce abnormal proliferation

NEW YORK (Reuters Health) – Translocation of Helicobacter pylori's CagA protein into gastric epithelial cells dysregulates a cytoplasmic tyrosine phosphatase and leads to increased risk of gastric cancer, Japanese investigators report in Science Express for December 13.

Although cagA(+) H. pylori is associated with gastric cancer, the pathogenic role of CagA has yet to be described, Dr. Masanori Hatakeyama, of Hokkaido University in Sapporo, and colleagues note. In a new study, they transfected human gastric epithelial cells with different forms of CagA.

CagA was found to undergo tyrosine phosphorylation upon transfection, and transfected gastric epithelial cells assume the "hummingbird phenotype," in which they elongate and spread, the researchers report. However, phosphorylation-resistant CagA failed to induce any morphological changes.

Next, the researchers observed that the cytoplasmic tyrosine phosphatase SHP-2 and CagA co-immunoprecipitate from transfected cell lysates only when CagA is susceptible to phosphorylation. Furthermore, the phosphatase activity of SHP-2 becomes stimulated when it complexes with CagA. This complex appears to be essential for inducing the hummingbird phenotype.

Dr. Hatakeyama's team theorized that SHP-2 induced the morphological changes because CagA tethers it to the cell membrane. To prove their point, they added a membrane-localization signal to SHP-2, which did indeed provoke the same morphological changes induced by CagA.

"The number and sequence polymorphism of the CagA phosphorylation sites, which collectively determine binding affinity of CagA to SHP-2, may be important variables in determining the clinical outcome of infection by different cagA(+) H. pylori strains," the investigators conclude.

http://www.sciencexpress.org.

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