Abstract
Helicobacter pylori (H. pylori) is a causative agent of gastric diseases ranging from chronic atrophic gastritis to gastric adenocarcinoma. However, little is known about the molecular mechanisms by which H. pylori elicits pathogenic activity. Many strains of H. pylori produce an immunodominant protein called CagA. Recent studies have shown that the cagA-positive H. pylori strains are associated with higher grades of gastric inflammation, and they are thus considered to be more virulent than the cagA-negative strains. Furthermore, epidemiological studies reveal a positive relationship between cagA-positive H. pylori and gastric carcinoma.
CagA is delivered from H. pylori into bacteria-attached gastric epithelial cell via the type IV injection system. The injected CagA localizes the plasma membrane, undergoes tyrosine phosphorylation, and specifically interacts with SHP-2 tyrosine phosphatase in a phosphorylation-dependent manner. Upon complex formation, CagA stimulates SHP-2 phosphatase activity and thereby induces morphological transformation of the cell. Deregulation of SHP-2 by CagA may play an important role in the pathogenesis of cagA-positive H. pylori infection. Tyrosine phosphorylation site of CagA is characterized by the EPIYA motif. There is sequence diversity between Western and East Asian CagA species in their EPIYA-containing regions. Thus, East Asian CagA exhibits stronger SHP-2 binding and greater morphology-transforming activities than Western CagA does. Endemic circulation of H. pylori carrying more virulent CagA in East Asian countries may increase the risk of gastric carcinoma in these geographic areas. [Jpn J Physiol 54 Suppl:S57 (2004)]
