Malignant Helicobacter pylori-Associated Diseases: Gastric Cancer and MALT Lymphoma

Abstract

Helicobacter pylori is the first bacterium formally recognized to play a causative role in human malignancies, gastric cancer and gastric mucosa-associated lymphoid tissue (MALT) lymphoma. Evidence accumulates that H. pylori cagA-positive strains play a crucial role in the neoplastic transformation of mammalian cells. The cagA-encoded CagA protein is delivered into the host cells via bacterial type IV secretion, where it interacts with and thereby aberrantly activates pro-oncogenic phosphatase SHP2. The CagA-SHP2 interaction requires tyrosine phosphorylation of CagA at the Glu-Pro-Ile-Tyr-Ala (EPIYA) motif. The incidences of gastric cancer in East Asian countries such as Japan, China, and Korea are among the highest worldwide. A vast majority of H. pylori circulating in East Asia produce a CagA variant termed East Asian CagA, which possesses the SHP2-binding EPIYA motif (EPIYA-D) that is substantially diverged in sequence from the SHP2-binding EPIYA motif (EPIYA-C) of CagA isolated in the rest of the world (Western CagA). Tyrosine-phosphorylated EPIYA-D interacts with SHP2 approximately two orders of magnitude stronger than tyrosine-phosphorylated EPIYA-C does. The strong SHP2 binding of East Asian CagA is achieved by a cryptic interaction between the phenylalanine residue located at the +5 position from the phospho-tyrosine in EPIYA-D and a small hollow on the N-SH2 phosphopeptide-binding floor, the latter of which cannot be created by the corresponding aspartic acid in EPIYA-C. Thus, a variation in a single amino-acid residue determines the magnitude for the pathogenic/oncogenic action of CagA, which may influence the worldwide landscape in the incidence of H. pylori-associated malignancies, especially gastric cancer.

Keywords: EPIYA motif; Geographic polymorphism; H. pylori CagA; SHP2; Tyrosine phosphorylation.